Massive Science - Mind Control

A butterfly's wings are the perfect mold to grow neurons on

Reinack Hansen — Fri, 26 Nov 2021 10:56:00 EST

Around 15% of American adults report some trouble hearing. That is about 37.5 million people who may need hearing aids for the majority of their lives. A common cause of hearing loss stems from special cells called spinal ganglion neurons (SGN) that transmit signals from hair cells in the ear to the brain. In these cases, regenerating SGN in the inner ear is our best bet to restore hearing. However, controlling how and where nerve cells grow is notoriously difficult. Fortunately, our dependence on hearing aids may soon wind down thanks to the beautiful blue morpho butterfly.

When nerve cells grow on a surface, they respond to physical features such as bumps and grooves. They also communicate with neighboring nerve cells through electrical signals. So, a good growth surface for nerve cells must provide topological cues and be electrically conductive.

The blue morpho butterfly wing has an intricate structure consisting of parallel ridges. Turns out these ridges are perfect templates for cell growth. Engineering an equivalent surface with ridges that is flexible yet light is impossible with today's technology. Rendering a butterfly wing biocompatible on the other hand, is possible. This is what inspired scientists to consider growing cells directly on butterfly wings. In 2019, cardiac tissue assembled on blue morpho – carbon nanotube composites was shown to recover its beating ability. In that case, the elastic composite wing mimicked the cyclic contractions of cardiac cells and shifted colors. By simply observing color changes, they could assess if the cells were behaving as expected.

For nerve cells, which are long, could the parallel ridges on the wing also align neurons end-to-end and make them grow in one direction? This is what Renjie Chai and team at Nanjing University sought to find out, as directionally controlled regeneration of auditory nerve cells is critical to restore hearing. Through a collaborative effort involving university researchers and surgeons, they transferred a thin layer of super aligned carbon nanotubes onto the wing of a blue morpho butterfly to make it conductive. Not only was the conducting composite wing excellent at orienting nerve cells as they grew, it facilitated maturation of neuronal junctions, which is the site where nerve cells transmit electrical signals.

A close-up view of the veins and details of a blue morpho butterfly's wings

Tambako the Jaguar via Flickr

Interestingly, nerve cells grow on both plain butterfly wing and aligned carbon nanotubes. However, only when the two are combined do the cells grow in a specific direction and the neuronal junctions mature. Super aligned carbon nanotubes are special in that they are simply individual nanotubes connected end-to-end. This makes a sheet of this material extremely conductive along one direction – the direction in which the nanotubes are aligned. When these aligned nanotubes are transferred onto butterfly wings, the composite retains the parallel ridges of the wing below while acquiring high conductivity along the ridges thanks to the nanotubes. Further, being extremely thin and lightweight, they hardly add any heft to the wing structure.

Nerve cells have what's called a "growth cone," which is a protein supported structure that explores the environment, determines the direction of growth, and guides the nerve fiber to extend in that direction. Turns out that in the case of nerve cells grown on the composite wing, growth cones aligned along the grooves. Considering the fact that nerve cells grew on butterfly wings as is, this goes to show that these grooves are features that nerve cells readily sense and respond to as they grow. Even with aligned carbon nanotubes, the composite surface retained the ridged butterfly wing structure. Nerve cells could sense the grooves on the composite wing surface and orient within them, just like they would on the unmodified butterfly wing.

More importantly, the growth cone filopodia, which are antennas for nerve cells to probe the environment, was much longer for nerve cells that grew on the composite wing. This is important as longer filopodia is a sign of improved communication between nerve cells. Moreover, the density of neuronal junctions, also called synapses, was much higher. The orientation within ridges, long filopodia, and high density of synapses clearly show that nerve cells can be controllably cultured on conductive butterfly wings. As promising as these results are, the SGN used in this study was sourced from mice. So any hearing restorative treatment for humans based on this approach is still years away.

From a materials perspective, the structure of the blue morpho butterfly wing is decades ahead of any microfabrication process available today. As such, this study is a classic example of how borrowing ideas from seemingly unlikely sources in nature can yield incredible results. So the next time you see a butterfly, remember those pretty wings could be our gateway to perfect hearing.

Reinack Hansen studies

Materials Science

Caffeine keeps your body fat warm, on top of lighting up your brain

Pamela Hirschberg — Tue, 23 Nov 2021 10:26:16 EST

For many people, drinking a cup of coffee in the morning is a sacred ritual. It tastes great, and it helps the morning fog to dissipate. Since it's such a big part of our daily lives, it's hard to think of caffeine as a psychoactive drug. We know plenty about the alerting qualities of caffeine on the brain, but less about caffeine's other benefits. According to a study published earlier this year by a group from La Trobe University in Australia, lead-authored by Lachlan van Schaik, caffeine increases activity in brain regions associated with brown fat thermogenesis, and increases the temperature of brown fat.

You may be asking, "what is brown fat?" Well, it's is an important part of mammalian physiology. It exists in areas called depots near vital organs and produces heat to defend against cold temperatures. Heat production in brown fat is called "non-shivering thermogenesis" because it is different from shivering, which produces heat using the movement of your muscles.

Non-shivering thermogenesis requires a special protein found in brown fat cells. This protein adjusts the normal energy-producing chain in the mitochondria of the brown fat cells. This change causes them to produce heat instead of energy for other cellular processes. Because brown fat burns fuel to make heat independently from exercise, this tissue is a hot topic among endocrinologists as a potential therapeutic avenue to treat type 2 diabetes and other diseases associated with obesity.

Although there have been studies in the past that measured the effects of caffeine on brown fat, this one did something a little different. The researchers wanted to be completely sure that they could attribute the effects of caffeine on brown fat to its actions on the brain. Other studies administered caffeine throughout the body, either by injection or ingestion. These researchers cut out the middleman and injected the caffeine straight into live male mouse brains.

They facilitated the injection of caffeine into the brain by surgically placing a tiny metal tube that fed into the ventricles of the brain. The caffeine could then be fed directly through this tube into the ventricles. The ventricles are where the fluid that bathes the brain moves freely, so the caffeine could potentially act on any area of the brain.

The mice used in this study were given doses of caffeine proportionate to those consumed by humans in one cup of coffee. After they injected the caffeine into the mice, the researchers measured activity of brain areas associated with brown fat thermogenesis. They did this by staining brain tissue for the presence of a specific marker for neuronal activity, then looking at it under a microscope.

The brain staining experiment revealed that several regions of the brain were activated in response to caffeine injection, including regions of a brain area called the hypothalamus. Some of these regions of the hypothalamus were previously found to play a role in the brain's control of brown fat thermogenesis.

After just 10 minutes, they found that the brown fat got warmer in response to the caffeine

The researchers performed other experiments to observe the brown fat response to caffeine as well. They chose the most direct measurement of brown fat heat production, which was to simply measure the temperature of the tissue. They surgically placed a tiny thermometer in the mice beneath their brown fat deposits to monitor its temperature of their tissue in real time. After just 10 minutes, they found that the brown fat got warmer in response to the caffeine. This temperature increase was independent of the overall body temperature of the mice, which is important in order to distinguish caffeine's effect on the temperature of the whole body versus just the heat production in the brown fat.

Although these results seem to indicate that caffeine ingestion helps increase heat production in brown fat, it doesn't mean you should immediately quit your workout routine and celebrate with a piping hot cup of joe. One main reason is because this study completely ignored female mice. This often happens because researchers do not want to deal with the added variable of hormonal fluctuations associated with their estrus cycles. Understanding the link between caffeine and thermogenesis in female mice will be an important follow-up to know how caffeine could potentially affect the brown fat of female mice, particularly because brown fat thermogenesis is modulated by estrogens.

Thus, the results of this study are potentially translational and valuable to healthy males of a normal weight, but the study of brown fat is very often impactful because of its therapeutic potential for diabetic or overweight men and women. Future research should focus on the effect of brain caffeine on brown fat of male and female mice, including diabetic and overweight mouse models.

Despite the caveats in these results, they did reveal that caffeine turns on brain regions that are responsible for brown fat thermogenesis, and that it may help some people burn fat. So until the next set of results come in, we can all patiently sip our coffee or tea, awaiting the heat.

Pamela Hirschberg studies
Cellular Neuroscience
at
Rutgers University
.

A new drug reduces risk of psychosis relapse in patients with dementia

Soren Emerson — Tue, 16 Nov 2021 13:09:33 EST

Dementia is a constellation of progressive cognitive problems, such as memory loss and disorientation, which occurs in Alzheimer’s disease, Parkinson’s disease, and other diseases that reduce brain function.

But dementia affects more than cognition.

Hallucinations occur in up to 50% of the 50 million cases of dementia worldwide, and delusions occur in up to 75% of cases, together collectively referred to as "dementia-related psychosis." Although not as well known as the hallmark cognitive decline, dementia-related psychosis takes a heavy toll on people who experience psychosis symptoms and those who care for them.

There are no approved medications for dementia-related psychosis. Off-label use of antipsychotic medications, developed to treat the psychosis symptoms associated with schizophrenia, is common in clinical practice. But, the use of traditional antipsychotics for dementia-related psychosis is problematic because these drugs are often ineffective and come with a litany of dangerous side-effects, including excessive sedation, cardiovascular problems, and increased cognitive decline. In fact, the FDA issued a black-box warning against treating dementia-related psychosis with some traditional antipsychotic medications due to safety concerns. With limited treatment options for dementia-related psychosis and the number of cases of dementia increasing by 10 million per year, developing safe and effective medications for dementia-related psychosis is a major clinical need.

Now, as the result of work conducted by researchers at the University of Exeter and Acadia Pharmaceuticals, scientists may have identified a drug that can prevent dementia-related psychosis for a long period of time with few side-effects. The drug, called pimavanserin, affects the brain differently than the antipsychotics developed for schizophrenia by specifically and strongly blocking a type of serotonin receptor in the brain called 5-HT2A.

The likely explanation for why traditional antipsychotic medications don't work for dementia-related psychosis is that they were never developed to treat episodes of psychosis in elderly people with dementia; they were developed for young people with schizophrenia. Dementia and schizophrenia are different diseases with different neurological causes, so there is no guarantee that their symptoms will respond to the same medications. In addition, levels of neurotransmitters in the brain change as humans age, which could influence the effects of psychoactive drugs.

In preclinical studies, pimavanserin reduced psychotic behavior in rodents and clinical testing sponsored by Acadia Pharmaceuticals showed that pimavanserin improved psychosis symptoms in people with Parkinson's disease and Alzheimer's disease. In 2016, pimvanserin became the first drug to receive FDA approval as a treatment for Parkinson's-related psychosis and was taken to market by Acadia Pharmaceuticals under the brand name NUPLAZID.

With positive clinical data for psychosis symptoms in Alzheimer's disease and FDA approval for psychosis symptom's in Parkinson's disease, Acadia Pharmaceuticals initiated a clinical trial of pimavanserin for additional subtypes of dementia-related psychosis in 2017. A total of 392 people with Alzheimer's disease, Parkinson's disease, Lewy body, frontotemporal, or vascular dementia participated in the study and the results were published in the New England Journal of Medicine in July of 2021.

For the first 12-weeks of the study, all the participants received pimavanserin open-label. After week 12, participants who met a certain threshold of symptomatic improvement were randomly assigned to receive either pimavanserin or a placebo for 26 weeks to determine if the drug could prevent relapse of psychosis symptoms. The drug was found to be so effective at preventing relapse of psychosis symptoms, however, that the trial was stopped before its intended endpoint at 26 weeks because it would have been unethical to continue giving the control group the placebo. When the trial was stopped, relapse occurred in 28.3% of the placebo group compared to just 12.6% in the pimavanserin group, with minimal side-effects.

The results of the study are encouraging, but it had several limitations due to the participants it included. One of the more glaring issues is that over 98% of study participants included in the trial after week 12 were white. This, despite “white” individuals being at a lower risk of dementia compared to “African American” and “Hispanic” individuals according to the Centers for Disease Control and Prevention. In addition, 15% of the participants had dementia-related psychosis due to Parkinson’s disease, a condition for which pimavanserin has already been approved for as a treatment. Therefore, as the researchers admit, the data generated by these participants “may have skewed the results in favor of pimavanserin.”

But the study's most significant limitation, at least as far as FDA approval is concerned, is that the trial had insufficient statistical power to detect whether pimavanserin improved psychosis symptoms in individual subtypes of dementia. In April of 2021, the FDA notified Acadia Pharmaceuticals that after reviewing the existing clinical trial data the agency would not approve pimavanserin as a treatment for dementia-related psychosis, citing an insufficient number of participants with less-common dementia subtypes and a lack of statistical significance in some subgroups of dementia.

For the team at Acadia Pharmaceuticals, the FDA's decision came as a surprise. Generating and analyzing clinical data from study populations that include a mix of dementias without necessarily separating them has become an accepted practice when treating the psychosis symptoms associated with dementia.

Although next steps are not certain, Acadia CEO Stephen Davis outlined three possible outcomes. First, as is the company's position, they could proceed by performing additional statistical analyses of the existing data without additional clinical trials and seek FDA approval for pimavanserin as a broad-spectrum medication for multiple dementia subtypes. Second, rather than seeking broad-spectrum approval, the company could seek approval for pimavanserin as a medication for a smaller number of dementia subtypes such as Alzheimer's dementia or dementia with Lewy bodies, the subtypes for which the company believes they have the strongest data. Under this scenario, the company would not conduct additional clinical trials. Third, as is the FDA's position, the company could conduct additional clinical trials of pimavanesin in each dementia subtype.

The company has scheduled a meeting with the FDA to discuss the path forward for pimavanserin's development and expects to report on the outcome of this meeting before year end.

Despite the set backs regarding FDA approval, the trial results are an important step forward for clinical neuroscience and dementia research. Although the clinical trial results may be insufficient for FDA approval at present, they suggest that a badly needed safe and effective medication for dementia-related psychosis could come in the next few years.

Soren Emerson studies
Neuroscience
at
Vanderbilt University
.

Cuttlefish can learn with the brains they keep in their arms

Julia A Licholai — Fri, 12 Nov 2021 00:02:16 EST

Here's a puzzle for you. Using the building blocks of a nervous system, design the perfect brain.

You have two types of cells to work with: neurons, and glia. Where would you put this agglomeration inside a body? For an animal to be considered relatively intelligent, they should have memory. Would your brain be solely focused on retaining and recalling events from the past, or should it also help the creature see and touch… maybe even move? You probably would design a brain unlike any other, but nature might have made one that’s even more bizarre. Cue the cephalopods.

Cephalopods are octopuses, squids, cuttlefish, and nautiluses. These animals are grouped together not only because they all possess many arms but also because they share an evolutionary tree branch with a common ancestor from around 500 million years ago. Their central brains form a ring around their esophagus and their arms are constantly testing the environment, processing the information they gather, thinking for themselves.

Despite their donut brain, some cephalopods are lauded for being the most intelligent invertebrates. Cuttlefish can count up to 5, on par with infant humans and young monkeys. Octopus are creative and use tools, seen awkwardly carrying their home for protection. Hungry cuttlefish will resist mediocre treats for tastier ones delivered later, a sign of intelligence thought to be important for decision making and planning. While researchers have only recently started to systematically characterize the cognitive capabilities of these animals, decade old stories hint at an incredible mind.

In addition to a smart brain, some cephalopods have arms with little "brains" of their own. Invertebrate nervous systems often have dispersed clusters of neurons (called ganglia) in a line or aligned in pairs like a ladder. In cephalopods, some of these ganglia lumped together to form a central brain while some information processing capabilities stayed behind to control the arms. As the central brain is thought to direct generalized arm movements, nuanced movements are driven by the arm-specific nerve-bundles. Despite the arms sometimes described to have their own “brains,” these structures are too simple to produce what we might consider a consciousness. Regardless, the majority of the animals’ neurons reside in the arms and these arms can act on their own.

Since these arms have such incredible information processing capacities, a recent study asked whether individual cuttlefish arms can learn. The cuttlefish were presented with prey (a prawn) in a clear tube. The cuttlefishes initially lunged toward the prawn guided by their arms, but they would slowly decrease this behavior as they learned that the prawn is inaccessible.

The researchers then looked for molecular traces of memory formation by counting the number of cells in the arm containing a protein in a certain configuration. This protein, called CREB, can be found immediately after cells are active and is a popular protein to track in learning studies.

