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Neuroscience

Neuroscience Research Fellow Discovers the Power of Perseverance – St. Lawrence University Saints

Nadiana Acevedo 24 isnt afraid of a challenge. When she set out to investigate the effects of an anti-cancer drug this summer, she discovered that sometimes the best learning experiences can come from trial and error.

As part of the Collegiate Science and Technology Entry Program (CSTEP), Nadiana spent eight weeks conducting research alongside Professor of Biology and Psychology Ana Estevez. The scholar program is designed to increase the number of historically underrepresented and economically disadvantaged students in mathematics, science, technology, and health-related fields.

Nadiana shared what fueled her curiosity for research and how she defines success.

(Note: Responses have been edited for length.)

Major: Neuroscience

Hometown: Buffalo, New York

Project Title: "Observing Cell Viability of HT-22 Hippocampal Cells When Exposed to Anti-Cancer Dye MKT-077"

The focus of my research is looking at an anti-cancer dye, MKT-077. This dye is known to be selective to cancer cells meaning it only kills cancer cells. I am testing the drug on a mouse hippocampal neuronal cell line called HT-22 (brain cells) to observe the drug's effect on the cells' viability.

Cancer research is challenging and exciting because it is full of trial and error. I was interested in looking at how this drug would affect neuronal cells because there is a lack of data specific to neurons. I was intrigued that MKT-077 is selective to cancer cells because other drugs kill both healthy and cancerous cells.

The research process was difficult at times because my mentor and I did not know how the MKT-077 would affect the HT-22 cells. The data seemed off in the beginning. We weren't sure if there was an issue with fluorescence when the microplate reader was collecting data. We had to run a test to determine if the MKT-077 had its own fluorescence that would interfere with the dye we used to measure viability. The data showed no conflict between the MKT-077 and the CYQUANT dye we used to measure cell viability.

I did not get discouraged by the research outcomes and was able to complete my summer research and presented my findings.

Dr. Ana Estevez is an amazing advisor and mentor. I built a connection with her over the summer and learned many skills. She has helped me become a well-rounded researcher.

It is possible to succeed and gain knowledge regardless of the data outcome. There is always something to gain from every experience and there is always something new to discover.

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Neuroscience Research Fellow Discovers the Power of Perseverance - St. Lawrence University Saints

Neuroscience

COVID-19 Linked to Excessive Destruction of Connections Between Nerve Cells – Neuroscience News

Summary: COVID-19 infection causes microglia to excessively engulf synaptic structures and the upregulation of factors involved in phagocytosis.

Source: Karolinska Institute

Researchers at Karolinska Institutet have in a new study used cellular reprogramming to create human three-dimensional brain models and infected these models with SARS-CoV-2.

In infected models, the brain immune cells excessively eliminated synapses and acquired a gene expression pattern mimicking what has been observed in neurodegenerative disorders.

The findings could help to identify new treatments against persistent cognitive symptoms after a COVID-19 infection.

Multiple studies have reported persistent cognitive symptoms after a COVID-19 infection but the underlying mechanisms for this remains unknown.

The researchers behind the study, published as an Immediate Communication in the journalMolecular Psychiatry, have from human induced pluripotent stem (iPS) cells created three-dimensional models of the brain in a dishso-called brain organoids.

The model differs from previous organoid models as the researchers also included the brainimmune cellsmicrogliain the model.

In the infected models, microglia excessively engulfed synaptic structures and displayed upregulation of factors involved in phagocytosis. The developed model and the findings in the study could help to guide future efforts to target cognitive symptoms in the aftermath of COVID-19 and other neuroinvasive viral infections.

Cognitive deficits after the infection

Interestingly, our results to a large extent mimic what has recently been observed in mouse models infected with other neuroinvasive RNA viruses such as the West Nile virus. These viruses are also linked to residual cognitive deficits after the infection, and a persisting activation of microglia leading to an excessive engulfment of synapses, which has been suggested to drive these symptoms.

Multiple studies have now also reported remaining cognitive symptoms after a COVID-19 infection, as well as an increased risk of receiving a diagnosis of a disorder characterized by cognitive symptoms, says co-first author of the study Samudyata, postdoctoral fellow in Sellgren lab at the Department of Physiology and Pharmacology at Karolinska Institutet.

Connections to Parkinsons and Alzheimers disease

Microglia are the resident immune cells of the brain but also carries out important regulatory functions of the neuronal circuitries in the developing and adultbrain. One of these crucial functions is to engulf unwanted synapses, a process that is believed to improve and maintain cognitive functions.

However, excessive engulfment of synapses has been linked to both neurodevelopmental disorders, such as schizophrenia, as well as to neurodegenerative disorders including Alzheimers disease.

By sequencing genes insingle cells, the authors could also study how different cell types in the model responded to the virus.

