Tag Archives: #neurons

New Tool Activates Deep Brain Neurons by Combining Ultrasound, Genetics (Neuroscience)

It is the first work to show that sonothermogenetics can control behavior by stimulating a specific target deep in the brain

Neurological disorders such as Parkinson’s disease and epilepsy have had some treatment success with deep brain stimulation, but those require surgical device implantation. A multidisciplinary team at Washington University in St. Louis has developed a new brain stimulation technique using focused ultrasound that is able to turn specific types of neurons in the brain on and off and precisely control motor activity without surgical device implantation. 

The team, led by Hong Chen, assistant professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, is the first to provide direct evidence showing noninvasive, cell-type-specific activation of neurons in the brain of mammal by combining ultrasound-induced heating effect and genetics, which they have named sonothermogenetics. It is also the first work to show that the ultrasound- genetics combination can robustly control behavior by stimulating a specific target deep in the brain.

Results of the three years of research, which was funded in part by the National Institutes of Health’s BRAIN Initiative, were published online in Brain Stimulation May 11, 2021.

The senior research team included renowned experts in their fields from both the McKelvey School of Engineering and the School of Medicine, including Jianmin Cui, professor of biomedical engineering; Joseph P. Culver, professor of radiology, of physics and of biomedical engineering; Mark J. Miller, associate professor of medicine in the Division of Infectious Diseases in the Department of Medicine; and Michael Bruchas, formerly of Washington University, now professor of anesthesiology and pharmacology at the University of Washington.

“Our work provided evidence that sonothermogenetics evokes behavioral responses in freely moving mice while targeting a deep brain site,” Chen said. “Sonothermogenetics has the potential to transform our approaches for neuroscience research and uncover new methods to understand and treat human brain disorders.” 

Using a mouse model, Chen and the team delivered a viral construct containing TRPV1 ion channels to genetically-selected neurons. Then, they delivered small burst of heat via low-intensity focused ultrasound to the select neurons in the brain via a wearable device. The heat, only a few degrees warmer than body temperature, activated the TRPV1 ion channel, which acted as a switch to turn the neurons on or off.

“We can move the ultrasound device worn on the head of free-moving mice around to target different locations in the whole brain,” said Yaoheng Yang, first author of the paper and a graduate student in biomedical engineering. “Because it is noninvasive, this technique has the potential to be scaled up to large animals and potentially humans in the future.”

The work builds on research conducted in Cui’s lab that was published in Scientific Reports in 2016. Cui and his team found for the first time that ultrasound alone can influence ion channel activity and could lead to new and noninvasive ways to control the activity of specific cells. In their work, they found that focused ultrasound modulated the currents flowing through the ion channels on average by up to 23%, depending on channel and stimulus intensity. Following this work, researchers found close to 10 ion channels with this capability, but all of them are mechanosensitive, not thermosensitive.

The work also builds on the concept of optogenetics, the combination of the targeted expression of light-sensitive ion channels and the precise delivery of light to stimulate neurons deep in the brain. While optogenetics has increased discovery of new neural circuits, it is limited in penetration depth due to light scattering and requires surgical implantation of optical fibers.

Sonothermogenetics has the promise to target any location in the mouse brain with millimeter-scale resolution without causing any damage to the brain, Chen said. She and the team continue to optimize the technique and further validate their findings.

This work was supported by the National Institutes of Health (NIH) BRAIN Initiative (R01MH116981) and NIBIB (R01EB027223 and R01EB030102). This work was supported by the Hope Center Viral Vectors Core at Washington University School of Medicine.


Reference: Yang Y, Pacia C, Ye D, Zhu L, Baek H, Yue Y, Yan J, Miller M, Cui J, Culver J, Bruchas M, Chen H. Sonothermogenetics for noninvasive and cell-type specific deep brain neuromodulation. Brain Stimulation, In Press, published online May 11, 2021. https://doi.org/10.1016/j.brs.2021.04.021


Provided by McKelvey School of Engineering

Team From UHN, CAMH Identify Unique Characteristics of Human Neurons (Neuroscience)

These findings may have implications for brain disease, disorders

Scientists at the Krembil Brain Institute, part of University Health Network (UHN), in collaboration with colleagues at the Centre for Addiction and Mental Health (CAMH), have used precious and rare access to live human cortical tissue to identify functionally important features that make human neurons unique.

This experimental work is among the first of its kind on live human neurons and one of the largest studies of the diversity of human cortical pyramidal cells to date.

“The goal of this study was to understand what makes human brain cells ‘human,’ and how human neuron circuitry functions as it does,” says Dr. Taufik Valiante, neurosurgeon, scientist at the Krembil Brain Institute at UHN and co-senior author on the paper.