By looking at neurons in the arms, they found more CREB-expressing cells in cuttlefish that learned to stop attacking a tubed prawn than in cuttlefish who were not trained. These CREB expressing neurons clustered around the suckers which are involved in obtaining touch and taste information. Seeing CREB by the sensory apparatuses, the researchers wondered if all of the learning is occurring in the arms without input from the brain.

This is an interesting investigation raising a fascinating question regarding how much these limbs are capable of, but there are major caveats to this study. For example, does CREB really indicate that a memory formed here or does it just indicate the arm was recently touching something? And one is left to wonder how much influence the central brain has in this kind of learning or whether the arms truly learn on their own. While the implications are exciting, the findings here are still very preliminary.

Most intelligent animals have nervous systems resembling our own brain and a spinal cord. Meanwhile, some cephalopods have keen intelligence with a donut-shaped brain and a more dispersed nervous system. How did this happen?

Michal B via Unsplash

Cephalopods and humans are distant evolutionary relatives sharing a common ancestor from about 600 million years ago. This makes us more related to insects than cephalopods and they are in turn more related to oysters and clams. Since the evolutionary split occurred in a common ancestor that had a rudimentary nervous system, we all have similar neurons. Humans and cephalopods use the same signals between neurons (neurotransmitters) and our neurons function similarly. The most notable differences between our nervous systems and theirs seem to be structural.

The striking differences in brain structure and the large evolutionary gap indicates intelligent brains evolving twice: once in vertebrates and separately in cephalopods. These brains are also thought to have evolved under different pressures with mammals and birds evolving to accommodate social environments while cephalopods needed to evade predators and creatively eat other sea creatures. With these differences, it’s interesting to note that some types of memory and learning are present in both groups of animals (like episodic memory, semantic memory, spatial memory, and social memory). Additionally, these clever animals all have specialized brain regions dedicated to processing information, rather than relaying sensory or motor signals. And it’s this structure that forms and retains long-term memories.

With such different evolutionary pressures, a brain that defies age related cognitive decline is also possible. Another recent study assessed episodic-like memory in cuttlefish and saw that old animals performed just as well as young ones (episodic memory relates to remembering specific past events). The researchers trained cuttlefish to recognize that a black and white stiff flag signals food. Two identical flags would be presented at once and then replaced with a mediocre or tasty treat. After the initial reveal, the animals had to remember where the flags were and which location corresponded to which treat for later snack retrievals. The location of these flags changed daily, so the cuttlefish also had to learn to remember which new location was associated with their preferred food. The food delivery also differed by food type, so they had to get the timing right too.

When cuttlefish were trained to remember when and what they were fed, the older cuttlefish did just as well as the young cuttlefish even though they showed other signs of aging. Most of the older cuttlefish even died naturally just days after the experiment (RIP). Episodic and episodic-like memory decline is seen in older humans, non-human primates, and rodents, so this finding in cuttlefish is quite impressive. In the other animals, memory decline is attributed to age related changes in a part of the brain called the hippocampus. Cuttlefish, however, don’t have a hippocampus so learning and memory are said to instead involve their vertical lobe.

Some researchers have wondered whether cognitive deterioration with time is only natural and unavoidable, but perhaps this isn’t the case. Maybe, just maybe cuttlefish hold the key to having a sharp mind indefinitely.

Julia A Licholai studies
Neurobiology
at
Brown University
.

How a tiny pet store fish became the center of neuroscience research

Sahana Sitaraman — Mon, 01 Nov 2021 23:46:10 EST

I spent the better half of my twenties peering at tiny little fish under the microscope, and it was one of the most exciting time of my life.

Every morning, I would rush to the lab to see if my fish had laid eggs. I watched the brain cells of these completely transparent organisms multiply under the lens. I still remember the first time I saw a live neuron grow in front of my eyes, in the brain of a young fish larva. This striped tropical fish could fit in the palm of my hands, and yet is one of the most important organisms in biology, allowing researchers to answer fundamental questions in neuroscience, developmental, cancer, disease and regenerative biology.

The beginnings of zebrafish research can be traced back to early 1930s when Charles Creaser at Wayne State University in Detroit began using zebrafish (Danio rerio) eggs to show students the development of a live embryo and the movement of blood inside its arteries. Creaser was able to do this because zebrafish females release eggs from their body which are fertilized by the sperm released from the male. The freshly formed embryo is accessible to the observer from the moment it is fertilized. The fact that zebrafish embryos and larvae are transparent means studying the internal parts of the animal is a breeze. Creaser established methods for rearing, feeding and breeding zebrafish in the lab, but widespread use of the animal did not take off for another three decades.

Like Mendelian genetics, zebrafish had to be rediscovered. In the late 1930s, George Streisinger and his family moved across the Atlantic in an attempt to escape the anti-Semitic living conditions of 20th century Hungary. Streisinger's passion for science got him a job under Myron Gordon, one of the fish researchers at the New York Zoological Society.

A school of adult zebrafish

Streisinger dedicated almost two decades of his career to studying the genetic code of viruses that infect bacteria, called bacteriophages. He used these viruses to decipher the way genetic material is coded in living beings. Despite having made such fundamental contributions to science using phages, Streisinger wished to switch to a different system. He aspired to understand the developmental of the nervous system in vertebrates, especially how neurons find their partners and make connections. At this time, in early 20th century, animals such as medaka fish and goldfish were the go-to choices for researchers interested in understanding development. But Streisinger went another way. “The story goes that he walked into a pet store in Oregon, and asked the owner, ‘what’s a good simple vertebrate that I could study?’ and the owner pointed at zebrafish. At least that’s what fishlore says," recounts Karuna Sampath, a professor studying control of embryo development at Warwick Medical School.

George Streisinger

Having already worked with zebrafish at the Zoological Society in New York, he was aware of the immense potential the fish held for biology experiments. When he joined the University of Oregon in 1960, Streisinger jumped headfirst into generating mutant fish strains. His initial lab was a converted army barrack, inside which he and his colleague Charlene Walker reared zebrafish in tanks. Zebrafish are naturally found in tropical climates of South Asia and can only survive in temperatures from 24°C-38°C, which meant that Streisinger and Walker had to get creative in maintaining the temperature of the hut at a sweet spot. In summer, water was poured on the roof to keep things cool, while in winter, electric heaters kept the hut toasty. Things soon started to pick up. In the two decades that Streisinger dedicated to zebrafish research before his death, he not only worked on deciphering neuronal development in the fish brain, but also set up techniques for linking mutations in the fish genome to changes in the fish’s appearance.

Streisinger’s goal of bringing zebrafish up to par with model systems of the likes of Drosophila and rodents was carried to fruition by the army of colleagues he had inspired. Zebrafish's ease of maintenance and breeding, year round supply of embryos, external fertilization giving access to embyros from hour zero, and transparent young stages of development makes observation easy. But to really put the animal over the top, it was important to show that it was amenable to mutations, a key tool for biologists.

That’s exactly what Christiane Nusslein-Volhard at the Max Planck Institute in Tubingen and Wolfgang Driver at Massachusetts General Hospital did. They spearheaded the "Big Screen," spread across multiple labs over the two continents, to produce about 4000 fish strains, each of which had a different aspect of early development disrupted. The result of this massive project was published as a collection of 37 papers in a single issue of the journal Development, finally announcing to the academic world that zebrafish was here to stay. On the heels of this accomplishment came the sequencing data of the entire zebrafish genome in 2001, which gave the community the ability to pick out the genes and match them to the changes observed in the big screen fish mutants.

Zebrafish larva bioengineered two have blood vessels glow in red and blood vessel cell nuclei in green

NIH via Flickr

What began as an animal picked up from the local aquarium is now an established vertebrate model system used across thousands of labs to answer questions about the formation of the nervous system, evolution of behaviors, development and treatment of cancers, regeneration of tissues and much more. One can actually look at the activity patterns of every cell in the entire zebrafish brain while the fish swims around. You can screen thousands of candidate drugs by just dumping them into the water with the fish and watching what happens.

“It's a good balance of being simple enough to get a holistic understanding of mechanisms underlying behaviour, while at the same time sharing a lot of conserved similarities in terms of anatomy, genes, molecules, that you can link to mammals and to humans”, says Caroline Wee, a neurobiologist lab at the Institute of Molecular and Cell Biology, A*STAR Singapore.

Julien Vermot, who runs a lab at the Department of Bioengineering, Imperial College London uses these fish for something unique. To study the effects of mechanical forces on the development of the heart, students in his lab stop the zebrafish heart from beating for as long as a couple of days. It’s one of very few animals that can survive this. Despite such unique advantages, the model isn’t everyone’s first choice and certainly not as popular as mice or rats. As Vermot puts it, “It's a fish. And we are not fish. So, you need to convince people that what you do is meaningful for the entire community.” Wee adds, “You can argue they're similar, but it's hard to mentally draw the link between fish and humans.”

While the connection between zebrafish research and humans may not be obvious, the benefits for them are. Rita Fior, group leader at the Champalimaud Centre for the Unknown has shown how these animals can be used to test chemotherapy treatments for cancers growing in actual human patients. Fish injected with cancer cells from patients and given the same treatment as the patient show 84% similarity in the response to the drugs. This sets up precedence for potentially screening drug combinations in fish to look at their efficiency in reducing growth of cancerous cells before administering them to patients.

Sahana Sitaraman studies
Neuroscience and Behavior
at
National Centre for Biological Sciences, India
.

Some people just don't age, at least not like most

Kelly Cotton — Fri, 29 Oct 2021 10:04:00 EST

When you look at a face, a different area of your brain is active than when you look at, say, a house. Neuroscientists can measure this difference in activity.

As you age, your brain shows less of this neural differentiation, and in most older adults over the age of 60, the patterns of brain activity when looking at one type of object look similar to the patterns when looking at another type. However, one group of older individuals has patterns of brain activity that look more like the activity seen in the brains of younger adults. These "Super Agers" also have better memory overall and could help us better understand the potential cognitive decline seen in typical aging.

A recent study by authors Yuta Katsumi and colleagues at Massachusetts General Hospital and Harvard University examined the brain activity of a group of younger adults, older adults, and Super Agers — older adults who performed at least well as the average young adult on a memory recall test — while they learned and remembered information. The researchers focused specifically on two brain regions, the fusiform gyrus and parahippocampal gyrus, areas previously associated with face processing and scene processing, respectively.

Previous research has found structural differences in the brains of Super Agers, including increased brain volume in several brain regions compared to age-matched controls, as well as increased volume specifically in a brain region involved in many cognitive functions, compared to both older and middle-aged adults. Super Agers also show continued high behavioral performance on tests of memory, attention, language, and executive function for at least 18 months, suggesting a lack of the typical age-related cognitive decline. The present study expands this previous work to include functional brain activity during both the learning and retrieval phases of a recognition memory task. By studying Super Agers brains while they are actually creating and recalling a memory, the researchers believe they have identified a potential mechanism that explains these individuals superior memory performance.

The 91 participants included 41 younger adults, 23 typical, non-Super Ager older adults, and 17 Super Agers who underwent a functional magnetic resonance imaging (fMRI) scan while completing an associative memory task. During the learning phase of the task, the participants were shown a series of 80 images (either a face or an outdoor scene) and word pairs, such as an image of a man's face with the word "FRIENDLY". They were asked to judge whether the word and image were semantically related to guarantee the participants were sufficiently processing the image-word pair. After 10 minutes, the participants were again shown 80 image-word pairs, some of which they have seen previously and some of which were rearranged into new image-word pairs, and asked to indicate if they had seen this pair before.

A diagram of fMRI brain scans showing BOLD activation

Via Wikimedia

The researchers then examined the participants' brain activity – the changes in blood oxygen-level dependent or BOLD activation – that occurred during the different phases of the task and how this activity related to their performance on the memory task. They found that the Super Agers performed better than the typical older adults and just as well as the young adults on the recognition memory test. Importantly, they found that the activity in the brains of the Super Agers was much different from the typical older adults. The Super Agers showed greater neural differentiation compared to typical older adults, meaning their brain activity varied more depending on the image they saw, much like the younger adults. The researchers also found that more neural differentiation during the encoding phase of the memory test led to the same brain activity patterns reappearing during the retrieval phase, referred to as neural reinstatement, and subsequently better memory performance.

Despite its focus on the atypical activity in both brain and behavioral function of the Super Agers, this study and future research with these individuals may also reveal much about typical aging and how to prevent cognitive decline and memory loss. The authors suggest that these results may depend on individual neuroplasticity, which could be a target for future interventions, though their research does not directly address this.

For example, one study trained participants to better distinguish between images of fish and found that people were able to improve their sensitivity to certain important features after three training sessions. However, the findings on the long-term efficacy of cognitive training are often mixed, with a recent large-scale study finding no generalized benefits to cognitive performance. Perhaps future research will be more successful with a more specialized focus in both training and outcome measures, like the present study with its focus on differentiation during encoding and retrieval in memory tasks.

While the results of this study provide several insights into why Super Agers may outperform their more typical peers, continuing to understand the longitudinal nature of these findings is imperative. The findings leave open many questions, and tracking these people over time may help answer whether Super Agers have better baseline cognitive functioning than most people or if there is some sort of lifestyle or environmental factor that allows them to maintain their brain health.

Kelly Cotton studies
Cognitive Psychology
at
City University of New York
.

Students can learn with their mouths as well as with their eyes and hands

Alyssa Paparella — Tue, 12 Oct 2021 22:35:11 EST

The first time that I met a blind scientist, I was in an NSF Research Experience for Undergraduates at the University of Delaware, a program geared toward disabled students interested in pursuing STEM research. Until that point, it had never occurred to me how science education excludes blind students. My daily experience in classrooms consisted of professors drawing molecules on the board or writing out an equation with the assumption that students in the class could see what was being written, very rarely even stating what they were writing. But what about the blind and low-vision students in the classroom?

According to the National Science Foundation's 2021 report on Women, Minorities, and Persons with Disabilities in STEM, as of 2019, 9.1 percent of those graduating with a doctoral degree reported having a disability, a figure that includes people who are blind or low-vision. Inclusive teaching methods are needed to increase accessibility in STEM.

A recent paper from Baylor University, led by Katelyn Baumer and Bryan Shaw and published in Science Advances, was inspired by exactly this problem. They designed a study to assess whether people could learn to recognize 3-D models, like those often used to teach science, with their mouths instead of with their eyes. “I probably wouldn’t be working in this area if it was not for my own child who is visually and hearing impaired and autistic,” Shaw stated in an email interview. Having his son be diagnosed with retinoblastoma at such a young age changed Shaw’s view of science and encouraged him to increase accessibility for blind or low-vision scientists within his field.

“Oral somatosensory perception is hardwired into us..."

Shaw is certainly not the first person to take advantage of the ability of our mouths and lips to spatially discriminate between items. For example, a Hong Kong student named Tsang Tsz-Kwan has taught herself to read Braille with her lips. Although not a traditional method to learn Braille, this case suggests that the mouth is able to recognize and distinguish patterns.

Shaw's research builds on the fact that brain imaging has revealed that the feeling of touch, called somatosensory input, from our tongues, lips, and teeth converge onto the primary somatosensory cortex to produce an image generated entirely by signals from our mouths. The primary somatosensory cortex is a region in the brain that receives input to produce images.

A 2021 paper in Nature found that when primates showed the same brain circuit activation when grasping objects with their hands and when moving an object with their tongue. This indicates that there may be underlying similarities of physical manipulations of the hand and the mouth, but much remains unknown. Signals from manipulation with either the hands or the mouth are sent to the cerebral cortex, but as Shaw points out “the fine structure of how it is all sorted and processed remains unknown.”

A student studies a protein model with their mouth

Courtesy of Bryan Shaw

Baumer, Shaw, and their colleagues found that there was comparable manual touch recognition with hands to mouth manipulation recognition when using these models. Both college students and grade-school students (4th and 5th grades) participated in the study, with 365 college students and 31 elementary school students represented. The participants were blindfolded and then split into two groups, one assigned to manipulate objects by hand, and one to manipulate the objects with only their mouths. Each participant was given a single model protein to study. They then were asked to identify whether each of a set of eight other protein models matched the original they were given. Of those eight, one was a match.

Shaw expected the results to be similar across the two age groups, as “Oral somatosensory perception is hardwired into us, the tongue develops very early and we likely start doing oral somatosensory perception in utero." The research team saw that both age groups of students were able to successfully distinguish between models, and the accuracy of recalling the structures was higher in people who only assessed the models through oral manipulation in about 41 percent of participants.