Microglia displayed a distinct gene signature largely characterized by an upregulation of interferon-responsive genes, and included pathways previously linked to neurodegenerative disorders such as Parkinsons and Alzheimers disease.

This signature was also observed at a later time-point when the virus load was minimal, says co-author of the study Susmita Malwade, doctoral student in Sellgren lab at the Department of Physiology and Pharmacology at Karolinska Institutet.

The researchers will now study how different pharmacological approaches can reverse the observed changes in the infected models.

Author: Press OfficeSource: Karolinska InstituteContact: Press Office Karolinska InstituteImage: The image is in the public domain

Original Research: Open access.SARS-CoV-2 promotes microglial synapse elimination in human brain organoids by Samudyata et al. Molecular Psychiatry

Abstract

SARS-CoV-2 promotes microglial synapse elimination in human brain organoids

Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown.

In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini.

Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure.

We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synapse engulfment.

To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection.

Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19.

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COVID-19 Linked to Excessive Destruction of Connections Between Nerve Cells - Neuroscience News

Neuroscience

Patients With Clinical Depression Stopped Seeking Treatment During the COVID Waves – Neuroscience News

Summary: During the COVID-19 pandemic, the number of patients admitted to hospitals for clinical depression care dropped significantly. However, the number of people seeking outpatient care for depression increased.

Source: European College of Neuropsychopharmacology

In the first study of its kind, German researchers have shown that the COVID pandemic saw a huge drop in the number of patients being admitted to hospital for clinical depression.

Independently of these national statistics, the researchers found that the number of outpatients they dealt with increased over the same period in their department. As inpatient treatment offers more intensive levels of care, this implies that many patients did not receive care appropriate to their condition.

It is not yet known if this shift in treatment is also seen in other countries.

The researchers, from the University Hospital in Frankfurt, looked at German national databases. They found that during the first COVID wave new hospitalisations for first time clinical depression dropped by 57.5%, from 13457 in January 2020 down to 5723 in April 2020. In the same period, the number of patients being hospitalised for recurrent depression dropped by 56.3%, from 22188 down to 9698.

Lead researcher, Dr Mareike Aichholzer said We also saw a decrease in inpatient treatment of recurrent depression in our own hospital in Frankfurt. In addition to the stricter admission rules, this rather seemed to be due to a drop in demand from the patients themselves.

In contrast, the number of new outpatients being treated for clinical depression at the University Hospital in Frankfurt remained stable and the number of patients with recurrent depression showed a significant increase between 2019 and 2021.

However, Dr Aichholzer notesThis is data from a single center, so we need to wait to see what other centers say.

She continued, The results indicate that patients who have repeatedly suffered from depression during their lives were less likely to be admitted to hospital during the pandemic. However, these patients are often so severely affected by depression that outpatient treatment alone is not sufficient to bring about a satisfactory improvement in symptoms.

The result is that patients lose their quality of life in the long term. The actual reason for this observation is unclear. Although our study was not designed to identify the reasons for those changes, we however suspect that clinically depressed patients in particular withdraw more often from society/their friends/their family and that this behavior was more common during the times of the lock-down and the strict hygiene guidelines.

Moreover, we suspect, that clinically depressed patients avoided the hospital, because they were afraid of being infected with COVID-19 on the ward.

The data from our hospital in Frankfurt indicates that patients with clinical depression seem to have withdrawn themselves, rather than seeking adequate mental health help. To be prepared for the winter with potentially increasing COVID numbers, we have to provide easily accessible help and raise awareness for this topic.

Clinical depression, also known as Major Depressive Disorder (MDD) is a serious mental illness, affecting more than 6% of Europeans at any one time. The majority of sufferers can be treated with pharmaceuticals and/or counseling, although a minority of patients dont respond to treatment.

Commenting, Professor Brenda Penninx, Professor of psychiatric epidemiology at the Department of Psychiatry, University Medical Centre, Amsterdam, said:

The figures found by the Frankfurt team confirm a familiar pattern. We have recently found that quite a few countries are beginning to report a decreased pattern of mental health care use during the first pandemic years.

It is extremely important that in the next few years we follow whether postponed treatments may result in increased mental health problems.

This also illustrates that mental health care deserves adequate clinical attention during future pandemics.

This is an independent comment, Professor Penninx was not involved in this research.

Author: Tom ParkhillSource: European College of NeuropsychopharmacologyContact: Tom Parkhill European College of NeuropsychopharmacologyImage: The image is in the public domain

Original Research: The findings will be presented at the 35thEuropean College of Neuropsychopharmacology

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Patients With Clinical Depression Stopped Seeking Treatment During the COVID Waves - Neuroscience News

Neuroscience

Can Obesity and Stress Influence Appetite? – Neuroscience News

Summary: Stress impacts the brains response to food, researchers report. Additionally, both lean and obese people react to food cues in brain areas associated with reward and cognitive control.