“In our study, we wanted to understand how human pyramidal cells, the major class of neurons in the neocortex, differ between the upper and bottom layers of the neocortex,” says Dr. Shreejoy Tripathy, a scientist with the Krembil Centre for Neuroinformatics at CAMH and co-senior author on this study.

“In particular, we wanted to understand how electrical features of these neurons might support different aspects of cross-layer communication and the generation of brain rhythms, which are known to be disrupted in brain diseases like epilepsy.”

With consent, the team used brain tissue immediately after it had been removed during routine surgery from the brains of patients with epilepsy and tumours. Using state-of-the-art techniques, the team was then able to characterize properties of individual cells within slices of this tissue, including visualizations of their detailed morphologies.

“Little is known about the shapes and electrical properties of living adult human neurons because of the rarity of obtaining living human brain tissue, as there are few opportunities other than epilepsy surgery to obtain such recordings,” says Dr. Valiante.

To keep the resected tissue alive, it is immediately transferred into the modified cerebrospinal fluid in the operating room then taken directly into the laboratory where it is prepared for experimental characterization.

It is rare to study human tissue because accessing human tissue for scientific inquiries requires a tight-knit multidisciplinary community, including patients willing to participate in the studies, ethicists ensuring patient rights and safety, neurosurgeons collecting and delivering samples, and neuroscientists with necessary research facilities to study these tissues.

After initial analysis, members of the Krembil Centre for Neuroinformatics used further large-scale data analysis to identify the properties that distinguished neurons in this cohort from each other. These properties were then compared to those from other centres doing similar work with human brain tissue samples, including the Allen Institute for Brain Sciences in Seattle, Washington.

Noted in the team’s findings:

  • A massive amount of diversity among human neocortical pyramidal cells
  • Distinct electrophysiological features between neurons located at different layers in the human neocortex
  • Specific features of deeper layer neurons enabling them to support aspects of across-layer communication and the generation of functionally important brain rhythms

The teams also found notable and unexpected differences between their findings and similar experiments in pre-clinical models, which Dr. Tripathy believes is likely reflective of the massive expansion of the human neocortex over mammalian and primate evolution.

“These results showcase the notable diversity of human cortical pyramidal neurons, differences between similarly classified human and pre-clinical neurons, and a plausible hypothesis for the generation of human cortical theta rhythms driven by deep layer neurons,” says Dr. Homeira Moradi Chameh, a scientific associate in Dr. Valiante’s laboratory at Krembil Brain Institute and lead author on the study.

In total, the team was able to characterize over 200 neurons from 61 patients, reflecting the largest dataset of its kind to-date and encapsulating almost a decade’s worth of painstaking work at UHN and the Krembil Brain Institute.

“This unique data set will allow us to build computational models of the distinctly human brain, which will be invaluable for the study of distinctly human neuropathologies,” says Dr. Scott Rich, a postdoctoral research fellow in Dr. Valiante’s laboratory at the Krembil Brain Institute and co-author on this work.

“For instance, the cellular properties driving many of the unique features identified in these neurons are known to be altered in certain types of epilepsy. By implementing these features in computational models, we can study how these alterations affect dynamics at the various spatial scales of the human brain related to epilepsy, and facilitate the translation of these ‘basic science’ findings back to the clinic and potentially into motivations for new avenues in epilepsy research.”

“This effort was only possible because of the very large and active epilepsy program at the Krembil Brain Institute at UHN, one of the largest programs of its kind in the world and the largest program of its kind in Canada,” says Dr. Valiante.

Featured image credit: Science Photo Library – KTSDESIGN / Getty Images


Reference: Moradi Chameh, H., Rich, S., Wang, L. et al. Diversity amongst human cortical pyramidal neurons revealed via their sag currents and frequency preferences. Nat Commun 12, 2497 (2021). https://doi.org/10.1038/s41467-021-22741-9 (DOI: 10.1038/s41467-021-22741-9).


Provided by University Health Network

DNA Damage ‘Hot Spots’ Discovered Within Neurons (Neuroscience)

NIH labs collaborate to develop new methods for studying genome-wide DNA damage and repair

Researchers at the National Institutes of Health (NIH) have discovered specific regions within the DNA of neurons that accumulate a certain type of damage (called single-strand breaks or SSBs). This accumulation of SSBs appears to be unique to neurons, and it challenges what is generally understood about the cause of DNA damage and its potential implications in neurodegenerative diseases.

Because neurons require considerable amounts of oxygen to function properly, they are exposed to high levels of free radicals–toxic compounds that can damage DNA within cells. Normally, this damage occurs randomly. However, in this study, damage within neurons was often found within specific regions of DNA called “enhancers” that control the activity of nearby genes.