Part of the design process was to have the models be portable, convenient and affordable, since they would eventually have to be produced in mass quantities. As noted by Shaw, often biochemistry textbooks have over a thousand illustrations, which further emphasizes the need of the models to be small and cheap. The first person Shaw gave the models to was Kate Fraser, a science teacher at the Perkins School for the Blind in Massachusetts, which also was Helen Keller’s alma mater. He chose the school because they offered significant support by personally traveling to his family’s apartment and offering interventional help after Shaw’s son had his eye removed.

Although this study did not involve blind or low-vision students, it sets the basis for expanding into them next. These models have shown comparable results to manual manipulation and may offer a way to have science become more accessible, which is the ultimate goal. By increasing the number of disabled scientists, STEM will benefit from the diverse perspectives which will ultimately lead to better science.

Alyssa Paparella studies
Biomedical Sciences
at
Baylor College of Medicine
.

A new molecule and an under-appreciated neuron have been implicated in Parkinson's disease

Julia A Licholai — Sun, 29 Aug 2021 21:07:39 EST

In 1817, James Parkinson described the symptoms of his namesake disease in Essays on the Shaking Palsy. In his patients he saw movement abnormalities, including altered postures and tremors.

As the medical field expanded their understanding of Parkinson’s disease over the next 200 years, so have the available treatments, though there is still no cure despite it being the second most common neurodegenerative disorder. Perhaps invigorated by the stalls in new therapies available for brain-related diseases, researchers have started adopting new perspectives to study the brain. For Parkinson’s disease, this includes looking at more than one type of cell.

Decades after Parkinson’s symptoms were first vaguely attributed to the brain, physicians started speculating that damage to a particular brain region was the cause of the motor problems. This region of the brain is dark in appearance because of pigmented cells and is aptly named the “black substance” in Latin, or substantia nigra. As these cells die, there are less pigmented cells, making this brain region lighter in color. The pigmented cells normally release dopamine, and the loss of these cells is thought to underlie the many symptoms of Parkinson’s disease.

Cells talk with each other. For example, dopamine is a neurotransmitter famous for its association with happiness, but it's also critically important for movement. Parkinson’s disease is caused by the death of dopamine-releasing cells that project to and communicate with another brain region called the striatum. Dopamine is used as a language to communicate with medium-sized prickly-looking neurons called medium spiny neurons. These projecting neurons also disappear in people with Parkinson’s disease, so popular ideas for tackling Parkinson’s disease have been to restore dopamine availability in the striatum, such as by giving patients precursors of dopamine (L-DOPA).

A diagram of a brain in profile showing the location of the substantia nigra

Via Wikimedia

The striatum is known for its role in movement coordination and most of the neurons here (90-95%) are these medium spiny neurons. Research on movement coordination and motor dysfunctions often focus on the medium spiny neurons, but these neurons are regulated by cholinergic interneurons (ChIs; "cholinergic" refers to their responsiveness to acetylcholine and "interneuron" signifies that the neurons stays within a particular brain region). ChIs are massive cells that only make up 1-2% of the neurons in the striatum, but ChIs send out a web of axons to make hundreds of thousands connections per cell. Some previous studies have linked Chl activity with Parkinson’s disease, though the details have been lacking.

In April, Yuan Cai and his colleagues published a study that explored whether ChIs could be manipulated to restore motor functions in Parkinsonian mice. Medium spiny neurons and ChIs talk to each other, so the group wanted to see if ChIs are altered in Parkinsonian mice. The researchers modeled early-stage Parkinsonism by partially damaging a small part of the mouse brain, somewhat resembling how neurons die in people with Parkinson’s disease. Initially, they found no changes in ChIs.

Then, instead of only passively recording from ChIs, the researchers pivoted to recording the ChIs's responses to dopamine and they saw an abnormality. They mimicked natural dopamine input to the area by stimulating dopamine releasing cells. They saw a longer pause in ChIs activity (less electrical changes and therefore less communication with other cells) in the Parkinsonian mice. Cai and his collaborators realized that the abnormal ChI activity was because these cells are unable to detect glutamate — another neurotransmitter released by dopamine secreting cells.

A bottom-up diagram of a brain of a patient with Parkinson's disease illustrating loss of pigmented cells in the substantia nigra

Via Wikimedia

Additional tests confirmed that rather than glutamate availability, the receptors detecting glutamate was altogether missing. For example, Cai and his colleagues measured ChI responses in animals that had reduced glutamate, but did not see the abnormal ChI pause. This meant that glutamate availability was not the culprit. They also found that glutamate receptor mRNA levels (the amount of available blueprint to make a protein) was lower in the ChIs of their experimental group, hinting at less available glutamate receptors. The researchers then detected lower glutamate triggered signaling within ChIs, meaning cells were making less of a fuss when glutamate was detected. When the number of glutamate receptors was increased, ChI activity was corrected back to normal.

When studying the animal as a whole, manipulating ChIs to produce more glutamate receptors dramatically improved the behavioral outcomes Parkinsonian mice. The experimental mice group that usually developed Parkinsonian motor deficits with asymmetrical forelimb movement (measured by comparing when a mouse uses their left or right paw for reaching up, which they normally do equally with either paw) and poorer balance when trotting on a rotating wheel had movements similar to healthy mice when more glutamate receptors were made.

The preventative efforts reported in this paper are extremely exciting, however this is still an understudied cell in relation to motor abnormalities. The preview of this paper lists several important questions that scientists should answer before escalating the importance of glutamate and dopamine release in movement for clinical applications. Are glutamate and dopamine the only molecules released, or can dopamine be released with other molecules to influence movement?, And, is glutamate detection altered as described in human patients with Parkinson’s? Do the results translate from mice to humans?

Julia A Licholai studies
Neurobiology
at
Brown University
.

Huntington's disease is caused by more than a mutated protein

Marina Olle Hurtado — Sun, 23 May 2021 21:18:00 EST

One of the most critical functions of a cell is to create proteins. For this, the cell need instructions, which are written in the DNA. However, DNA is too precious to put at risk of any damage, and therefore, it never leaves the cell's nucleus. The solution is RNA, a copy of the DNA's instructions that travel from the nucleus to the protein factories.

The process of copying DNA's instructions into RNA can sometimes go wrong, creating instructions that are misleading and end up making a defective or mutated protein. This is the case for Huntington's disease. Huntingtin protein is found in most of the body's tissues, with the highest levels of activity in the brain. Its exact function is unknown but is essential for normal development before birth and it appears to play a fundamental role in neurons. But some mistakes in the instructions responsible for creating the huntingtin protein cause the protein to lengthen like a tape measure, becoming toxic for the nerves in the brain. The defective huntingtin protein forms clumps in brain cells, damaging and eventually killing them.

Researchers investigating Huntington's disease have been focusing most of their attention to study the wrongly copied RNA and its resultant mutated protein. However, this protein alone isn't enough to explain all the effects of the disease.

The mice promptly developed symptoms similar to human Huntington's, showing that these small RNAs were enough... to create disease

The idea that the mutated huntingtin protein has some accomplices has gained interest in recent years. While the origin of the disease has been associated with the abnormal functioning of the mutated protein, a few studies have showed the involvement of other molecular mechanisms.

That is the case of a recent study published in Acta Neuropathologica, in which researchers from the University of Barcelona describe new accomplices known as small RNAs. As their name indicates, small RNAs are shorter forms of RNA which are not used to build proteins, but instead help with other functions, like turning on or off other genes.

To know if those small RNAs could act independently from the mutated huntingtin protein, the researchers isolated them from the brains of deceased people with Huntington's disease who had donated their tissues to science, then injected them into the brains of healthy mice. The mice promptly developed symptoms similar to human Huntington's, showing that these small RNAs were enough, all on their own, to create disease.

The scientists also wanted to know if all of the small RNAs came from wrongly copied huntingtin RNA or if some of them were coming from other sources. To find this out, they specifically blocked small RNAs with the same sequence as the wrongly copied RNA, thus inhibiting their function. The blockage alleviated the symptoms, but only to a limited extent. This indicated that there were some small RNAs, acting independently from both the mutated huntingtin RNA and protein, that contributed to the disease seen in the mice.

Figure showing the healthy huntingtin protein (top) and the mutated version (bottom)

National Institute of General Medical Sciences, National Institutes of Health on Wikimedia Commons

This finding holds great promise for diagnosing the Huntington's before the symptoms appear. Currently, a DNA test can determine if a person has the faulty gene that causes Huntington's disease. This is called predictive testing. When the gene is mutated, it contains an expanded segment, which contains several repetitions of the same DNA sequence.

Doctors interpret the results of the test based on the number of repetitions they see in the DNA that codes for the huntingtin protein. If there are only a small number of repetitions, 26 or fewer, disease can be ruled out. On the other hand, a higher number of repetitions, 40 or above, is always associated with the development of the disease at some point in the future. In the intermediate range, between 27 and 39 repetitions, whether or when, if at all, a person will develop Huntington's disease symptoms cannot be predicted with certainty. It is also possible that healthy people with an intermediate number of repetitions could still pass on Huntington's disease to their children.

How could the newly found small RNA help with giving those patients a clearer answer?

Before a person with Huntington's even manifests any symptoms, within the body cellular gears are slowly turning, accruing damage to neurons, ultimately causing disease years later. The wrongly copied RNAs create mutated proteins, both of which accumulate in the person's neurons, disrupting the normal functions of these cells. Over time, their neurons die, causing uncontrolled movements, loss of thinking ability and emotional problems.

Once researchers identify which small RNAs play an essential role in Huntington's disease, they could measure them to diagnose the disease in advance, while symptoms are still developing.

Besides changing how we could diagnose the disease in the future, this discovery also changes how we could treat it. So far, medications used help keep symptoms under control. Still, there is no cure for Huntington's disease or any treatment to stop it from getting worse over time. Small RNAs could provide a new target for the treatment of Huntington's disease. Although more research is needed, new drugs directed against these small RNAs could inhibit their effects and help treat the condition.

These findings are not only significant to Huntington's disease but also many other neurodegenerative disorders. For example, researchers have also detected changes in small RNAs in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, highlighting the importance of these molecules and the possibility of using them to diagnose the conditions, monitor their progression and create new treatments.

Marina Olle Hurtado studies
Biotechnology
at
MDPI
.

There's a neurological reason you say ‘um' when you think of a word

Adriel John Orena — Wed, 19 May 2021 00:17:24 EST

Eishi Asano's latest work sheds light on those seemingly pesky words that litter our speech: uhs and ums.

As a neurologist at Wayne State University, Asano works on mapping human abilities to brain regions. One such important ability is the ability to use language. Neuroscientists have discovered that, like many little cogs in a wheel, a wide network of brain regions all work together to produce language. Certainly, the ability to communicate with others affects all aspects of life. Thus, protecting these brain regions during brain surgery is of high priority.

Asano has an opportunity few have: to study the brain in action. During a pre-surgical procedure called an electrocorticography (ECoG), an incision is made in a research participant's skull, and electrodes are placed directly on the exposed surface of their brain. He then presents them with photographs of complex scenes and asks them to describe it.

“This one has some, uh, hippos, who are swimming in the, uh, swamp, during the summer,” a research participant in his study might say.

When they ran this study, Asano and his team were originally interested in deciphering which regions of the brain were responsible for describing what was in the picture (hippo), what they were doing (swimming), where (swamp) and when (summer). But, as his team rummaged through transcripts, what transpired between these words – the uhs – caught their attention.

In a task developed by Dr. Eishi Asano and his team, participants are asked to describe the 4 Ws (What, Who, Where, and When) of complex scenes like the one pictured here

Aji Vinister Denistan on Unsplash

Referred to as a “disfluencies” by linguists, uhs and ums are often viewed as disruptions to the flow of speech. They are littered across our speech in all contexts, whether in presentations to a large audience, or in conversations with your closest pal. Estimates vary, but one research group found that such disfluencies pop up every 4.6 seconds, on average. They are equally short and overrepresented in all languages: French speakers say euh, Mandarin speakers say 那个, and ASL signers sometimes wiggle their fingers.

But while uhs and ums may seem like accidental nonsense words, disfluencies can actually provide us a rare window onto what’s going on in the brain as we speak. For example, psycholinguists (scientists who study the psychology of language) argue that disfluencies can actually convey meaning. When researchers scoured through a corpus of transcribed speech, they found that a large proportion of disfluencies arose in specific locations: before difficult-to-pronounce and difficult-to-name words, or before words that haven’t been recently discussed. In short, when we need some time to think of the next word, we make use of uhs and ums.

Asano’s recent work, published in Scientific Reports, shows an example of this. Asano and his team inspected the brain activity of three adolescents that performed the scene-describing task depicted above. While three participants is a smaller sample size than is typical in neuroscience research, the technique used in this study, ECoG, provides more reliable data compared to other neuroscience methods. The fact that electrodes are placed directly on the cerebral cortex makes this technique less susceptible to "noise" in the data, such as from accidental movements by participants.

The three research participants varied in how disfluent they were, with one participant producing seven times more uhs and ums than another. Findings about brain activity, nonetheless, were consistent. “[When the participants] produced the disfluency, extensive areas of the association cortex showed activation," Asano says.

The association cortex is a group of areas on the surface (cortex) of the brain, which has previously been linked with language tasks that require relatively high amounts of linguistic effort. For example, these regions are highly engaged when producing words that have competing meanings. When producing the word “orange,” our brains have to suppress the sense of the word that conveys a fruit if we are thinking about the color.

These findings reiterate the idea that uhs and ums, in and of themselves, are not causing speech to be disfluent

These findings reiterate the idea that uhs and ums, in and of themselves, are not causing speech to be disfluent. Rather, they are behavioral markers that speakers are working hard to find the next word, Asano says. When a speech task is more difficult, the association cortex works harder. And when the association cortex works hard, we sometimes produce disfluencies to fill the space.

Every person's brain is wired slightly differently, so having precise knowledge of the brain regions responsible for speaking, listening, and yes, even for being disfluent, is important for neurosurgeons who have to make important decisions for their patients.

“I remove brain regions that generate seizure activity for epileptic patients,” Asano explains. “But, if you remove the wrong areas, then functionally important areas will be damaged.” Indeed, there is some evidence that when parts of the association cortex sustain damage, patients may experience difficulty organizing their speech.

So, while they moonlight as mere speech errors, uhs and ums can actually give us insight into the brain. A healthy number of disfluencies in our speech let neuroscientists, and other listeners, know that we're experiencing a difficult speech moment — which is a perfectly acceptable sentiment to convey in many contexts. To err is human, after all.

Adriel John Orena studies
Language Acquisition
at
University of British Columbia
.

How COVID-19 has worsened the lives of Alzheimer's and Parkinson's patients

Burcin Ikiz — Tue, 11 May 2021 23:41:40 EST

Alicia Del Blanco — a 68-year-old retired French teacher from Madrid, Spain — had big plans. She was about to become a grandmother for the second time, was going to spend the summer in her house in Huelva, and join a daily therapy program specially designed for people with Alzheimer’s. Like all of us, her plans upended with the pandemic.

On March 14th, 2020, Spain entered a nearly three-month lockdown where residents were not allowed to leave their houses unless for medical emergencies or getting groceries. Then came the closures of Del Blanco’s favorite past times — theaters, restaurants, and musical venues — along with the restrictions on social gatherings and the discontinuation of her Alzheimer's therapy program. Del Blanco struggled to comprehend the reason behind all these changes. While she was able to maintain her daily walks around Madrid’s largest park — El Retiro — after the lockdown ended, her accelerating cognitive decline became disturbingly noticeable to her husband, Armando Guerra.

“One day I asked [Del Blanco] to pour water in a glass,” Guerra said, “and realized that she no longer understood what a glass meant unless I pointed at it.” Her neurologist confirmed Guerra’s observations. Del Blanco’s cognitive decline in the last six months was equivalent to what was supposed to happen in two years. And hers was not the only case.

Researchers from Santa Maria University Hospital in Lleida, Spain, examined 40 patients with mild Alzheimer’s five weeks after the lockdown and compared their evaluations to the ones they did a month before the pandemic. They found that — following the lockdown — the patients showed a worsening of neuropsychiatric symptoms, including increased agitation, apathy, and aberrant motor activity.