Source: Johns Hopkins Medicine

In a series of experiments using functional magnetic resonance imaging (fMRI) to measure brain activity across networks in the brain, Johns Hopkins Medicine researchers looked at how stress might increase appetite in obese and lean adults.

The researchers found that stress impacts the brains responses to food, and that both lean and obese adults react to food cues in areas of the brain associated with reward and cognitive control.

The findings of the studywere published Sept. 28 inPLOS ONE.

For the study, the researchers analyzed data from 29 adults (16 women and 13 men), 17 of whom had obesity and 12 of whom were lean. Participants completed two fMRI scans, one following a combined social and physiological stress test.

Participants were given afood word reactivity testduring both scans. Thistestinvolved looking at how peoples brains reacted to food words, such as menu items on a chalkboard.

To maximize the appetitive response in the brain, the researchers asked participants to imagine how each food looked, smelled and tasted, and how it would feel to eat it at that moment.

They were also asked how much they wanted each food, and if they felt they should not eat that food, to see how they approached decision-making related to each food.

The experiments showed that obese and lean adults differ somewhat in their brain responses, with obese adults showing less activation of cognitive control regions to food words, especially to high-calorie foods, like for example, grilled cheese, says lead researcherSusan Carnell, Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

The study also showed that stress impacts brain responses to food. For example, obese individuals showed greater activation of the orbitofrontal cortex, a brain reward region, after the stress test.

We also found evidence for links between the subjective stress experienced and brain responses in both groups. For example, lean individuals who reported higher stress following the test showed lower activation of the dorsolateral prefrontal cortex, a key brain area for cognitive control, says Carnell.

Author: Marisol MartinezSource: Johns Hopkins MedicineContact: Marisol Martinez Johns Hopkins MedicineImage: The image is in the public domain

Original Research: Open access.Obesity and acute stress modulate appetite and neural responses in food word reactivity task byCarnell et al. PLOS ONE

Abstract

Obesity and acute stress modulate appetite and neural responses in food word reactivity task

Obesity can result from excess intake in response to environmental food cues, and stress can drive greater intake and body weight. We used a novel fMRI task to explore how obesity and stress influenced appetitive responses to relatively minimal food cues (words representing food items, presented similarly to a chalkboard menu).

Twenty-nine adults (16F, 13M), 17 of whom had obesity and 12 of whom were lean, completed two fMRI scans, one following a combined social and physiological stressor and the other following a control task. A food word reactivity task assessed subjective food approach (wanting) as well as food avoidant (restraint) responses, along with neural responses, to words denoting high energy-density (ED) foods, low-ED foods, and non-foods.

A multi-item ad-libitum meal followed each scan. The obese and lean groups demonstrated differences as well as similarities in activation of appetitive and attention/self-regulation systems in response to food vs. non-food, and to high-ED vs. low-ED food words.

Patterns of activation were largely similar across stress and non-stress conditions, with some evidence for differences between conditions within both obese and lean groups. The obese group ate more than the lean group in both conditions.

Our results suggest that neural responses to minimal food cues in stressed and non-stressed states may contribute to excess consumption and adiposity.

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Can Obesity and Stress Influence Appetite? - Neuroscience News

Neuroscience

Reductionism as a Dead End in Neuroscience Captured in an Essay – Walter Bradley Center for Natural and Artificial Intelligence

University of Sussex professor of cognitive and computational neuroscience Anil K. Seth, during a routine dismissal of Ren Descartes (15961650), assures us, It looks like scientists and philosophers might have made consciousness far more mysterious than it needs to be.

More mysterious than it needs to be?

As noted earlier, what makes understanding the human mind necessarily complex is that it is both the entity we are trying to perceive and the tool by which we hope to perceive it. Such a problem is like trying to imagine a five-dimensional box in relation to the real world. Unlike the five-dimensional box, consciousness is part of the life experience of every human being.

How would Dr. Seth unravel the problem? In a classic essay, he reassures us,

Once, biochemists doubted that biological mechanisms could ever explain the property of being alive. Today, although our understanding remains incomplete, this initial sense of mystery has largely dissolved. Biologists have simply gotten on with the business of explaining the various properties of living systems in terms of underlying mechanisms: metabolism, homeostasis, reproduction and so on. An important lesson here is that life is not one thing rather, it has many potentially separable aspects.

Well, wait. We know a great deal more than we did centuries ago about the circumstances that enable a life form to keep itself alive and pass on that state to a further generation. But we are still at a complete loss as to the origin of life.

This is despite hundreds of speculative papers published every year. Eminent chemist James Tour has often remarked on well, expostulated about this problem. Its fascinating. It is especially relevant to the search for life on other planets in our galaxy. But looking for evidence of lifes existence is quite different from explaining lifes origin.