Fully mature cells like neurons do not need all of their genes to be active at any one time. One way that cells can control gene activity involves the presence or absence of a chemical tag called a methyl group on a specific building block of DNA. Closer inspection of the neurons revealed that a significant number of SSBs occurred when methyl groups were removed, which typically makes that gene available to be activated.

An explanation proposed by the researchers is that the removal of the methyl group from DNA itself creates an SSB, and neurons have multiple repair mechanisms at the ready to repair that damage as soon as it occurs. This challenges the common wisdom that DNA damage is inherently a process to be prevented. Instead, at least in neurons, it is part of the normal process of switching genes on and off. Furthermore, it implies that defects in the repair process, not the DNA damage itself, can potentially lead to developmental or neurodegenerative diseases.

This study was made possible through the collaboration between two labs at the NIH: one run by Michael E. Ward, M.D., Ph.D. at the National Institute of Neurological Disorders and Stroke (NINDS) and the other by Andre Nussenzweig, Ph.D. at the National Cancer Institute (NCI). Dr. Nussenzweig developed a method for mapping DNA errors within the genome. This highly sensitive technique requires a considerable number of cells in order to work effectively, and Dr. Ward’s lab provided the expertise in generating a large population of neurons using induced pluripotent stem cells (iPSCs) derived from one human donor. Keith Caldecott, Ph.D. at the University of Sussex also provided his expertise in single strand break repair pathways.

The two labs are now looking more closely at the repair mechanisms involved in reversing neuronal SSBs and the potential connection to neuronal dysfunction and degeneration.

Featured image: Neurons (labeled in purple) show signs of an active DNA repair process (labeled in yellow). The cells’ DNA itself is labeled in cyan (in this image, overlap between cyan and yellow appears green). Image courtesy of Ward lab, NINDS


Reference: Wu, W., Hill, S.E., Nathan, W.J. et al. Neuronal enhancers are hotspots for DNA single-strand break repair. Nature (2021). https://doi.org/10.1038/s41586-021-03468-5 https://www.nature.com/articles/s41586-021-03468-5


Provided by NIH/NINDS

New Signaling Pathway in Neurons (Neuroscience)

A new signaling pathway has been identified that can prevent the overproduction of certain RNA-protein complexes in neurons. These complexes play an important role in neurodegenerative diseases.

Neurodegenerative diseases, such as various forms of senile dementia or amyotrophic lateral sclerosis (ALS), have one thing in common: large amounts of certain RNA-protein complexes (snRNPs) are produced and deposited in the nerve cells of those affected – and this hinders the function of the cells. The overproduction is possibly caused by a malfunction in the assembly of the protein complexes.

How the production of these protein complexes is regulated was unknown until now. Researchers from Martinsried and Würzburg in Bavaria, Germany, have solved the puzzle and now report on it in the open access journal Nature Communications. They describe in detail a signaling pathway that prevents the overproduction of snRNPs when they are not needed. The results should make it possible to better understand the processes in motor neuron diseases and senile dementia.

The research group led by Professor Michael Sendtner and Dr. Michael Briese from the Institute of Clinical Neurobiology at Julius-Maximilians-Universität Würzburg (JMU) was in charge of the publication. Professor Utz Fischer and Pradhipa Ramanathan from the JMU Institute of Biochemistry were also involved, as was a team from the Max Planck Institute of Biochemistry in Martinsried.

The next steps in research

Further investigations shall now show how the synthesis and degradation of excess snRNPs are regulated in nerve cells. The scientists hope that in the end they will be able to identify new therapeutic options for neurodegenerative diseases.

This work was financially supported by the German Research Foundation and the European Research Council.

Featured image: The molecule Larp7 plays an important role in the assembly of snRNP complexes. It accumulates in nerve cells (arrow) where the complexes are formed. (Image: Changhe Ji / Universität Würzburg)


Publication

Ji, C., Bader, J., Ramanathan, P. et al. Interaction of 7SK with the Smn complex modulates snRNP production. Nature Communications 12, 1278 (24 February 2021). https://doi.org/10.1038/s41467-021-21529-1


Provided by University of Wurzburg

Reactivating Aging Stem Cells in the Brain (Neuroscience)

As people get older, their neural stem cells lose the ability to proliferate and produce new neurons, leading to a decline in memory function. Researchers at the University of Zurich have now discovered a mechanism linked to stem cell aging – and how the production of neurons can be reactivated.

The stem cells in our brain generate new neurons throughout life, for example in the hippocampus. This region of the brain plays a key role for a range of memory processes. With increasing age, and in patients suffering from Alzheimer’s disease, the hippocampus’ ability to create new neurons declines steadily – and with it, its memory functions.