Alicia Del Blanco and Armando Guerra take a daily walk in El Retiro park in Madrid, Spain

Courtesy of Armando Guerra

A study published in January from Columbia University showed similar effects on Parkinson’s patients. To assess the impact of COVID-19 and social distancing, the researchers sent out a survey in May 2020 to the mailing lists of the Parkinson’s Foundation and Columbia University Parkinson’s Disease Center of Excellence asking the patients about their physical and social activities and their moods. Of the 1,342 responses they received, half of the patients reported a negative change in their symptoms, along with mood disturbances, such as deepened anxiety and depression.

According to Roy Alcalay — an associate professor of Neurology at Columbia University and the principal investigator of the study — these results were not surprising. “There's no question that the lack of activity, the lack of services, and the emotional stress of not seeing the family take a toll,” he says, “and the toll for people with Parkinson's is the progression of the motor symptoms.”

Alcalay plans on following up his study with a survey to be sent out to the same people a year after the pandemic to determine the long-term effects of COVID-19 on these patients. He also believes that more needs to be done to make sure that the patients are not permanently harmed any further.

The question for us doctors and policymakers is what can we do to ease the chronic effects of the pandemic for people with Parkinson's,” Alcalay says. To him, the answer includes facilitating and improving telemedicine visits, promoting outdoor exercises, providing emotional and psychological assistance, and getting the patients vaccinated.

People with Alzheimer's and Parkinson’s depend on daily socialization, therapy, and physical activity for their disease management. So, it is no surprise that increased stress, social isolation, and confinement during the pandemic would be especially destructive to them. A recent analysis done by researchers from Case Western Reserve University in Cleveland, Ohio, shows, however, that the disruption of daily routines is not the only reason why COVID-19 has been so detrimental to these patients.

An infographic summarizing the results of the COVID-19 survey done by Alcalay's group at Columbia University in collaboration with the Parkison's Foundation

Courtesy of the Parkinson's Foundation

The analysis — which studied the electronic health records of 61.9 million patients in the US — found that people with dementia are twice as likely to get COVID-19 compared to patients without dementia even after adjusting for demographics and COVID-19 risk factors. This could explain the 16% increase in Alzheimer’s and dementia deaths observed in the U.S. alone since the beginning of the pandemic.

While the study does not say why these patients are more vulnerable, the researchers discuss two possible explanations. One is that — given the symptoms of the diseases, such as memory loss and motor impairment — the patients may not be able to comply with preventative behaviors for COVID-19, such as hand washing, wearing a mask, and social distancing. Another reason could be the patients’ damaged blood-brain barrier, which allows certain bacteria and viruses to access the brain more easily and make patients more susceptible to bacterial, viral, and fungal infection.

According to Alcalay, despite all its negative impact, the pandemic had one surprising change for the better — the uptick of patients and clinicians using telemedicine — which he hopes to be permanent. While in-person visits are still necessary for certain physical examinations, Alcalay thinks that there are several advantages to telemedicine, such as in the cases when a patient is disabled and cannot leave their house, or if they live in a different city from the best available doctor. “I don't think [telemedicine] is gonna replace in-person care,” says Alcalay, “but it's going to supplement it.”

The pandemic had a silver lining for Guerra and his wife as well. “This year taught me to prioritize what is really important in my life,” Guerra says. “Being with family and loved ones — no matter the circumstances — gives me the greatest joy.”

Burcin Ikiz studies
Neuroscience
.

Neuroscience has a part in why you're playing Taylor Swift's songs on repeat

Sarah Anderson — Thu, 08 Apr 2021 22:44:37 EST

Fifty thousand-seat concerts that sell out in minutes. Crowds gathered outside her apartment building, hoping to catch a glimpse as she exits. Pandemonium whenever she releases new music.

It may be tempting to dismiss Taylor Swift’s popularity as obsession or fandom, but there’s no denying that she will go down in history as one of the greatest musicians of our time. Her earlier work has produced so many hit radio singles that it could have its own station, while her recent album releases were widely celebrated as one of 2020's few welcome surprises. Some may even say she has music down to a science.

And if you can’t stop listening to Taylor Swift’s songs, science may be to blame.

Scientists have studied the elements that make music, well, good, and Swift's discography ticks all the boxes. For instance, researchers have identified the qualities of catchy songs, which include distinct “melodic turning points” between different sections of the song, such as the verse, chorus, and bridge. In Swift’s music, these turning points are often achieved by using a one-note melody in one section of the song. A great example is her early hit “Our Song,” the verse melody of which largely consists of a single note. As the BBC writes of Taylor Swift’s one-note verse songs, “When the chorus soars up the musical scale, it’s like a rush of energy.” Anyone who has ever belted out “Our song is a slamming screen DOOOOR” knows exactly what they’re talking about.

Researchers have also used brain imaging techniques to try to better understand how our brains respond to certain music. In one study, neuroscientists used functional magnetic resonance imaging to measure activity in different regions of the brain as participants listened to unfamiliar music. When the participant liked the song, their brain scan showed interactions between the brain's reward system and structures involved in analysis and memory. This study suggests that our brains naturally search new songs for recognizable features that allow us to anticipate what's next. Based on this finding, researchers propose that the pleasure we derive from music is closely tied to the process of making predictions, and having them confirmed or violated in exciting ways.

The emotional high people experience from forming and testing predictions about music is likely a factor in the success of Taylor Swift's songs. Swift has mastered the art of crafting a song to set up, and then play with, the listener's expectations. As the songwriting experts of Switched On Pop explain, “What Taylor’s great at is establishing a pattern, and then twisting it, and tweaking it, and surprising you with some variation.” As an example, they point to the key change in “Love Story,” which sent chills down my spine both when I listened to the new re-recorded version in February and when I first heard the song back in 2008.

While scientists can map your brain activity while you listen to music, there are also a lot of external factors — including individual circumstances and global events — that influence your personal music taste. It’s critical to consider this larger context when discussing folklore and evermore, Taylor Swift’s “sister albums” that were released in July and December of 2020, respectively. Some critics say that folklore marks the transition to Swift's "late period," the phase of an artist's career in which their work become more experimental. These albums generally lack the catchy musical elements identified by scientists, and several of the songs use strange, disorganized structures, making it difficult for the listener to predict what will come next. Additionally, rather than sticking to her customary autobiographical subject matter, these albums tell the stories of fictional characters.

And yet, despite all the ways that folklore and evermore depart from Swift's earlier body of work, they were still massively popular, receiving both high praise from fans and critical acclaim — folklore won this year's Grammy Award for "Album of the Year." If there is a scientific explanation for the albums' positive reception, it likely has more to do with what’s happening in the world than specific melodic devices.

Her omnipresence is just another way that Taylor Swift has science on her side

Psychology’s “transportation theory” describes the sensation of becoming immersed in a story to the point that one’s current reality is suspended. Transportation into a story has been found to provide a form of escape during times of crisis or stress. It makes sense, then, that songs that favor narratives so compelling that they inspired pitches for movies over tried-and-true hitmaking musical elements would be so readily embraced in the midst of the COVID-19 pandemic.

Although folklore and evermore may not have lit up your brain's pleasure centers initially, they probably do after playing them on repeat. Another brain imaging study found that the listener's familiarity with a piece of music is a more powerful indicator of activation of the brain's reward system than how much they claim to enjoy it. As "Shake It Off" and "Blank Space" are inevitably familiar to anyone who's ever gone grocery shopping or ridden in an Uber, even non-Swifties likely have a neurological pleasure response to her music. Her omnipresence is just another way that Taylor Swift has science on her side.

Even as Taylor Swift’s music has evolved, she continues to include the unique songwriting elements that she has relied on throughout her career to place her personal signature on her songs. One of these is a distinct descending melody, so ubiquitous in her catalog that it's earned the moniker "the T-drop."

Another classic Swift move is to repeat the opening lines of a song at the end. As for whether these elements are proven to be the makings of good music, we don’t yet have any scientific studies to tell us. But I’d argue that her success is compelling evidence of its own. Fifty thousand-seat concerts that sell out in minutes. Crowds gathered outside her apartment building, hoping to catch a glimpse as she exits. Pandemonium whenever she releases new music.

Sarah Anderson studies
Chemistry
at
Northwestern University
.

The neurons that make fruit flies interested in sex are turned on by song

Ashley E Peppriell — Tue, 02 Mar 2021 23:41:18 EST

For years scientists were puzzled by how the song of one lover influences another. Now, scientists at Howard Hughes Medical Institute’s Janelia Research Campus have helped piece it together. The researchers discovered a neuronal circuit in the female fly that influences her receptivity to a potential mate’s song.

Fruit fly courtship begins with the male’s song. To entice his partner, the male fly sings by extending a wing and vibrating it to produce an acoustic signal. If the male successfully woos the female, she will open her vaginal plates to mate.

“The male has to develop the correct song, meanwhile the female must recognize it,” said Kaiyu Wang, co-lead author of the Nature paper describing the work Like all good social communication, it takes two.

Previously, the researchers uncovered neural networks in the male that compel him to sing, but how the melody influences female receptivity was unknown.

Head of the lab Dr. Barry Dickson, had a hunch. He understood that in the fly brain there are circuits unique to each sex “that make the male and female behave differently.” To identify the neurons responsible for vaginal plate opening, the researchers studied female-specific neurons.

This was no easy task. According to neurogenetics expert Dr. Douglas Portman, “this work could not have been done without the huge amount of work behind the scenes,” referring to a collection of genetic tools developed by the authors. The tools are analogous to a molecular switchboard; researchers can use them to switch “on” or “off” neurons of interest. Portman is an Associate Professor of Biomedical Genetics and Neuroscience at the University of Rochester unaffiliated with the study.

The class of neurons called the vpoDN (in yellow) inside the female fly brain integrate the male serenade in her decision to mate

Dickson lab

Two additional resources were crucial to the work: optogenetic tools and the Connectome. Optogenetic tools use laser lights to control brain cell, or neuronal, activity in living flies. The Connectome, once complete, will be a full map of all the neurons in the fly brain and how they are connected. Portman emphasized that Dickson’s use of the partial Connectome was a trailblazing endeavor; the resource has been around since 2017, but has only been used a handful of times to define the relationship between neuron activity and behavior.

With lasers and brain-map in hand, the authors peered into the female fruit fly brain during various experimental conditions to uncover which neurons were important for vaginal plate opening and mating.

In certain conditions, the male sang and sang, but to no avail. Such conditions informed the researchers that a class of female-specific descending neurons, called the vpoDN, integrate the male serenade as sensory information to open the vaginal plates.

When the vpoDN were experimentally turned off with optogenetic technology, so were the females, despite even the best serenade. Similarly, when the researchers clipped off the male’s wings to eliminate the love song, or deafened the female, she was disinterested. However, even in the mute male and deaf female, the researchers were able to activate the female vpoDN using optogenetic technology.

“This song really matters; that’s how they make the choice”

“When you activated the vpoDN, you would get vaginal plate opening. Conversely, when you silence them, females are unreceptive,” said Dickson. “Identifying that these neurons were responsible was a huge result.”

Dickson explained it is essential that the female hear the right male, meaning one of her species. The team showed that females are attuned to a species-specific chord in the song. However, if the recorded song of a different fly species was edited to include the species-specific melody, even virgin females would open their vaginal plates. Dickson believes this to be “the most beautiful result in the whole paper” because it demonstrates how crucial it is for the female to hear the song of her species.

“This song really matters; that’s how they make the choice,” he said.

But it wasn’t all about the male’s song. The team realized that physiological cues from the female’s body needed to integrate with extrinsic cues of the love song. The receptivity of the female is also influenced by whether or not she has previously mated. According to Dickson, a second class of neurons deactivate after a female mates, eliminating the signal to open the vaginal plates.

Dickson and his team illuminated part of the neural circuitry behind the fruit fly serenade, an essential mating behavior. For the female fruit fly, the decision to accept a mate requires the right musical performance in the context of previous mating behavior.

Animals can display a diverse assortment of behaviors to woo potential mates. Dickson’s discovery at the level of individual neurons and their connections provides a paradigm for thinking about how brains work to influence behavior. By mapping the vpoDN connections, Dickson’s team exemplified how a brain can funnel multiple kinds of inputs, compare them, and ultimately make a decision.

It's not just the song and it’s not just the singer; it’s the audience that determines an effective serenade.

Ashley E Peppriell studies
Toxicology
at
University of Rochester
.

The mother's gut microbiome helps a child's brain develop its senses

Simon Spichak — Sun, 08 Nov 2020 18:05:25 EST

Long before humans and other animals roamed the planet, microbes were alone. Humans co-evolved within the context of these microbes, so it is no surprise that a community of microbes now reside in our guts. They aid in stress responses, digestion, and even help establish our immune system. Incredibly, these microbes communicate and work with our bodies. These interactions are altered in many different disorders of the brain.

Gut microbes send signals to each other to communicate. Their language consists of chemical signals that are released into the gut. Like many languages with similar or identical words, our bodies recognize some of these words.

In September, researchers studying mice found microbial signals from the gut microbes of pregnant mice inside the fetus's growing brain. The study suggests that maternal microbes influence the development of brain cells in the thalamus, the part of the brain that receives touch, smell, visual, and auditory information. It builds upon decades of elegant research, impacting our understanding of brain development.

Without microbial signals from their mother...mice would relay sensory information slower to the rest of their brain

The simplest way to understand the function of something in biology is to remove it and see what breaks. Consequently, researchers developed sterile environments and techniques to ensure animals could be born without any microbes. In the 1940s, many researchers first identified the profound importance of gut microbes by generating these germ-free rodents. Mice born without these microbes had an elevated stress response as well as other alterations in the size and structure of different brain regions. Scientists began to wonder whether these microbes influence other behaviors or brain functions.

In this latest study, scientists assessed exactly how microbes influenced the developing mouse brain. They compared the fetal brains of developing mice that developed with normal and altered presence of gut bacteria in the mother. Some of the pregnant mice were germ-free, other mice had a normal gut community but received antibiotics, while the final group served as controls and had normal gut microbiomes. Removing the gut bacteria or just adding antibiotics (to kill off the gut microbiome) drastically changed gene expression in the fetal brains.

When compared to controls, a swath of gene expression involved in the development of individual nerve cells changed in the absence of maternal gut bacteria. These genes help neurons grow out long thin axons that allow them to communicate with their neighbors. Some of these genes play important roles in the thalamus, which accepts and relays sensory information to the rest of the brain. To confirm their findings, they used microscopy techniques to visualize this region of the brain to count the amount of these axons. The thalamus of mice whose mothers were germ-free or received antibiotics had less axon growth. Since nerve cells lacked these axons, the mice might experience deficits in processing sensory information.

The human thalamus, highlighted in red

Via Wikimedia

To test out whether these mice had long-term deficits, they compared how quickly they were startled by sounds as adults. Mice with mothers without gut microbes as well as mice with mothers who received antibiotics showed a slower response. This indicated that maternal microbes were necessary for proper thalamus development. Without microbial signals from their mother present during development, mice would relay sensory information slower to the rest of their brain. Next, they found that giving germ-free mothers specific groups of gut bacteria could help these axons grow as normal, while also reversing the sensory deficit.

Pregnant mice without microbes showed a reduction of specific microbial signals in their bloodstream. Even though the signals impact the mice, they are only produced by bacteria. These findings suggest these microbial signals travelled from the bloodstream of the pregnant mouse to the fetal brain. Four of these signals were reduced in the fetal brains of mice whose mothers were germ-free or received antibiotics. Remarkably, if some brain cells were sampled, grown in a lab, and injected with these four metabolites, their growth was restored to normal.

Do these microbial signals send similar signals in humans?

These findings are incredible in part because of the challenges posed to researchers. Fetal mouse brains are incredibly tiny, difficult to work with and grow in a dish. Some limitations of this study stem from this difficulty. Researchers only looked at one point in time during pregnancy. While impaired offspring had altered brain development, it's unclear whether this sensory alteration is a substantial impairment. These findings don't rule out that microbes might simply speed up fetal development either.

Nonetheless, these differences may impact brain development or behavior later in life. These animal studies necessitate larger epidemiological studies in humans. Many people are administered antibiotics during pregnancy, but few studies assess the impacts on the baby. Could antibiotics at certain points of fetal development increase the risk of poor outcomes in the brain? Answers to these questions will guide future clinicians when deciding whether or not antibiotics may harm a developing brain.