Origin of consciousness is in roughly the same state as origin of life. We have vast amounts of useful information about being conscious but we have no idea how it comes about.

What does Dr. Seth say about consciousness (or selfhood)?

Of the many distinctive experiences within our inner universes, one is very special. This is the experience of being you. Its tempting to take experiences of selfhood for granted, since they always seem to be present, and we usually feel a sense of continuity in our subjective existence (except, of course, when emerging from general anaesthesia). But just as consciousness is not just one thing, conscious selfhood is also best understood as a complex construction generated by the brain.

There is the bodily self, which is the experience of being a body and of having a particular body. There is the perspectival self, which is the experience of perceiving the world from a particular first-person point of view. The volitional self involves experiences of intention and of agency of urges to do this or that, and of being the causes of things that happen. At higher levels, we encounter narrative and social selves. The narrative self is where the I comes in, as the experience of being a continuous and distinctive person over time, built from a rich set of autobiographical memories. And the social self is that aspect of self-experience that is refracted through the perceived minds of others, shaped by our unique social milieu.

In daily life, it can be hard to differentiate these dimensions of selfhood.

The problem isnt so much that it is hard to differentiate these dimensions of selfhood as that it is hard to believe that a simple, reductionist approach to the question will provide much insight.

For example, Dr. Seth writes, The specific experience of being you (or me) is nothing more than the brains best guess of the causes of self-related sensory signals. That seems inconsistent with the council of selves that Dr. Seth himself sketches out in the paragraph quoted above. If he is right, your local town council votes may be less frenetic at any given time than what is going on in your own mind but that is not an argument for reductionism.

It becomes even more confusing when Dr. Seth tells us,

This returns us one last time to Descartes. In dissociating mind from body, he argued that non-human animals were nothing more than beast machines without any inner universe. In his view, basic processes of physiological regulation had little or nothing to do with mind or consciousness. Ive come to think the opposite. It now seems to me that fundamental aspects of our experiences of conscious selfhood might depend on control-oriented predictive perception of our messy physiology, of our animal blood and guts. We are conscious selves because we too are beast machines self-sustaining flesh-bags that care about their own persistence.

So, contemplating the vast mystery as well as complexity of consciousness, Dr. Seth asserts that it shows that we too are beast machines.

Actually, it provides a convincing demonstration of how reductionism does not work well in neuroscience. At most, it would mean that animal consciousness is more complex than we have earlier supposed. For that, at least, we have a growing body of evidence.

You may also wish to read: Psychiatry has always been difficult but its unclear how trashing almost every philosophical tradition from which it is approached will really help. Understanding the human mind is necessarily complex because it is both what we are trying to perceive and the tool by which we hope to perceive it.

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Reductionism as a Dead End in Neuroscience Captured in an Essay - Walter Bradley Center for Natural and Artificial Intelligence

Neuroscience

How I used my background in neuroscience to make it as a lawyer – Legal Cheek

Bristows Gregory Bacon on his transition from academia to IP and what STEM students can offer law firms

Gregory Bacon, partner and patent litigation specialist at Bristows, is well-placed to discuss a career change from science to law. He completed a PhD in neuroscience at Oxford University and spent time as postdoctoral researcher at Kings College London.

Intellectual property is often considered one of the areas of law most accessible to those with a background in science, technology, engineering and mathematics (STEM). The highly technical nature of projects in this area offers an array of challenges for those with puzzle-oriented minds.

Bristows represents huge clients at the cutting-edge of the science and technology sector, working with mega-brands like Google, Facebook and Samsung. They also have an impressive life sciences client base and the firm worked with AstraZeneca and Oxford University on their Covid jab during the pandemic. Bringing new products and technologies to the commercial market can be a difficult process and Bacon specialises in helping clients navigate disputes over their patents.

He describes a case he is currently working on for a drug developed and licensed to treat multiple sclerosis, a lifelong condition affecting the brain and spinal cord. Treatments available still dont cure the disease, but they can significantly reduce underlying autoimmune reactions and slow disease progression, he explains. My client, a pharmaceutical company, developed and sells one of these treatments. Earlier this year, we made some new case law in relation to patent rights in the UK for that product, and whether these can be asserted before the patent is granted. Being an effective lawyer means coming up with solutions for your client, including sometimes ones that have not been tried before. Another case Bacon is working on involves a dispute between two pharmaceutical companies as to whether contractual royalties are payable in relation to a product that is licensed and sold by one of them for the treatment of rare forms of childhood epilepsy.

Whilst a STEM background is not a requirement to be a good patent lawyer, Bacon continues, it helps to have a basic grounding of scientific knowledge. He is quick to point out that the niche knowledge from his PhD is often not as helpful as the ability to interpret evidence. Being able to take data and understand it is key. For example, you need to be able to read scientific literature and understand how the information in that article can support your case or maybe actually supports the other sides case! Bacon says.

Enthusiasm for learning about technology is also an important quality for this kind of work, which is often something that STEM students develop through their studies. He says:

You need to want to keep learning about the technology as well as about the law. So when you get a new project on a chemical youve never heard of before or an interaction with an organ that youve never dealt with before, you think this sounds really interesting I want to get to know more!

Bacon acknowledges that his transition from science into law is made more unusual by his direct route. Strangely, I didnt go for a vacation scheme, I went straight for a training contract. I was offered an interview here at Bristows 20 years ago, and the interview went well. After accepting their offer of a job and completing his conversion course, Bacon started his training contract with the firm. I just loved every aspect of it, every seat! he reveals. But his interest in patent law had already taken root and after qualifying, he was offered a permanent position in their patents team.

After twenty years with Bristows, Bacons enthusiasm for what he does has in no way diminished. He describes finding an unexpected source of enjoyment in the management responsibilities that come with being a partner. It is quite an unusual step to go from not having any management responsibilities to having almost the full suite of management responsibilities, he explains. It brings with it a whole host of extra skills that you have to have to develop to be a partner. After eight or ten years of your post-qualification career, you take on all these new responsibilities: training junior colleagues, recruitment, winning client pitches and keeping clients happy. I think I enjoy this almost as much as doing the fee-earning work for the clients.

This split between his responsibilities as a fee earner and as a partner is also something that characterises his daily work. My day is split around 70:30. Seventy percent of my time is spent doing legal work, calls with clients, deciding on strategy, drafting documents, preparing cases for court, reading technical documents and speaking with international lawyers. Then the remainder of my time is involved in the management of the group, my department, and the wider firm. This includes ensuring my junior colleagues have enough work and theyre getting enough exposure to the right levels of work. And some general admin of course!

Considering his own career journey, what advice would he give to students looking at making the transition from STEM to law?

Do your research, Bacon stresses. Try and go to an open day or a law fair. If you can really get to see the firm as it operates behind the scenes, youll get a better feel for what the job looks like. Thats important because if youre a STEM student, youre looking at around a four-year process before youre qualified as a solicitor, and youve got something to show for all that work. So do the research and make sure it is something you want to invest four years of your time into.

Gregory Bacon will be speaking at STEM Focus: Life as an intellectual property lawyer with Bristows, a virtual student event taking place on Thursday 20 October. You can apply to attend the event, which is free, now.

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How I used my background in neuroscience to make it as a lawyer - Legal Cheek

Neuroscience

Research Paves Way for Innovative Theory of Cognitive Processing – Neuroscience News

Summary: A new theory suggests glial cells, specifically astrocytes, play a key role in cognitive processing.

Source: University Health Network

A team of scientists from the Krembil Brain Institute, part of the University Health Network in Toronto, and Duke University in Durham, North Carolina, has developed the first computer model predicting the role of cortical glial cells in cognition.

The paper was published today in the prestigious journalProceedings of the National Academy of Sciences(PNAS).

The role of neurons is well documented, but neurons are interspersed with glial cells and many synapses in the brain have glia nearby, says Dr. Maurizio De Pitt, a scientist at the Krembil Brain Institute and the first author of the study. We currently do not understand how neurons and glia work together, or how glial dysfunction contributes to cognitive deficits.

Glial cells are abundant throughout the brain and play several important roles. These cells have long been thought to be passive bystandersphysically supporting neurons and synapses, bringing nutrients to neurons, and removing toxins and waste products. However, scientists have recently discovered that glia interact with neurons in a fashion similar to the way that neurons communicate with one another through chemical signals.

This paper presents the first theory of the role glia play in cognitive processing, in the brain. The type of glial cells that we studyknown as astrocytescan modify the activity of our brain circuits and influence the way we behave, says Dr. De Pitt.

The study looked at the role of astrocytes in working memory, which is the ability to store information for ongoing tasks, such as following the storyline of a movie or counting to ten.

We know that astrocytes release specialized chemical signals and we have shown that this signalling could mediate different readouts of working memory, says Dr. De Pitt.

Revealing that chemical interactions between neurons and astrocytes could be at the core of working memory, also tells us what could go wrong when we have working memory deficits, which are often warning signs of major brain disorders.

He adds, If we want to truly understand dysfunction in working memory, we need to consider the interaction between glial cells and neurons.

Also noted in the article:

Like radio systems, synapses have been traditionally thought to transmit on a single frequency band. Taking astrocytes into account, we now know there can be multiple frequency bands.

It is generally believed that different forms of working memory rely on a variety of circuits; however, this study shows that the same neuron-glial circuits could encode for various forms of working memory.

The way that astrocytes are arranged with respect to neurons could control our working memory capacity, or how many things we can keep in mind simultaneously.