More broadly, this study contributes to the exciting area for deciphering microbial communication. Several signals generated by microbes in the pregnant mouse communicated with the fetal brain. Do these microbial signals send similar signals in humans? If they do, it might provide us with a specific marker of the developing brain.

Finally, this research further establishes that microbes during pregnancy are important. Once we learn which microbes produce the specific signals our bodies need for proper development. Ten or twenty years from now, we could assess the gut microbes from someone's feces to determine if they might be missing certain microbial signals or words. Then we could simply provide them with a microbe that will generate these signals, ensuring proper infant development.

Simon Spichak studies
Neuroscience
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A potential new treatment for premature aging diseases keeps stem cells fresh longer

Deanna MacNeil — Thu, 05 Nov 2020 23:25:03 EST

The ends of our DNA, called telomeres, get shorter as we age. Our cells lose a bit of telomere every time they divide. This shortening is a normal and needed process that serves a protective function against cancer. This is because the older our cells get, the more likely they are to have accumulated damage or mutations that make them function incorrectly. Telomere shortening helps to take old cells that are reaching their “best before date” off the shelf before they can cause trouble.

But this can backfire: cells can shorten their telomeres too quickly, age rapidly, and die. This is what causes a subset of genetic premature aging diseases, including idiopathic pulmonary fibrosis, forms of aplastic anemia, and a rare disease called dyskeratosis congenita. Unfortunately, there are currently no available drug-based therapies for treating telomere-driven premature aging diseases.

Now, a candidate drug has found a new potential purpose in treating premature aging disease.

This drug, called RG7834, was originally identified as an inhibitor of hepatitis B virus (HBV). While it has been found to be well-tolerated in short-term administration to living organisms (like rodents and primates), this drug does not cure HBV, and is not yet publicly available. Interestingly, the host cell proteins affected by RG7834 are two enzymes that modify many different RNAs. These enzymes can cause degradation of host cell RNA — so RG7834 keeps RNA around that the cell otherwise might get rid of.

Think of the telomerase protein (called TERT) as a lamp, and the telomerase RNA as a light bulb in the lamp

Stem cells help maintain our immune system, are important for tissue regeneration, and are crucial for development. To keep themselves active, these cells rely on the enzyme telomerase, which most cells do not express, to maintain their telomere length. Insufficient telomerase in stem cells causes them to age at an accelerated rate because their telomeres shorten too quickly — which can contribute to premature aging disease.

A major challenge to treating premature aging diseases is targeting stem cells with treatments that improve telomere maintenance without turning on the telomerase enzyme in normal cells. It seems like RG7834 could achieve this by exploiting telomerase's unique construction.

Telomerase is a two-parter: it has a protein component and an RNA component. The protein literally carries the RNA and uses it as a tool to lengthen telomeres. The RNA component is at the heart of many different genetic presentations of these diseases, as the levels of this RNA component are often very low in patients.

Think of the telomerase protein (called TERT) as a lamp, and the telomerase RNA as a light bulb in the lamp. The light bulb cannot produce light if the lamp is off or broken, but even when the lamp is working, how bright your room is depends on the brightness of the light bulb.

TERT is naturally present in stem cells but absent from most other cells. Some premature aging patients, like those with the X-linked form of dyskeratosis congenita, have low telomerase RNA levels. Increasing the amount of telomerase RNA component throughout the entire body is an appealing strategy to activate telomerase enzyme specifically in stem cells. This is because increasing the telomerase RNA levels in normal cells that naturally lack TERT will not activate telomerase. Bringing a light bulb into a room with no lamp will not brighten the room. Only cells with TERT will benefit from increased telomerase RNA.

Recent advances in our understanding of what keeps the levels of telomerase RNA in check led to the discovery that one of the host cell enzymes that regulates hepatitis B can also reduce telomerase RNA. Building upon this knowledge, two recent studies tested the ability of RG7834 to treat the defects of premature aging. Independent research groups at Harvard and Washington University in St. Louis both developed models for assessing the effects of the inhibitor RG7834 on telomeres and stem cell function.

Bringing a light bulb into a room with no lamp will not brighten the room. Only cells with TERT will benefit from increased telomerase RNA.

Photo by Matteo Kutufa on Unsplash

The Harvard-based team generated human stem cells that were genetically engineered to mimic low telomerase RNA levels similar to those seen in premature aging disease. They then transplanted these cells into mice with or without RG7834 in their drinking water. When the stem cells with low telomerase RNA levels were transplanted into mice treated with RG7834, the telomerase RNA levels increased, leading to longer telomeres. This is in contrast to the stem cells transplanted into mice that did not receive RG7834, which maintained low telomerase RNA levels. The St. Louis team also made use of genetic engineering in human stem cells, and introduced a mutation that causes the the X-linked form of dyskeratosis congenita into the stem cells, which they studied in cell culture. The team found that RG7834 treatment not only increases the telomerase RNA levels and telomerase activity in cultured cells carrying this mutation, but also that RG7834 treatment makes these diseased stem cells develop in a way that resembles healthy stem cells.

To date, the only treatments for premature aging diseases caused by accelerated telomere shortening are ones that offer symptom management. The major treatments available to patients currently are hormone therapies and transplantations to temporarily replace stem cells or entire organs which have aged too quickly. Unfortunately, these invasive treatment options are often associated with poor outcomes and do not treat the disease itself. A drug like RG7834, which can be taken orally, would provide a treatment option that does not involve surgery or a major procedure of any kind. Oral availability in this case also means that RG7834 has the potential to reach all stem cell compartments of the body where telomerase function is needed.

Importantly, however, RG7834 is not a cure for telomere-driven premature aging. We don't yet know whether RG7834 would need to be taken for a patient's entire lifetime. While no negative side-effects of this drug have been observed in model organism studies, long-term studies are still needed to know whether administering this drug for an extended length of time in humans would be safe. RG7834 also may not necessarily improve patient outcomes that are independent of the telomerase RNA component, which would make genetic pre-screening for therapeutic potential crucial. For instance, if a patient carries a mutation that disrupts TERT, the protein component of telomerase, the lamp of the telomerase enzyme, then increasing the brightness of the bulb with RG7834 might not be an effective treatment.

Deanna MacNeil studies
Cell Biology
.

Brain banks are key to understanding COVID's mysterious symptoms, but only if people are willing to donate

Kathryn Vaillancourt — Tue, 20 Oct 2020 14:13:02 EST

After 7 months and counting, we've all had first-hand experience with the stress and uncertainty that have hitched a ride with the COVID-19 pandemic.

This situation is pushing our mental health to its limits. Some patients have been reporting strange neurological symptoms that suggest that the virus might be able to hit the human brain directly. If we’ve learned anything from similar viruses in the past, it’s that the effects of COVID-19 on the human brain may last for months or years after the pandemic is over.

This is precisely why donations to brain banks are vitally important.

The method for preserving brains was created in the 1600s, and curious physicians and anatomists have been collecting brains ever since. But the systematic banking of brain tissue that exists today began in the early 20th century, arising from a need to study mysterious brain diseases. Today, there are brain banks throughout the US, Canada, Europe, and Australia that each focus on collecting and characterizing samples from specific brain disorders, and providing crucial resources to the research community. Although the details differ between platforms, people can agree to have their brains donated to a brain bank, or their next of kin may be approached by a brain bank team about the possibility of donation after they’ve died. Whether they’ve been diagnosed with an illness or not, each brain donation is meticulously categorized and preserved so that they can continue to be studied, sometimes decades later.

After the SARS pandemic in 2003, researchers used brain donations to discover that the virus could infect brain cells. This could explain why some SARS patients had symptoms like dizziness, confusion and anosmia (loss of the ability to smell). Curiously, reports have started to come out that COVID-19 can cause similar brain-related symptoms in some patients; the most common are headache, anosmia and brain fog, but COVID-19 can also cause seizures, strokes, or comas. There’s even some evidence that these symptoms are related to changes in brain structure, but without donated tissues it’s almost impossible to tell how the virus gets into the brain, or if it infects brain cells at all. It's possible that the virus infiltrates individual brain cells, causing them to malfunction, but the troubling symptoms that some patients experience could also be a side effect of the fever and inflammation that COVID-19 inflicts on the body as a whole. This means that for doctors struggling to find the right treatments and scientists looking for breakthroughs, brain banks might hold the answer.

doctors struggling to find the right treatments and scientists looking for breakthroughs, brain banks might hold the answer.

Naguib Mechawar, director of the Douglas Bell Canada Brain Bank (DBCBB) in Montreal, says that to truly understand COVID-19, brain banks are "more than useful, they’re essential." Whether the virus works through direct contact with brain cells, or through inflammation of the blood vessels in the brain, he adds that "access to human brain samples is required to understand the mechanisms underlying these symptoms. Models remain important, but there’s nothing like patient samples to understand this human illness."

Today, there are brain banks throughout the US, Canada, Europe, and Australia that each focus on collecting and characterizing samples from specific brain disorders, and providing crucial resources to the research community.

Wikimedia

For the virus to actively attack brain cells, it would have to get through the blood-brain barrier — the tight network of cells that plays bodyguard between the brain and the body — first. It turns out that some brain cells express the ACE2 protein that SARS-CoV-2 binds to in the respiratory tract, so it’s possible that they’d be vulnerable to such an attack. Plus, in the lab, the virus seems capable of infecting brain organoids — three dimensional cell cultures that are used to model brain biology — but we can't know if it holds true in humans unless we have access to human brains. Luckily, scientists have started to look at autopsied COVID-19 brains, and in one case, they’ve found bits of the virus inside some brain cells. Once inside, it's possible that the virus can reproduce and spread; but as Serena Spudich, a neurologist who wrote a review about these cases, said to the Guardian “It’s really hard to make firm conclusions based on one or two autopsies.”

Brain banks offer the solution to this problem. By collecting samples from people who were infected with the virus while they were alive, whether they had neurological symptoms or not, and from people who died from other causes, brain banks will be the steady, stable resource for COVID-19 brain research that they have been for other brain-related diseases. Banked brain samples have helped researchers understand how brain-specific immune cells react in Alzheimer’s disease, and how a specific group of cells could be a target for schizophrenia treatment. By accessing medical records, interviewing family members, and carefully examining tissues, brain banks are uniquely able to capture information about an illness before and after it has taken hold of a patient.

In 2000, brain bank scientists from Germany, Austria, and the US, banded together to understand how multiple sclerosis (MS) develops. One of the biggest challenges in treating MS is that the disease can present itself differently in different patients; according to the National Multiple Sclerosis Society, "no two people have the exact same symptoms, and each person's symptoms can change or fluctuate over time."

Together, the team led by Claudia Lucchinetti collected more than 80 patient brain samples, and although they found MS-related brain cell damage in all their samples, they noticed some interesting patterns. By carefully examining the distribution, size, and protein composition of the damaged cells, they found four distinct patterns that gave them clues about how the disease developed in each patient. These patterns could help doctors to diagnose and treat MS in living patients, and they would not have been found without donations to brain banks.

Brain banks will become even more important in the fight against COVID-19

Brain banks will become even more important in the fight against COVID-19 as we understand more about the behavior of the virus and the symptoms of COVID-19 patients. In addition to neurological symptoms experienced during their sickness, a troubling number of people have reported continued confusion and memory difficulties, called "brain fog", in the months after they've recovered.

Fortunately, efforts are underway to begin collecting COVID-19 brains, and Mechawar says "We [at the DBCBB] have been working actively to set up some mechanisms to collect such brains, but it has been difficult, namely because autopsy rooms have been shut down during the pandemic. But I’m glad to say that we’ve managed to establish new partnerships and purchase new equipment to facilitate things and that we will soon be able to initiate the collection process."

Although it’s not clear whether brain banks will help find a vaccine for SARS-CoV-2, they will continue to be an important pillar of COVID-19 research as the pandemic dies down. If they receive enough donations, that is.

Kathryn Vaillancourt studies
Neuroscience
at
McGill University
.

The protein Klotho could extend the life of the brain. Is that a good thing?

Dan Samorodnitsky — Sun, 18 Oct 2020 21:11:23 EST

Now's the time to live forever. Futurologists and transhumanists are poking themselves with what molecules they can, seeing what there is that might extend their lives or preserve their brains. One of the most intriguing molecules out there is called Klotho. Identified in 1997, it's named for the Fate of ancient Greek mythology who spun the thread of life. Mice that have a severely limited amount of Klotho in their body age rapidly and die prematurely. On the other hand, mice that carry more Klotho than normal live longer lives and appear to be resistant in some ways to aging.

Last April, an article appeared in the New York Times, titled "One Day There May Be a Drug to Turbocharge the Brain. Who Should Get it?" Massive contributor and neuroscientist Yewande Pearse and editor Dan Samorodnitsky sat down (in front of their computers) to talk about Klotho — what it is, what it does, and whether prescribing a drug to supercharge the brain is a good idea.

Dan Samorodnitsky: Would it have to be prescribed by a doctor? Bought over the counter? Available at *chuckles to self* "Klotho shops"?

Yewande Pearse: This is a really interesting question because unlike a lot of other drugs, Klotho is a) a naturally occurring protein and b) has the potential to protect, treat and enhance the brain, therefore, the answer depends on the circumstances.

Mouse studies have revealed that Klotho plays an important role in the aging process. Mice with mutations in the Klotho gene have phenotypes which resemble different aspects of human aging, such as slowed growth, calcifying blood vessels, osteoporosis, and premature death. With respect to brain function, when mice with symptoms of age-related Alzheimer's disease are given Klotho, they are protected from cognitive decline. However, the exact biological function of Klotho and the way in which Klotho deficiency contributes to age-related diseases is not understood in mice, let alone humans.

...simply taking Klotho orally is not as simple as it sounds

Klotho has also has been shown to decrease with age in human blood serum samples, which may have something to do with cognitive decline in aging. Having said that, we all age, but we don't all develop Alzheimer's disease. Interestingly, people who carry a genetic variation of the Klotho gene that causes them to produce more Klotho, seem to not only be protected from Alzheimer's disease, but also perform better on cognitive tests like the Mini-Mental State Exam (MMSE) than people who produce average levels of Klotho.

Therefore, this becomes a question of dosage. To answer whether Klotho would have to be prescribed, we need to figure out the dose of Klotho required to prevent, treat, and enhance, and whether there are dose dependent risks. Perhaps a good starting point would be to calculate how much extra Klotho people with that gene variant produce compared to the average person versus how much less Klotho people who develop Alzheimer's disease have compared to those who do not of the same age.

It is also important to think about the structure and expression of Klotho when answering this question. Klotho is actually a transmembrane protein which means that it sits in the cell wall. Most of Klotho exists outside of the cell, but can be chopped off and released into the blood, urine, and cerebrospinal fluid. These different forms of Klotho all have different functions. Therefore, simply taking Klotho orally, is not as simple as it sounds, as it is unlikely that it will get it into its natural place in the body, especially if we are trying to get it to the brain where it would have to cross the blood-brain-barrier, which prevents large molecules from passing through. To properly capture the full range of Klotho functions, we may be better off thinking about targeting the gene expression of Klotho itself — something that may go beyond even a doctors prescription.

Multi-color whole brain image taken by fMRI

NIH via Flickr

But are naturally occurring levels of Klotho at the evolutionarily "correct" expression level?

Klotho is considered to be an aging-suppressor gene with multiple functions that protect organs. However, this protection doesn't last forever as Klotho declines with age.

To answer this question, we need to address a different question first: How and why do we age? There is no unified theory to explain the overall transformation taking place in the body during aging, but several theories, such as random mutation of genes, accumulation of damage by free radicals and the degeneration of functions like immunity are all valid on a local level. The reduction in Klotho as we age, for example, might fall into the last category, helping to explain dementia in the aging brain.

The "why?" is about trying to understand aging in terms of its necessity for survival. That sounds like a contradiction but is important when considering whether or not we should be taking Klotho as a drug. In 1889, August Weismann proposed that aging is a natural process of wearing out. If this is the case, then it is tempting to argue that there is no evolutionarily "correct" expression level of Klotho beyond child-bearing age. Klotho protects us for long enough to pass on our genes, after which point evolution has no reason to select for prolonged lifespan. This is why we don't all carry the "extra Klotho" genetic variant. However, the fact that better health care has granted us longer life regardless means that having higher levels of Klotho to maintain cognition is certainly preferable, and we could also argue that naturally occurring levels of Klotho are inadequate and should be augmented. Does that make sense?