Currently, there are no effective techniques to record glial activity in the human brain. The researchers hope to eventually create a high-fidelity modela digital twinof the brains neuron-glia circuits, from genes to cells.

Such a model can help to uncover markers of neuron-glial interactions and improve the diagnosis and treatment of various brain diseases, such as Alzheimers, Parkinsons and epilepsy.

With our new theory, we are not just looking at the brain in black and whitethat is, whether given neuron populations are active or inactive. Rather, we are viewing the brain in technicolour, gaining a deeper understanding of cellular communication by including glia and their signalling, says Dr. De Pitt.

This gives us a much more comprehensive and realistic picture of the complexity of the brain.

As technology advances, De Pitt and his team at the Krembil will use their models to develop techniques to modify neuron-glial circuit activity to treat disease. Our ultimate goal is to study neuron-glial interactions to uncover new therapeutic targets for brain disorders.

Funding: This work was funded by an FP7 Marie Skodowska-Curie International Outgoing Fellowship.Research at Dr. De Pitts lab is supported by operating grants from the Krembil Research Institute, the European Research Commission, the Krembil Foundation and UHN Foundation.

Author: Ana FernandesSource: University Health NetworkContact: Ana Fernandes University Health NetworkImage: The image is in the public domain

Original Research: Closed access.Multiple forms of working memory emerge from synapseastrocyte interactions in a neuronglia network model by Maurizio De Pitt et al. PNAS

Abstract

Multiple forms of working memory emerge from synapseastrocyte interactions in a neuronglia network model

Persistent activity in populations of neurons, time-varying activity across a neural population, or activity-silent mechanisms carried out by hidden internal states of the neural population have been proposed as different mechanisms of working memory (WM).

Whether these mechanisms could be mutually exclusive or occur in the same neuronal circuit remains, however, elusive, and so do their biophysical underpinnings.

While WM is traditionally regarded to depend purely on neuronal mechanisms, cortical networks also include astrocytes that can modulate neural activity.

We propose and investigate a network model that includes both neurons and glia and show that gliasynapse interactions can lead to multiple stable states of synaptic transmission.

Depending on parameters, these interactions can lead in turn to distinct patterns of network activity that can serve as substrates for WM.

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Research Paves Way for Innovative Theory of Cognitive Processing - Neuroscience News

Neuroscience

Pain Relief Without Side Effects and Addiction – Neuroscience News

Summary: Researchers have developed a new substance that activates adrenalin receptors rather than opioid receptors to help relieve chronic pain. The new compounds have similar pain-relieving qualities as opioids but do not appear to induce respiratory depression or addiction.

Source: Friedrich-Alexander-Universitt Erlangen-Nrnberg

New substances that activate adrenalin receptors instead of opioid receptors have a similar pain-relieving effect to opiates, but without the negative aspects such as respiratory depression and addiction.

This is the result of research carried out by an international team of researchers led by the Chair of Pharmaceutical Chemistry at Friedrich-Alexander-Universitt Erlangen-Nrnberg (FAU).

Their findings,which have now been published in the renowned scientific journalScience, are a milestone in the development of non-opioid pain relief.

Opiates cause addiction, new substances do not

They are a blessing for patients suffering from severe pain, but they also have serious side effects: Opioids, and above all morphine, can cause nausea, dizziness and constipation and can also often cause slowed breathing that can even result in respiratory failure.

In addition, opiates are addictive a high percentage of the drug problem in the USA is caused by pain medication, for example.

In order to tackle the unwanted medical and social effects of opioids, researchers all over the world are searching for alternative analgesics.

Prof. Dr. Peter Gmeiner, Chair of Pharmaceutical Chemistry is one of these researchers. We are focusing particularly on the molecular structures of the receptors that dock onto the pharmaceutical substances, says Gmeiner.

It is only when we understand these on the atomic level that we can develop effective and safe active substances.

Collaborating with an international team of researchers, Prof. Gmeiner discovered an active substance in 2016 that bonds to known opioid receptors and that offers the same level of pain relief as morphine, even though it has no chemical similarity to opiates.

New approach: Adrenaline receptors instead of opioid receptors

Peter Gmeiner is currently following a lead that seems very promising: Many non-opioid receptors are involved in pain processing, but only a small number of these alternatives have as yet been validated for use in therapies, he explains.

Gmeiner and a team of researchers from Erlangen, China, Canada and the USA have now turned their attention to a new receptor that is responsible for binding adrenaline the alpha 2A adrenergic receptor. There are already some analgesics that target this receptor such as brimonidine, clonidine and dexmedetomidine.

Gmeiner: Dexmedetomidine relieves pain, but has a strong sedative effect, which means its use is restricted to intensive care in hospital settings and is not suitable for broader patient groups.

The aim of the research consortium is to find a chemical compound that activates the receptor in the central nervous system without a sedative effect. In a virtual library of more than 300 million different and easily accessible molecules, the researchers looked for compounds that physically match the receptor but are not chemically related to known medication.