A lack of Klotho in the body has been shown to correlate with a number of psychological conditions

It does make sense. Should we be concerned about, I don't know how to put it, over-correction? It feels like a moving target to nail down a dosage of Klotho that works well with any individual's natural expression of Klotho, natural variants, mutations, the three different variants of Klotho, just the overall difficulty of nailing down medications aimed at the nervous system.

Definitely, I think that caution is certainly needed given the fact that some studies have shown that one variant is actually associated with increased dementia and schizophrenia, suggesting that positive effects of Klotho on cognition may actually be limited by time, sex, and other factors. Having said that, all drugs, many of which have saved and improved lives, face the same challenge.

I think that Klotho research should focus on preventing the development of Alzheimers in people at risk first. In other words, trying to better understand Klotho as a potential biomarker, not just a treatment. There are no human studies to show what happens when Klotho is given to those who already have dementia, so early intervention is probably key. For the rest of us, research should focus on how our natural expression level of Klotho might be impacted by diet, exercise, etc., rather than heading straight down the pharmaceutical rout. For example, studies show that exercise, carbs, activated charcoal, probiotics and even statins can all increase the production of Klotho.

Is there evidence of disease from lack of Klotho in the body (maybe similar to imbalances occurring in some mental illnesses)?

The first clues about the function of Klotho came from mouse studies in which, the Klotho gene was deliberately mutated so that they didn't produce the normal level of Klotho. These mice had shorter life-spans and interestingly, showed a rapid decline in cognitive function, but only after a certain age. With mouse studies continuing to support the idea that Klotho expression levels correlate with both body (Klotho is made in the kidney too!) and brain function, there is now a lot of interest in Klotho as an indicator of health and disease.

A lack of Klotho in the body has been shown to correlate with a number of psychological conditions from chronic stress, which can lead to other psychiatric illnesses, and bipolar disorder. Lower levels of Klotho have also been associated with disease severity in multiple sclerosis and epilepsy. Generally, Klotho levels are lower in older people, but in Alzheimer's disease, patients, especially female patients, have even less Klotho.

A cross-section of a mouse cerebellum

NIH via Flickr

Also, and I'm sorry to keep harping on this, there's this quote from the original New York Times article that started this conversation:

"Some people carry a genetic variation that causes them to produce higher levels of Klotho than average in their bodies. Dr. Dubal and her colleagues identified a group of healthy old people with the variant and tested their cognition.

They scored better than people who make an average level of Klotho. “It’s not like they didn’t undergo cognitive decline,” said Dr. Dubal. “It’s just that they started off higher.”

Maybe I'm just confused about the difference between Klotho making people "smarter" and people having "higher cognition" or something?

This is the part of the article that really jumped out at me. This is an important distinction. In this study, they found that differences in cognition as measured by IQ scores were only apparent after the age of 60. This means that these individuals experienced a delay in cognitive decline compared to people of the same age with the normal level of Klotho. Before 60, IQ scores were comparable but then after 60, people with lower levels of Klotho experienced a drop in IQ. Klotho is all about anti-aging, so we need to thinking about cognitive decline as a feature of aging and Klotho as an anti-aging protein. Assuming that we have the same IQ and we don't have the Klotho variant, if you were to start taking Klotho now (pretend they've cracked the issues above) and I didn't, I don't think you'd suddenly get smarter, I just think that when we got older, I'd start experiencing cognitive decline before you.

Do you worry about the number of apparent medical functions Klotho has ascribed to it? Increases overall brain function (but doesn't make you smarter), increases lifespan, and protects against a bunch of different, un-related diseases like Alzheimer's, Parkinson's, and MS? Seems like a lot of effects for one protein.

I am fascinated by the fact that Klotho has so many effects! It's a bit of a super protein. I am not surprised though because although all these effects seem disparate, they share common pathways upon which Klotho acts. For example, Kotho has antioxidant effects that are important for multiple functions both in the brain and the kidneys.

What I am worried about though is the fact that little is actually known about the function of Klotho and how aging suppression might work. I think we should be very careful about altering something that does indeed have so many actions and effects. Once Klotho is secreted, it enters the blood stream and goes everywhere, but by taking Klotho orally, I am not sure how can we ensure Klotho is going to the right places in the right quantities in a way that is effective and safe.

Do you worry about the ethics of taking Klotho? Taking it as a replacement drug, like if someone has low Klotho, seems fine, but beyond that? Should neuroscience researchers worry about that?

Are you asking me whether I think it's unethical to want to live longer and better? I'm tempted to go off on a tangent about our human endeavor to live forever and what that is doing to the environment. But, if we are going to live longer, is it wrong to want a better quality of life as measured by staying sharper into out 70s, 80s and 90s? I don't think that desire is unethical.

However, if we are talking about the ethics of taking an enhancement drug that not everyone has access to then my answer would lean more towards no — but I'd say the same about food equity and a hundred other things that influence our health and well-being. I guess that answer is more personal. As a neuroscience researcher, my priority is safety and the ethics around that. If we can ensure that taking "extra" Klotho is safe and effective then, I don't think we should be worried. I mean, I can't speak for neuroscientists everywhere, but if some of us are willing to research how zapping the brains of healthy adults to improve memory and potentially improve cognitive function, then relatively speaking, I don't think researching the additive effects of a naturally occurring protein is a concern.

Dan Samorodnitsky studies
Senior Editor
.

Neuroscientist seeks love molecule: a conversation with Bianca Jones Marlin

Claudia López Lloreda — Sat, 17 Oct 2020 18:54:45 EST

From the volcanoes of Costa Rica to the deepest reaches of the galaxy, discover the innovative scientific research and incredible personal stories of six #WomenInScience working at the forefront of their fields.

Watch Science Friday’s latest film series at BreakthroughFilms.org. This episode: The Trauma Tracer

The brain contains hundreds of chemicals that control everything from our mood to how we move. One of these, the love hormone oxytocin, captured Bianca Jones Marlin, a neuroscientist seeking to merge her love for the understanding behavior with social justice. Jones Marlin talked to Massive about what she loves about oxytocin, the process of opening her lab (coming in 2021 to Columbia University), and why science needs her. This conversation has been edited for clarity.

Claudia López Lloreda: As a neuroscientist, a lot of times I find myself asking why I decided to study something as complex as the nervous system and the brain. Why did you decide to study the brain?

Bianca Jones Marlin: There are always questions that I find myself asking: Why is this behavioral outcome coming from this individual? Why did this person respond way better than I would have responded? When I think about those questions, while sipping coffee and pondering life, they all go back to decision making in the brain. I am just interested in figuring it out. I get to be the first one to know the answer to that, there's something magical about that. I love studying the complexity of the brain because it's interesting and it's fun. Whether or not I figure out how the brain works, the brain is still going to work. Also, we can apply [the findings] to pathological situations and to individuals who may not have the same access to things that others have that leads to a more traumatizing life or a less equal life. If I can find out mechanisms and apply those to people in life, then I've found my mission on Earth.

I follow you on Twitter and your bio says that you have a PhD in “bad parenting." Can you tell us what that means and why it's important for us to understand?

Yes, I wish Twitter gave me more space to explain that, hopefully they don't just think I'm a bad parent. My PhD work looked at maternal behavior. When a mom mouse hears the sound of a baby crying, whether it's hers or another baby crying, she’ll orient towards the sound and she'll pick it up. When a virgin mouse, who has never given birth, hears a sound, she usually will ignore it, or she'll cannibalize it. The same sound of a baby crying gives two different behavioral responses. How does the brain change to say, "I no longer can eat this annoying sound, I need to take care of it"?

I found that oxytocin, the love hormone, changes the way the hearing centers of the brain respond to a baby crying once a mother gives birth because once you give birth, there's a lot of oxytocin release. So, we took a virgin mouse and added oxytocin to the brain. We saw changes in the way the neurons responded, they [the neurons] stopped speaking like bad nanny, where they would fire randomly, but instead they changed it to a mother's signature of neural responses. That was really cool, because the nanny stops cannibalizing and ignoring the pup and started taking care of [it]. We made a virgin into a mom without ever experiencing birth just by adding this love hormone oxytocin.

Bianca Jones Marlin

Screenshot via SciFri/YouTube

Would you say that oxytocin is your favorite molecule? What do you like about it?

I don't want to say oxytocin is my favorite because I haven't dabbled in all of them. I need to check out noradrenaline and cortisol to see what's going on. But oxytocin is amazing. The cool part is oxytocin is released during these social interactions: eye contact, soft touch, orgasms, breastfeeding. One holding a child or being caressed. There's something beautiful about that. In that manner, I do think it's a pretty cool neuromodulator.

It seems like it's become a household name now. Do you have any qualms with how nonscientists talk about it?

It's a mixed response. On one hand, I'm happy people are using the word oxytocin. I'm really excited that people are engaging in the science. The part that scares me and [the part] that I'm so happy that my work is able to inform is that you can't buy oxytocin on Amazon and use it as a drink potion on your date. That's not the way oxytocin works. We need to understand the mechanisms before we use them as treatment. When we know how oxytocin works in the mammalian brain, then we can start talking about how it can work in society. I want to make sure that it's informed engagement and people aren't spending money to buy it on Amazon.

It's unfortunate that my work is driven by the evils in society, but this is my way of standing against them

You just got appointed as an assistant professor, congratulations! Can you tell me a little bit about the process of opening your own lab?

I'll be starting my lab at the Zuckerman Institute in Columbia in the department of psychology and neuroscience. I'm in the process of reaching out to figure out what I what, my first graduate student, my first postdocs, all the while engaging in social justice. How will I practice what I preach when it comes to the people I invite into my lab? All the other labs I've been in the culture has [already] been made. I have the chance to create my own culture in the lab. What is the Marlin lab going to reflect in its scientists and society? These are things I'm thinking about all the while ordering gloves and putting plant pots in my office. It's an exciting journey because it only happens once in a PI's life. I'm really excited about setting the culture and making sure that it stands for the integrity that I believe it should, and what I want it to reflect with society.

Have you encountered discrepancies between what your expectations and what setting up a lab really means?

I was very concerned about no one wanting to join my lab. There are also other insecurities surrounding being a female PI, being a Black PI, insecurities are reinforced by society. After a while, I concluded that this within itself is a litmus test. This is already a filter. If you don't think I'm capable of being an amazing mentor and PI because of my blackness, or because of my womanhood, then you don't belong in the lab anyway. Then it reinforces that integrity and mantra that I want my lab to be. Also, I'm getting people who are reaching out to me, left and right, who are very interested in being part of the lab. Those two things together really helped ease that anxiety. If you don't think I'm capable of being your PI, then you shouldn't be in my lab and I don't have to prove anything in that matter. Because if you have a problem with me being here, you could take it up with Columbia, they hired me.

I am so impressed with Black in Neuro Week...if any of them want to join my lab, they should talk to me

Are you looking to continue the same research? Or are you looking for new avenues?

There are so many things I want to study. I have a book here [shows purple notebook that says Transgenerational on it]. I have so many — Evernote, my notes on my phone — and every time I'm walking around, and I see something cool to study I jot it down. Right now, I'm very interested in how stress in the environment affects the brain, the body and the children and the grandchildren of those that went through the stress. And using the senses to look at this. So, smell, taste, hearing, I'm using the senses to see how the brain changes and how that can affect subsequent generations. I am still looking at how parents change the lives of their offspring. As long as I'm surrounding how I can use science to change society for the better, those will be where my questions will lead. And as I learn more about society, those may change.

A litter of pups

Screenshot via SciFri/YouTube

Having participated in Black in Neuro Week, what does having that community and engaging in diversity, inclusion, and justice initiatives mean to you?

I will start by saying, I am so impressed with Black in Neuro Week. [They] have made moves that universities have spoken about for generations in the span of two weeks. If any of them want to join my lab, they should talk to me. With that being said, I do remember, in 2017 there was a string of Black male killings. It was one of the days that another Black man was murdered, we had lab meeting, and no one mentioned anything. Everyone went about their day; I was so confused. What I realized is that it's not [only about] serving on DI [diversity and inclusion] boards, speaking about diversity, teaching people who do not come from diverse backgrounds, [all of which] which I do, it's me being present. I think a lot of racism is surrounded by lack of understanding and knowledge of another human being. So, I understand that my presence within itself is a fight for equity and justice, because people get to know me as Bianca. They understand, "Oh, she is a mother. Oh man, she likes pizza. Oh my goodness, this is my favorite TV show, too. We're more similar than we are different. And she's actually cool.” I do all the other things, but also bringing people to my dinner table is social justice, because they get to see that I'm actually a full-on human being.

Beyond the science being interesting and valuable, what else drives you to continue studying this field?

If 2020 did not give me another boost to continue to be a neuroscientist, I don't know what would. People are suffering unnecessarily, based on the cruelty of other people. That moves me to emotion because it's unnecessary, but the ramifications of it can actually be permanent. If my job could in any way, shape, or form make that part malleable, make people suffer less, then that brings me joy. It's unfortunate that my work is driven by the evils in society, but this is my way of standing against them. I can do something really cool like take neuroscience and apply it to something I feel so strongly about, which is injustice, inequity, and injustice in education.

Racial injustice and the stress it puts on black and brown people, on people who actually care is so unnecessary. But yet we know it can have ramifications for generations, which is what I study now. If I have the ability to take these evils in society and do a little bit to move in a different direction, then that's what drives me.

Is there anything that you want to say to scientists of color in this moment and specifically, Black women?

Our presence as Black women in science is so needed because our unique perspective informs all of society. That's not to discount anyone else's perspective but because it's unique and underrepresented, it's all the more needed. Our unique perspective informs science for the better, our presence makes better science. I can also speak as a first generation American; our perspective is essential in science because we think of things differently because we've been raised differently. We figure out why there are certain diseases that affect Black American populations more than others and we figure out mechanisms that inform all populations about diseases.

We decide not to fund projects surrounding this, we decide not to publish papers surrounding this, and it's unfortunate that racism gets in the way of humanity. It's actually quite ignorant of science to allow racism to get in the way of progress of science. It's greedy, it's self-centered. And it's not what we as Black people, brown people, underrepresented people, disabled people should have to deal with. That's my message: that our unique perspective is essential. And when we're made to feel like we're not essential because of racism. Remember that that perspective does not trump the truth: that in science I'm needed. Science needs me.

Claudia López Lloreda studies
Neuroscience
at
University of Pennsylvania
.

A proposal to use CRISPR to prevent opioid overdoses is a useless approach to healthcare

Nicholas McCarty — Thu, 17 Sep 2020 22:59:36 EST

SARS-CoV-2 has swept us indoors and laid bare the social inequities in the American healthcare system. In many places, Black, Latino, and Indigenous people have been disproportionately infected by the virus. With a greater, global focus on public health, the pandemic's severity may have been reduced. America’s retroactive approach to medicine has failed again.

But another illness has already been testing our healthcare system. It, too, can trace its growth through discordant, half-assed measures. It, too, has highlighted the social inequities in the American healthcare system. But it will persist long after SARS-CoV-2 is beaten.

“...substantial work...needs to be done before this would be advisable”

According to the CDC, about 47,000 Americans died from an opioid overdose in 2018, a number that remained steady from the previous year. This is despite more than $9 billion in federal grants to states, largely for "medication-assisted treatment", over the last three years.

Craig Stevens, a professor of pharmacology at Oklahoma State University, outlined a proposal to prevent opioid overdose deaths by “turning off” a specific receptor for opioids in the brain. I first read his plan in an article for The Conversation, but Stevens also published this idea in a peer-reviewed article for the Journal of Neuroscience Research in May.

Stevens advocates for the genetic alteration of people struggling with opioid addiction by injecting CRISPR molecules into the brain via “a new neurosurgical microinjection technique.” The injected CRISPR molecules would render the mu opioid receptor nonfunctional in specific neurons. In this way, death by overdose — which is caused by slowed or impaired breathing — could be prevented. Opioid addiction, however, would persist.

Any treatment that claims it can save nearly 50,000 lives a year is worthy of our attention. But I take issue with this proposal because it reinforces America's long history of treating national medical crises — AIDS, SARS-CoV-2, mental health — reactively, rather than proactively, and on an individual, rather than societal, level. This approach has failed every time. The opioid epidemic is no different.

From a scientific perspective, Stevens’s proposal isn’t that far-fetched. In mice, deletion of the mu receptor in specific neurons prevented respiratory depression, or slowed breathing, even when opioids were given at high doses. In August, scientists at the Chinese Academy of Sciences, in Shanghai, also published a pre-print showing that CRISPR can mutate specific genes in the brains of adolescent rhesus monkeys.

“Yes, CRISPR-based therapies could technically be delivered in vivo to specifically delete a gene in the human brain,” said Randall Platt, an assistant professor at ETH Zurich, in Switzerland. But, he acknowledged, “substantial work on the clinical development front needs to be done before this would be advisable.”

Specifically, researchers will first need to find a way to prevent off-target effects — unintended changes in the genome — when editing a gene with CRISPR. Platt, who was among the first to use CRISPR to genetically edit genes in the brain of a mouse, told me that “there is absolutely no way to avoid these with 100% certainty.” Off-target effects were present in the so-called “CRISPR babies” that attracted international condemnation in late 2018, with as-yet unknown consequences.

Even though current technologies are not always perfectly precise, genetic engineering is being tested as a treatment for several diseases. There are clinical trials under way to correct Hunter syndrome, which is the first disease to be treated with in-body genetic editing, and to cure sickle cell disease by removing cells from a patient, editing a gene in those cells, and then placing them back into the body. CRISPR components directly injected into the retina are also being tested as a treatment for Leber Congenital Amaurosis, a form of inherited blindness. Genetic diseases, after all, may warrant genetic solutions.

Stevens is advocating for a research direction, not an urgent clinical intervention. Still, the cause of the opioid epidemic is not genetics: it is societal and healthcare shortcomings. Those are things CRISPR cannot fix.

The U.S. spends just 2.5% of its healthcare budget on public health. But the NIH, in 2016, spent more than half of its $26 billion budget on research directly “linked to search terms that include gene, genome, stem cells or regenerative medicine,” according to Erik Parens, a senior research scholar at The Hastings Center.

But the NIH may be changing their priorities when it comes to opioid addiction. The NIH HEAL (Helping to End Addiction Long-Term) initiative spent more than $945 million in 2019. This money includes funding for experimental treatments for opioid overdose, including a putative heroin vaccine and a sustained release implant of Naltrexone, a medication that helps patients avoid relapse into opioid dependence.

While these treatments sound promising, there are already ample tools to treat both opioid addiction and overdoses. In 2018, the entire European Union, including Norway and Turkey, saw fewer than 9,000 “drug-induced deaths.” France, which has one of the lowest rates of overdose-related deaths in Europe, has hundreds of harm reduction centers that provide needle exchange programs and access to social workers and psychiatrists.

Europe relies on social interventions to treat opioid addiction, and these same interventions can be implemented in the U.S. A study on overdose prevention in Skid Row in Los Angeles found that training people how to use Narcan — which can reverse the effects of an overdose — is a first step to treating overdoses. In a one-hour training session, participants were taught how to spot an overdose, call emergency services, and administer Narcan. Twenty-two of those participants would later respond to thirty-five overdoses, potentially saving dozens of lives.

A naloxone kit

Via Wikimedia

To learn what else could be done to treat opioid addiction in the U.S., I spoke with Lisa Parker, the director of the Center for Bioethics & Health Law at the University of Pittsburgh. When I set up that phone call, I didn’t mention Stevens’s article by name; I merely said that I was writing an op-ed on genetic engineering and the opioid epidemic. But my omission didn’t matter — when I got on the phone with Parker, she immediately said, “I assume you’re referring to this article in The Conversation.”

Parker studies informed consent, gene editing technologies, and opioid overdose risk factors. “What I’m working on is more social interventions,” she said. “My own view is that, for most health-related issues, intervening in social factors is often a better approach, or the first approach, to attempt prior to intervening in the genome.”

As a research program, Parker agrees that Stevens’s proposal is interesting, but argues that prior to therapies involving the genome, we should intervene on a social level.

“I think it is an example of a tendency that we have to look to individuals, and to individual level risks and individual level solutions, rather than looking to the messier, more-complicated social level.”

When I asked Parker what, specifically, could be done to treat opioid addictions on a societal level, she pointed to numerous changes; more follow-ups with patients, altered prescription practices to ensure that people with either pain or substance use disorders get treated for their condition, and wider access and training for Narcan.

“We have a lot of things that we know work to reduce risk of death from overdose, reduce overdoses, and reduce opioid addiction,” said Parker. “We just aren’t adequately doing them.”

These proposals deal with opioid addiction at a community level and will demand radical changes to how we, as a society, think about health. But they can be implemented today.

We have only been mucking about in the genome for a few years. We have already made mistakes. We will surely make more. Let's avoid making another.

Nicholas McCarty studies
Science Journalism
at
New York University
.

Yeast could soon make psilocybin cheaper than their magic mushroom cousins can

Sarah Laframboise — Tue, 01 Sep 2020 23:59:35 EST

Magic mushrooms have historically been associated with counter-culture. Their legal status is subject to debate and often dependent on what country or state you live in. In recent years, many studies have highlighted the potential benefits of the drug for the treatment of obsessive-compulsive disorder and migraine, in particular the active component of magic mushrooms, psilocybin.

Psilocybin itself is actually not psychoactive. Once psilocybin is ingested, it is converted into psilocin, which causes the hallucinations. Alternative methods of psilocybin ingestion that avoid the digestive tract cause no hallucinations at all. Psilocin is particularly interesting because it is structurally similar to serotonin, an important neurotransmitter in the brain, and can bind many of the same receptors. When psilocin binds these receptors it causes many of the hallucinogenic effects of mushroom ingestion.

But isolating psilocybin from mushrooms is expensive and there is high variability in the final product's psilocybin concentrations. The most common magic mushroom contains 10-12 mg of psilocybin per gram of dried mushroom, and its effective oral dose is 6 to 20 mg. Variability among magic mushroom species in the quantity of psilocybin makes it difficult to implement effective moderation of doses for clinical treatments. This is currently a severe limiting factor for the implementation of treatments on a large scale.

Psilocybe cubensis, a psilocybin-containing mushroom, could be replaced by faster-growing organisms

Alan Rockefeller via Mushroom Observer

It is because of this that research groups and biotechnology companies have been exploring alternative methods of production of psilocybin. Recently, COMPASS Pathway developed and patented a new method of isolating the compound through chemical synthesis, essentially creating psilocybin without the need of any mushrooms. This method can create pure psilocybin, but it uses a chemical called 4-hydroxyindole as a starting substrate. 4-hydroxyindole currently costs $224 USD per gram, making it a substantial financial barrier to running this process on larger scales.

It may be more efficient to bioengineer psilocybin in other, faster growing organisms. This type of process is already used for the production of drugs that we use every day, like insulin. Attempts to produce psilocybin have primarily been made in Escherichia coli. Through a series of genetic modifications, researchers at Miami University in Ohio were able to genetically modify E. coli to produce psilocybin at a yield of 1.16g/L.

However, these experiments are still limited by the cost of what you have to feed the E. coli in order to produce psilocybin — the same expensive chemical as the patented COMPASS isolation method, 4-hydroxyindole, had to be used as a starter to feed the E. coli. This makes the use of this method just as infeasible as chemical synthesis.

Spores from the Psilocybe stuntzii mushroom species seen under a microscope

A. Cortés-Pérez via Mushroom Observer

Now, researchers at the Technical University of Denmark have found a new, better vehicle to make psilocybin: baker’s yeast, Saccharomyces cerevisiae. Unlike E. coli, yeast are able to express a key enzyme from the natural magic mushroom production pathway of psilocybin. This means that by using yeast, this group of Danish researchers has eliminated the need for the expensive chemical that other bioengineering methods relied on.

In their experiment, the yeast group’s final production yield was about 627 mg/L of psilocybin and 580 mg/L of psilocin. Although this was less than the group using E. coli, it was also cheaper. There is, however, another limitation of this method of production; they lost almost half of their product to psilocin. As mentioned before, psilocybin converts into psilocin in the body. It is possible the experimental conditions that this group is working with were too similar to conditions in the human gut. Even when the group tried to control the pH of the experiment, they still produced the same high levels of psilocin.

One of the most remarkable features...is the ability to create molecules that are normally impossible to chemically synthesize in a lab environment, or even those that are new to nature

It will be important for the group to explore this balance in the production of both psilocybin and psilocin, and use it in a way that they can capitalize on. In terms of its use for drug purposes, psilocin can also be ingested directly and have the same effects as psilocybin. This is because it is eventually converted to psilocin by the gut. Psilocin actually has a higher binding efficiency to serotonin receptors which could make it a more viable candidate for therapies. However, going forward, the group will have to weigh out the challenges and benefits of this ratio of psilocybin and psilocin production in yeast.

To date, there are 49 clinical trials investigating the use of psilocybin for various psychiatric disorders, cancers, and diseases. The most common use of psilocybin is to treat Major Depressive Disorder (MDD), which, according to the National Institute of Mental Health, affected over 17 million people in the US in 2017.

One of the most remarkable features of this type of synthetic biology approach is the ability to create molecules that are normally impossible to chemically synthesize in a lab environment, or even those that are new to nature. These molecules could also hold clinical significance and be relevant to the treatment of many of the same diseases. By manipulating the pathway used previously to create psilocybin and psilocin, the group was able to create high yields of intermediates – molecular steps on the way to the final product – in the pathway.

Out of the many different intermediates, of particular interest is the production of psychedelic components of different mushroom species, such as the chemical aeruginascin from the mushroom Inocybe aeruginascens, as well as a variety of tryptamine derivatives which are also psychoactive. Many chemicals in this family have been used in the treatment of depression, as anti-microbials, sedatives, and more. The yeast group was also able to produce N-acetyl-4-hydroxytryptamine, a novel molecule that is structurally similar to the neurotransmitter N-acetylserotonin (normelatonin). Although they have not yet investigated it, there is potential that this novel chemical could have useful properties for clinical treatments.

Sarah Laframboise studies
Biochemistry
at
University of Ottawa
.

New research uses CRISPR gene editing to grow new neurons in diseased brains

Sahana Sitaraman — Tue, 18 Aug 2020 22:02:51 EST

The brain is a marvel of evolution, but in some animals, it has a few limitations. Unfortunately for humans, our brains are mostly incapable of generating new neurons. This inability becomes particularly problematic when the brain is affected by neurodegenerative disorders.

To treat neurodegenerative diseases, scientists can create new neurons from stem cells. In no time, new neurons can replace lost ones, and take over their job. A glaring drawback of this method is that these cells are formed outside the body and need to be transplanted into the brain. To date, this is the preferred method to repopulate lost neurons, but it’s far from ideal.

Transferring lab grown neurons into animal brains reduces the cells' viability — their chances of integrating well into the tissue — and the efficiency with which they can restore function. So scientists at Shanghai Research Center for Brain Science and Brain-Inspired Intelligence fashioned a method to regenerate neurons inside the brain. The method is similar to how one would revive a dying plant: by nurturing it with the right conditions for it to grow new leaves.

Building up on a previous study, Haibo Zhou, a postdoctoral researcher in Hui Yang’s lab, and colleagues, set up a method to convert non neuronal brain cells called “glia” into neurons. They did this by turning down a gene called PTBP1 in glia of different parts of the mouse brain, using the gene-editing tool CRISPR. Depending on which brain region was targeted, the glia gave rise to different kinds of neurons.

The method partially restored the normal motor behavior of the anima

Photo by Robina Weermeijer on Unsplash

Reducing PTBP1 levels presumably reverted glia to unspecified stem cells, which adopted varied neuronal identities based on which glia were targeted and the environmental signals they received. This was evident from the team’s successful attempts at restoring two different types of neurons and alleviating the symptoms associated with the loss of each.

The method is similar to how one would revive a dying plant: by nurturing it with the right conditions for it to grow new leaves

Parkinson’s disease occurs due to loss of dopamine-producing neurons and manifests as tremors, stiffness, and loss of balance. To test their method in rejuvenating this group of neurons, the team first got rid of them using a toxic compound in mice. The authors then converted glia into dopamine-producing neurons, and the new cells showed the same activity as their original counterparts.

This rescue was not limited to just the neuron population. It also partially restored the normal motor behavior of the animal. This is a huge step forward from drug induced alleviation of symptoms because it puts forth a more permanent solution.

The team also tackled retinal diseases caused by death of retinal ganglion cells, or RGCs, which leads to permanent blindness. Turning down PTBP1 in glia of the retina transformed them into RGCs. Astoundingly, these renewed neurons not only responded to light independently, but also sent their projections to the visual cortex correctly, restoring circuit function. This led to a partial recovery of eyesight in the treated mice.

Neurons in different regions of the brain vary a lot in their shapes, activity, function, and connectivity

Image by MethoxyRoxy, reproduced under CC BY-SA 2.5

The outcomes from this study are surprising in many ways. Neurons in different regions of the brain vary a lot in their shapes, activity, function, and connectivity. Neurons in young animals acquire these characteristics because of the multitude of developmental signals they receive. These cues might or might not be present in the adult brain. How do the reprogrammed neurons pull this off in the absence of such cues?

How do the reprogrammed neurons pull this off in the absence of such cues?

“Maybe the signals still exist in the mice at 8 weeks old. It’ll be very interesting to identify the instructive signals underlying glia-to-neuron conversion in the future”, Yang said in an email. Looking at natural regeneration in animals like zebrafish, where a similar mechanism of glia-to-neuron transformation is observed, could give us hints to what these signals might be.

The high efficiency and flexibility of this technique are appealing. But, given the notoriety CRISPR-based gene editing has garnered in the recent years, the safety of translating the technology into other methods is an open question. How will researchers ensure the system only edits the correct gene? How would one stop the editing once neurons are regenerated?

The authors chose to reduce the levels of PTBP1 by targeting the RNA, rather than DNA. For this they chose Cas13d because it's small, easy to deliver to the cells, yet highly specific and efficient in its action. Compared to conventional tools like Cas9, it's a significant improvement.

According to Yang, CRISPR RNA editing is safer than DNA editing since expression of Cas13d is turned down once neuronal conversion is complete. Unlike DNA editing, which alters the genetic makeup of an animal permanently, RNA editing affects the expression levels of specific genes, temporarily.

“We are now working on monkey model using this approach," Yang says. "Hopefully, we could apply this approach in humans in three to four years.”

If meticulously designed experiments provide evidence for safe therapeutic use in humans, it might open doors for using this method to generate various other cells of the body as well. Treatment options for disease like diabetes and sickle cell anemia could be well within reach. But that is a story for another time.

Sahana Sitaraman studies
Neuroscience and Behavior
at
National Centre for Biological Sciences, India
.

Scientists put visions of letters in blind people's brains

Meredith Schmehl — Fri, 31 Jul 2020 10:14:39 EST

Surrounded by the buzz of medical equipment, a blind man raises his hand to a touch screen. Pop! A vision of the letter "N," placed in his brain, flashes through his mind. He traces his finger across the screen, replicating the vision with perfect form.

It sounds like science fiction. But in a recent study at Baylor College of Medicine, researchers made the blind see. A team led by neurosurgeon Daniel Yoshor "drew" letters of the alphabet on blind people's brains by giving them specific patterns of electrical zaps. These patterns caused the participants to "see" the letters in their mind's eye. The results could improve medical devices for people who have experienced other types of sensory or motor loss.

A participant in the study is shown drawing a letter that was stimulated in his brain

Screenshot via Daniel Yoshor on YouTube

The researchers accomplished this by giving patterns of small electrical stimulations to the visual cortex. The visual cortex is one of the hubs in the brain that responds to what we see. This region contains a spatial map of our field of view, meaning particular sets of cells respond to visual information coming from particular locations in our line of sight. Turn on a light on the left side of your field of view, and one set of cells will respond by shooting off an electrical signal. Turn on a light on the right side, and a different set of cells will respond.

Yoshor's team took advantage of this map in a clever way. Because the cells in the visual cortex respond to patterns of light in space, the scientists could reverse the process — give a tiny electrical zap to a particular group of cells and cause someone to perceive a spot of light at a specific location. They performed brain surgery on blind adults to implant a small electrical device with several points of contact to the visual cortex. Each point could be activated individually or in combination with others to stimulate the brain in precise patterns. By carefully controlling the combinations of activated areas, the researchers could cause someone to "see" a specific shape, such as a letter of the alphabet.