After a series of complex virtual docking simulations, around 50 molecules were selected for synthesis and testing and two of these fulfilled the desired criteria. They had good bonding characteristics, activated only certain protein sub-types and thus a very selective set of cellular signal pathways, whereas dexmedetomidine responds to a significantly wider range of proteins.

Pain relief without sedation in animal models

By further optimizing the identified molecules, for which extremely high-resolution cryo-electron microscopic imaging was used, the researchers were able to synthesize agonists that produced high concentrations in the brain and reduced the sensation of pain effectively in investigations with animal models.

Various tests confirmed that docking on the receptor was responsible for the analgesic effect, explains Gmeiner. We are particularly pleased about the fact that none of the new compounds caused sedation, even at considerably higher doses than those that would be required for pain relief.

The successful separation of analgesic properties and sedation is a milestone in the development of non-opioid pain medication, especially as the newly-identified agonists are comparatively easy to manufacture and administer orally to patients.

However, Prof. Gmeiner has to dampen any hopes of rapid widespread use in human medicine: We are currently still talking about basic research. The development of medication is subject to strict controls and in addition to significant amounts of funding, it takes a long time. However, these results still make us very optimistic.

Author: Katrin PiechaSource: Friedrich-Alexander-Universitt Erlangen-NrnbergContact: Katrin Piecha Friedrich-Alexander-Universitt Erlangen-NrnbergImage: The image is in the public domain

Original Research: Closed access.Structure-based discovery of nonopioid analgesics acting through the 2A-adrenergic receptor by Peter Gmeiner et al. Science

Abstract

Structure-based discovery of nonopioid analgesics acting through the 2A-adrenergic receptor

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the 2A-adrenergic receptor (2AAR), seeking new 2AAR agonists chemotypes that lack the sedation conferred by known 2AAR drugs, such as dexmedetomidine.

We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential Giand Gosignaling. Experimental structures of 2AAR complexed with two of these agonists confirmed the docking predictions and templated further optimization.

Several compounds, including the initial docking hit 9087 [mean effective concentration (EC50) of 52 nanomolar] and two analogs, 7075 and PS75 (EC504.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation.

These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

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Pain Relief Without Side Effects and Addiction - Neuroscience News

Neuroscience

Secret Structure in the Wiring Diagram of the Brain – Neuroscience News

Summary: Study reveals a hidden order in seemingly random connections between neurons.

Source: University Hospital Bonn

In the brain, our perception arises from a complex interplay of neurons that are connected via synapses. But the number and strength of connections between certain types of neurons can vary.

Researchers from the University Hospital Bonn (UKB), the University Medical Center Mainz and the Ludwig-Maximilians-University Munich (LMU), together with a research team from the Max Planck Institute for Brain Research in Frankfurt, as part of the DFG-funded Priority Program Computational Connectomics (SPP2041), have now discovered that the structure of the seemingly irregular neuronal connection strengths contains a hidden order. This is essential for the stability of the neuronal network.

The study has now been published in the journal PNAS.

Ten years ago, connectomics, that is the creation of a map of the connections between the approximately 86 billion neurons in the brain, was declared a future milestone of science. This is because in complex neuronal networks, neurons are connected to each other by thousands of synapses. Here, the strength of the connections between individual neurons is important because it is crucial for learning and cognitive performance.

However, each synapse is unique and its strength can vary over time. Even experiments that measured the same type of synapse in the same brain region yielded different values for synaptic strength. However, this experimentally observed variability makes it difficult to find general principles underlying the robust function of neuronal networks, says Prof. Tatjana Tchumatchenko, research group leader at the Institute of Experimental Epileptology and Cognitive Research of the UKB and at the Institute of Physiological Chemistry of the University Medical Center Mainz, explaining the motivation to conduct the study.

Mathematics and laboratory combined purposefully

In the primary visual cortex (V1), the visual stimuli transmitted by the eye via the thalamus, a switching point for sensory impressions in the diencephalon, are first recorded.

The researchers took a closer look at the connections between the neurons that are active during this process.

To do this, the researchers measured experimentally the joint response of two classes of neurons to different visual stimuli in the mouse model. At the same time, they used mathematical models to predict the strength of synaptic connections.

To explain their lab-recorded activities of such network connections in the primary visual cortex, they used the so-called stabilized supralinear network (SSN).

It is one of the few nonlinear mathematical models that offers the unique possibility to compare theoretically simulated activity with actually observed activity, says Prof. Laura Busse, research group leader at LMU Neurobiology.

We were able to show that combining SSN with experimental recordings of visual responses in the mouse thalamus and cortex allows us to determine different sets of connection strengths that lead to the recorded visual responses in the visual cortex.