But there was one problem. Other researchers had tried similar experiments, but they hadn't been successful in creating a detailed image in someone's mind. These previous experiments stimulated discrete patches of cells, like a shape drawn with dotted lines. But instead of seeing a continuous shape, people just saw several blobs of light. In order to create a detailed mental image, Yoshor's team had to improve on existing techniques for stimulating the brain.

Participants described the image "like a line being drawn" in their mind's eye

They realized that they could borrow a technique that's common in cochlear implants and auditory therapy to improve the way they stimulated the brain's visual center. This new technique allowed them to replace their dotted sketch with a single continuous line to "draw" shapes such as letters on the brain. They reasoned that the brain might be able to make more sense of a stimulation pattern that is drawn continuously, since the pattern would more closely match the appearance of most letters in daily life.

To achieve this continuous drawing in a person's brain, the researchers gradually changed the level of activation of each point of contact. Instead of turning each point just on or off, they raised or lowered the dial on each one to create a wide range of activity in the corresponding brain cells. When they gradually increased the activation of one point of contact while gradually decreasing the activation of another, they caused people to "see" a continuous line of light corresponding to the space between the two active points of contact in the brain. Participants described the image "like a line being drawn" in their mind's eye.

Now that the researchers had improved their technique for stimulating the brain, they were able to test whether complex activation patterns could cause people to perceive shapes like letters. They stimulated groups of several points in the brain, adjusting the dial at each point to draw lines in spatial arrangements that matched the form of real letters. They asked people to replicate the shapes they saw on a touch screen, and also to respond aloud to indicate which letters they perceived.

The results from this study may help people better control their prosthetics

Photo by ThisisEngineering RAEng on Unsplash

The participants were consistently able to reproduce and name letters that matched the stimulation pattern drawn on their brains. When asked to name letters in rapid succession, they accurately named nearly 90 percent at a rate of 85 shapes per minute. In other words, the new stimulation technique successfully generated clearly shaped letters in people's minds.

But the technique isn't perfect. The activation patterns aren't precise enough to allow people to tell the difference between similar shapes, like the letters "C" and "O". And the participants in this experiment became blind as adults, meaning they already knew what the letters looked like. It's likely that it would have been more difficult to replicate the experiment's results in someone who had been born blind and had never seen letters or other shapes.

Nevertheless, this experiment is a promising step forward in scientists' ongoing effort to create a device that could restore vision to those who have lost it. With further improvements in the technology, scientists might be able to stimulate the brain with a finer resolution and generate more detailed mental images. The results could have implications for other types of sensory function, too. Finer stimulation methods could improve pitch perception in users of cochlear implants, where a version of this technique has already been tried, and could help restore a detailed sense of touch in cases of nerve damage.

Besides sensory systems, the results might also improve medical devices that help with motor control. For example, prosthetic limbs rely on technology that reads activity in the motor regions of the brain. Scientists could use their new knowledge about stimulating the brain to read and interpret the brain activity that controls a prosthetic, allowing people to control their new limbs in more precise ways.

It's clear that the results uncovered by Yoshor's team are a crucial development in the ongoing quest to create a visual aid for the blind. In the future, the technology might allow blind people to see the complex objects that surround them in real time.

Meredith Schmehl studies
Neurobiology
at
Duke University
.

Paralyzed man has sense of touch restored by brain-machine interface

Hayden Kee — Wed, 29 Jul 2020 00:04:41 EST

Ten years ago, while on vacation in North Carolina, Ian Burkhart broke his neck in a diving accident. The diagnosis was as life-changing as the injury: a complete spinal cord injury in the cervical spine. An injury of this nature often results in paraplegia. Burkhart might regain some movement and sensation in his shoulders and upper arm, doctors said. But the chances of ever moving his hands again were slim.

Burkhart made headlines in 2016 when Nature declared him the first paralyzed person to be “reanimated.” Researchers at Battelle Memorial Institute and the Wexner Medical Center at Ohio State University were able to use a brain-machine interface (BMI) to partially restore Burkhart's ability to move his own hand. A BMI implant in Burkhart’s motor cortex scans for motor intentions associated with hand movements. It relays this information to a computer, which sends a signal to an electrical stimulation sleeve on his arm that evokes muscular contractions operating the hand. The setup effectively bypasses Burkhart’s severed spinal cord, restoring the connection between his brain and the muscles in his forearm that control his hand.

In a recent article published in Cell, the team at Battelle and Wexner announced that they have now partially restored Burkhart’s sense of touch. The breakthrough depended on crucial theoretical insight and a bit of creative problem solving.

A BMI implant in Burkhart’s motor cortex scans for motor intentions associated with hand movements

Unsplash

Restoring Burkhart’s ability to control his own hand was a landmark in the history of neuroscience. But it was only one step towards restoring anything like full functionality. Burkhart's range of motion remains limited and imprecise. Part of the challenge was that though the original iteration partially restored Burkhart’s motor ability (the brain-to-body signal), it did not restore his somatosensory system (the body-to-brain signal).

Burkhart was learning to reach and grasp, but he could not touch or feel. And without the hand-to-brain sensory feedback, motor ability is remarkably hard to control. We rely on somatosensory feedback to regulate and fine-tune motor activity. When you grab an object, for example, the brain monitors somatosensory feedback from the body to adjust and correct the outgoing motor signal: a gentle grip for holding an egg, a firmer one for holding a dumbbell. Without this sensory feedback, it is very difficult to optimize grip intensity, resulting in crushed eggs and dropped dumbbells. Even with partially restored motor ability in his hand, Burkhart struggled to control grip intensity. And the absence of sensory feedback left him feeling alienated from his own hand, as though he were moving someone else’s body rather than his own.

A great deal has changed in neuroscience since Burkhart's injury, in part owing to tremendous advances in BMI technology. BMI devices work by scanning brain activity through devices installed inside the brain, on the surface of the brain, or on the outside of the skull. Computer algorithms then interpret the information from the brain and translate it into a decipherable output. A BMI’s primary clinical application is to replace or restore functionality to patients suffering from a variety of neuromuscular disorders. BMI allows immobilized patients to move a cursor on a computer desktop just by thinking about where they want the cursor to go. Others have been able to move robotic limbs. And thought-to-text BMI translates thoughts directly into digital text.

Scientists are increasingly recognizing that many clinically “complete” spinal cord injuries turn out to not be quite so complete as was once thought. In many cases, a residual connection between body and brain remains. This means that even though Burkhart is not consciously aware of any somatosensory feedback coming from his extremities, his brain might still be receiving some information. “Just because [Burkhart] can’t feel it doesn’t mean there isn’t any signal,” says Sam Colachis, one of the researchers on the Wexner-Battelle team working with Burkhart.

Many clinically “complete” spinal cord injuries turn out to not be quite so complete as was once thought

“There’s this notion of a complete injury. But it’s unlikely that the spinal cord is going to be completely severed. You still get those residual fibers," says Colachis. "We were surprised when we actually realized that there was some activity we could record. That was a cool finding, and we thought, 'That makes sense. It’s sub-perceptual, and maybe there’s a bit of activity there. How do we translate that to something that could actually help [Burkhart]?'”

The researchers were able to train an algorithm to discern the sensory feedback signal in Burkhart's brain amid the noise of everything else going on in the motor cortex. Because of the spinal cord injury, this signal was weak, and Burkhart had no conscious awareness of it. “We came up with the scheme of taking the data we record when he touches something and feeding it back into a haptic motor and putting it on a region up in the bicep where he can feel,” Colachis says. A haptic motor is a simple vibratory device, like your phone uses on the vibrate setting. The device buzzes on Burkhart’s arm when his hand touches something. “We’re taking subperceptual information and boosting it to something that’s perceptual, that he can feel.”

This perceptual somatosensory feedback allows Burkhart to modulate his grip much more accurately for different task demands, even when blindfolded. This is the first BMI to restore movement and touch simultaneously.

The steps Burkhart has taken with the help of a BMI and the Wexner and Battelle researchers in the past decade are remarkable. But there is still a long way to go before we have functional BMI technologies that people like Burkhart can use for everyday purposes. Right now, the BMI setup requires a desktop computer to run its algorithm, so Burkhart can only use it in the lab. Further, it requires a recalibration session every time Burkhart plugs into the system again. From an applied perspective, the next step is for researchers to reduce calibration time and develop more portable technologies that users can take home.

The 2010s were an astonishing decade for BMI. What do the 2020s have in store? And when will we start seeing BMI technologies meant not only to restore lost function for patients with neuromuscular conditions, but that enhance function and cognition for the general population? Colachis, for one, is not in a rush to get his own BMI implanted. “I don’t think people are going to willingly want to put things in their brains for at least a while,” he says. “If they can get to a non-invasive approach, then yes, totally, but I think we’re a ways away. EEG technology is nowhere near where it needs to be to have something that people like you and I are going to want to use in our day-to-day. But there’s a lot of traction that might speed it up over the next decade.”

Hayden Kee studies
Cognitive Science
at
Fordham University
.

What makes something smell good or bad?

Weihong Lin — Tue, 16 Jun 2020 12:16:00 EST

Pee-yew! Your old socks smell soooo bad.

But why?

Maybe you’ve learned to dislike the smell. Maybe your socks are full of gross bacteria. Or maybe, it’s both. Our team studies the brain and sense of smell — it’s one of our favorite topics. But first, how do you smell?

What is that smell?

The air is filled with many small odor molecules which are released from “smelly” things like perfume or food. Your nose has the astonishing ability to smell thousands of different scents because in your nose are millions of smell receptors — cells that can recognize odor molecules. When you sniff the air, these special cells are alerted.

These receptor cells then send a signal to your brain. Your brain recognizes many scents when different types of odors enter your nose. The smell of baking cookies, for instance, is composed of many odor molecules. Your brain can piece together all this information and let you know there are cookies baking in the oven.

Smells that make memories

Your brain is very good at memorizing good and bad experiences and associating particular smells with them. Scientists call these “olfaction-associated memories.”

One example of this is when you smell a favorite meal. It might remind you of someone who makes it for you, which triggers your brain to release chemicals that make you feel good and comforted.

Can you smell it from here?

Alexandra Gorn via Unsplash

Of course, smell can also be associated with unpleasant experiences. You have probably eaten some food that went bad, and you might find that you hate that food now. This is your brain associating getting sick with a certain smell, which stops you from eating something that could be bad for you. Memories linked to smells can form because of good and bad feelings.

Smells to warn you

But what about things that you know smell good or bad even if you’ve never experienced them? Scientists have found that although a lot of the smells people like come from past experiences, instincts play a big role.

Wet dogs are smelly dogs

Wikimedia

Scent tells you a lot about your environment, and your instincts help to decide what is safe or dangerous. For example, blood has been shown to repel humans and many prey species, like deer, but attract predators, like wolves. This guides people away from predators that might want to eat us, but lets the predator get its meal.

Smell can warn you when something could make you sick. When eggs rot, bacteria multiply like crazy inside them, breaking down proteins that release a toxic chemical called hydrogen sulfide. This produces a stench that makes you want to stay far away, stopping you from eating the egg and becoming ill.

As for your socks… if they smell bad now, don’t wait. Wash them with soap and water! The bacteria growing on your socks will be killed, which will stop that nasty smell.

Rakaia Kenney studies
Biology
at
University of Maryland, Baltimore County
.

Kayla Lemons studies
Neuroscience
at
University of Maryland, Baltimore County
.

Rare spindle-shaped neurons from deep inside the brain recorded for the first time

Burcin Ikiz — Tue, 02 Jun 2020 23:34:40 EST

About five years ago, researchers from the Allen Institute for Brain Science in Seattle received a special donation: a piece of a live, rare brain tissue. It came from a very deep part of the brain neuroscientists usually can't access. The donated tissue contained a rare and mysterious type of brain cells called von Economo neurons (VENs) that are thought to be linked to social intelligence and several neurological diseases.

The tissue was a byproduct of a surgery to remove a brain tumor from a patient in her 60s. The location of the tissue turned out to be in one of the deepest layers of the frontoinsular cortex, which is one of the few places where these rare neurons are found in the human brain. “This was one of the extremely rare chances that we received this tissue from a donor that had a tumor being removed from quite a deep [brain] structure,” said Rebecca Hodge, who is the co-first author of the study, published in Nature Communications on March 3rd. Hodge and her colleagues became the first scientists to record electrical spikes from these neurons. Further studies they did on these cells gave them clues about the VENs’ identity and function in the human brain.

Constantin von Economo

Wikimedia

VENs are large, spindle-shaped neurons. They were first identified by the Ukrainian scientist Vladimir Betz more than a century ago. They were later named after the anatomist Constantin von Economo, who described their shape and distribution through the human cortex. Only humans and especially social animals with large brains, such as great apes, whales, dolphins, and elephants have VENs. It is hypothesized that the cells evolved independently in these animals. Since common lab animals with smaller brains, like mice and rats, don't have VENs, it is difficult to study them in a lab environment.

Past studies linked VENs to social engagement and cognitive health. An analysis of "SuperAger" brains from older people who don’t suffer from the memory loss of "normal" aging showed a greater number of VENs compared to their cognitively average-for-their-age peers. Loss of VENs, on the other hand, has been observed in brains of patients suffering from a neurodegenerative disease called behavioral variant frontotemporal dementia, as well as from several other neurological disorders, including schizophrenia, autism, and possibly Alzheimer’s disease. None of these studies, however, offered clues about VENs’ exact function or unique properties. Unraveling the mystery of these neurons can help find therapies for these disorders.

The team at the Allen Institute tackled this mystery with two parallel studies: The first aimed at understanding VENs’ electrical properties, while the second one focused on their genetic identity. They didn't go exactly as planned.

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Our scientists are the first to get electrical recordings from a rare human brain cell, called the #vonEconomo neuron, in live brain tissue. These neurons could be involved in brain diseases and “super-aging.” #brainscience #ephys #neuroscience #ilovescience

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For the first study, neuroscientists Brian Kalmbach and Jonathan Ting, from the Allen Institute decided to capture VENs’ electrical activity using method called patch clamp. Patch clamp is a very delicate technique where a scientist carefully punctures a cell with a very thin piece of glass to record its electrical activity.

The scientists were experienced with this technique, but the VENs they received were much more fragile than what they were used to. Even a gentle touch would be enough to make them explode. In the end, the scientists were able to record from only three neurons. The neurons showed unique electrical properties compared to other neuron types. Though the sample size was small, it was still the first ever recording of VENs, and the data was promising.

Spindle neurons

Wikimedia

The second study provided more answers. Hodge and colleagues wanted to genetically identify VENs using a new genome sequencing technique they were trying to develop at the time called single nucleus RNA-sequencing. “We had the goal of turning that technique into kind of a big data pipeline,” Hodge said. "but we didn't have any methods for doing that in humans yet."

The question was: how do VENs genetically differ from the other neurons in the same region?

One of the challenges with this study was how sparse VENs are in the human brain. They only account for a very small fraction, about 1.25 percent, of all neurons in the frontoinsular cortex, and about 500,000 neurons brain-wide. The group was only able to capture data from a handful of them. “So that's sort of a big challenge of working in human brain where you have you don't have nice transgenic tools like you have in mouse,” Hodge said. "You just have to see what you can get using the tools that you have available."

Even a gentle touch would be enough to make them explode

From the gene sequencing analysis the group was able to identify new marker genes for VENs that could be used to differentiate them from other neurons besides looking at their unique shape (which isn't always easy due to their rarity). But, the data set they got from the study was also too small to interpret the results accurately.

To tackle this problem, they compared these human cells to cell types that were already defined in mouse tissue to see if any of them matched using a computational mapping technique. Jeremy Miller, the other co-first author of the paper and the bioinformatician that performed the analysis, called the technique “a computational advance” that allowed them to predict what kind of class of cells VENs belonged to. The finding was surprising. Given the unique shape of VENs, the scientists expected them not to match with any other cell types, but they did. VENs’ genetic signatures looked very similar to those of neurons that send their axons from the cortex to deeper regions of the brain called extratelencephalic-projecting (ET) excitatory neurons.

Miller thought this finding could have interesting implications for neurodegenerative diseases, such as the behavioral variant frontotemporal dementia, where VENs are thought to be selectively vulnerable. Future studies might look to see whether it is all of the ET-type neurons that are lost in disease or whether it's only VENs. This information would help with deciding which cell types to target for therapies. The group is currently repeating the study using new sequencing methods that allow them to get tens of thousands to millions of cells in order to better understand the genetic properties of these neurons.

Burcin Ikiz studies
Neuroscience
.