Sequence between the connection strengths is the key

The researchers found that there was an order behind the observed variability in synapse strength.

For example, the connections from excitatory to inhibitory neurons were always the strongest, while the reverse connections in the visual cortex were weaker. This is because the absolute values of synaptic strengths varied in the modeling as they had in the earlier experimental studies but nevertheless always maintained a certain order.

Thus, the relative ratios are crucial for the course and strength of the measured activity, rather than the absolute values.

It is remarkable that analysis of earlier direct measurements of synaptic connections revealed the same order of synaptic strengths as our model prediction based on measured neuronal responses alone, says Simon Renner, Ph.D., of LMU Neurobiology, whose experimental recordings of cortical and thalamic activity allowed characterization of the connections between cortical neurons.

Our results show that neuronal activity contains much information about the underlying structure of neuronal networks that is not immediately apparent from direct measurements of synapse strengths.

Thus, our method opens a promising perspective for the study of network structures that are difficult to access experimentally, explains Nataliya Kraynyukova, Ph.D., from the Institute of Experimental Epileptology and Cognitive Research of the UKB and Max Planck Institute for Brain Research in Frankfurt.

This study is the result of an interdisciplinary collaboration between the lab of Prof. Busse and Prof. Tchumatchenko, who worked closely together, building on the computational and experimental expertise of their labs.

Author: Inka VthSource: University Hospital BonnContact: Inka Vth University Hospital BonnImage: The image is in the public domain

Original Research: Open access.In vivo extracellular recordings of thalamic and cortical visual responses reveal V1 connectivity rules by Simon Renner et al. PNAS

Abstract

In vivo extracellular recordings of thalamic and cortical visual responses reveal V1 connectivity rules

The brains connectome provides the scaffold for canonical neural computations. However, a comparison of connectivity studies in the mouse primary visual cortex (V1) reveals that the average number and strength of connections between specific neuron types can vary. Can variability in V1 connectivity measurements coexist with canonical neural computations?

We developed a theory-driven approach to deduce V1 network connectivity from visual responses in mouse V1 and visual thalamus (dLGN). Our method revealed that the same recorded visual responses were captured by multiple connectivity configurations.

Remarkably, the magnitude and selectivity of connectivity weights followed a specific order across most of the inferred connectivity configurations. We argue that this order stems from the specific shapes of the recorded contrast response functions and contrast invariance of orientation tuning.

Remarkably, despite variability across connectivity studies, connectivity weights computed from individual published connectivity reports followed the order we identified with our method, suggesting that the relations between the weights, rather than their magnitudes, represent a connectivity motif supporting canonical V1 computations.

Originally posted here:
Secret Structure in the Wiring Diagram of the Brain - Neuroscience News

Neuroscience

Yale Study Revises Understanding of How the Brain Processes and Responds to Rewards – Yale School of Medicine

A new Yale study of neuron activity in the brain has revised scientists understanding of how the brain processes and responds to rewards.

Researchers have located a set of GABA neurons in the brains ventral tegmental area (VTA) that consistently respond to a primary reward. This response differs from the response of dopamine neurons, which previously have been thought to be the principal cells responsible for mediating reward-related behaviors.

Unlike the activity of dopamine neurons, the response in the GABA pathway does not change as animals learn that a cue predicts reward availability, scientists found. Instead, the GABA cells continue to provide a highly stable signal of the size of the primary reward. In reward learning tasks, stimulating this pathway improved the behavior and motivation of animals as they worked to receive rewards across multiple days.

These findings are exciting because they identify a brain pathway that stably signals the size and intensity of a reward and does not shift during learning, revising our understanding of how reward is encoded in the brain, said Marina Picciotto, PhD, Charles B. G. Murphy Professor of Psychiatry and professor in the Child Study Center, of neuroscience, and of pharmacology, and the studys senior author. This finding also provides a new way to think about how cells in the VTA calculate rewarded outcomes in learning tasks.

The findings were published in the journal Science Advances. They appear to clarify the role of dopamine and GAPA neurons in the VTA, located in the midbrain.

Dopamine neurons were thought to be principally responsible for mediating reward-related behaviors, however researchers now believe the neurons fire in response to cues that predict reward, and not to the presentation of the reward itself.

In contrast, GABA neurons in the VTA have been thought to primarily be local cells that inhibit dopamine neurons, but the study shows these neurons project out of the VTA to the ventral pallidum, the major output nucleus of the mesolimbic reward system. Importantly, the researchers found that these neurons respond consistently to a primary reward, and that the response of these neurons scales with the size of the reward.

Other Yale researchers involved in the study are Wenliang Zhou, PhD, associate research scientist; Kristen Kim, neuroscience graduate student; and Yann S. Mineur, PhD, research scientist.

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Yale Study Revises Understanding of How the Brain Processes and Responds to Rewards - Yale School of Medicine