Distribution of age-dependent cell damage

A study conducted by the research group of Sebastian Jessberger, a professor at the Brain Research Institute of the University of Zurich, shows how the formation of new neurons is impaired with advancing age. Protein structures in the nuclei of neural stem cells make sure that harmful proteins accumulating over time are unevenly distributed onto the two daughter cells during cell division. This seems to be an important part of the cells’ ability to proliferate over a long time in order to maintain the supply of neurons. With advancing age, however, the amounts of nucleic proteins change, resulting in defective distribution of harmful proteins between the two daughter cells. This results in a decrease in the numbers of newly generated neurons in the brains of older mice.

The central element in this process is a nuclear protein called lamin B1, the levels of which decrease as people age. When the researchers increased lamin B1 levels in experiments in aging mice, stem cell division improved and the number of new neurons grew. “As we get older, stem cells throughout the body gradually lose their ability to proliferate. Using genetic engineering and cutting-edge microscope technology, we were able to identify a mechanism that is associated with this process,” says doctoral candidate and first author Khadeesh bin Imtiaz.

Halting the aging process of stem cells

The research is part of several ongoing projects aiming to reactivate aging stem cells. The ability to regenerate damaged tissue generally declines with age, thus affecting almost all types of stem cells in the body. “While our study was limited to brain stem cells, similar mechanisms are likely to play a key role when it comes to the aging process of other stem cells,” says Sebastian Jessberger.

These latest findings are an important step towards exploring age-dependent changes in the behavior of stem cells. “We now know that we can reactivate aging stem cells in the brain. Our hope is that these findings will one day help increase levels of neurogenesis, for example in older people or those suffering from degenerative diseases such as Alzheimer’s. Even if this may still be many years in the future,” says Jessberger.

Funding

The research was funded by the European Research Council, the Swiss National Science Foundation, the Helmut Horten Foundation, the Wisconsin Partnership Program, an NIH New Innovator Award and the Neuroscience Center Zurich.

Featured image: Stem cells in the mouse hippocampus (in blue): With increasing age, their ability to form new neurons decreases as the amount of the nuclear protein lamin B1 (in red) drops. (Image: Khadeesh bin Imtiaz, UZH)


Literature:

M.K. bin Imtiaz, B.N. Jaeger, S. Bottes, R.A.C. Machado, M. Vidmar, D.L. Moore, S. Jessberger. Declining Lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity. 24 February 2021. Cell Stem Cell. DOI: 10.1016/j.stem.2021.01.015


Provided by University of Zurich

Signal Coupling Between Neuron-glia Super-network May Lead to Improved Memory Formation (Neuroscience)

Tohoku University scientists have shown that neuronal and glial circuits form a loosely coupled super-network within the brain. Activation of the metabotropic glutamate receptors in neurons was shown to be largely influenced by the state of the glial cells. Therefore, artificial control of the glial state could potentially be used to enhance the memory function of the brain.

The findings were detailed in the Journal of Physiology.

Although the glial cells occupy more than half of the brain, they were thought to act as glue–merely filling the gap between neurons. However, recent findings show that the concentration of intracellular ions in glia, such as calcium and proton, can fluctuate over time.

“Glial cells appear to have the capacity of coding information,” says professor Ko Matsui of the Super-network Brain Physiology lab at Tohoku University, who led the research. “However, the role of the added layer of signals encoded in the glial circuit has always been an enigma.”

Using patch clamp electrophysiology techniques in acute brain slices from mice, Dr. Kaoru Beppu, Matsui, and their team show that glial cells in the cerebellum react to excitatory transmitter glutamate released from synapses of neurons. The glial cells then release additional glutamate in return. Therefore, these glial cells effectively function as excitatory signal amplifiers.

The additional glutamate released from glial cells efficiently activate metabotropic glutamate receptors on Purkinje neurons–essential for cerebellar motor learning. The amount of feedforward excitation was controlled by the intracellular pH of the glia cells.

“Depending on the state of our mind, the same experience could become a lasting memory or could fade away,” says Matsui. “It is possible that the pH of the glial cells at the time of the experience could have a pivotal role on memory formation.”

In this study, light-sensitive proteins were genetically expressed in glial cells to control their pH at will. Such optogenetics technology would be difficult to apply in human patients. “Although it would take a long time for clinical use, it is possible to imagine a future where a therapeutic strategy is designed to target glial cells to control their pH for memory enhancement to treat dementia,” added Matsui.

Featured image: Optogenetic control of glial pH suppresses or enhances the glial release of glutamate © Ko Matsui


Publication Details: Title: Glial amplification of synaptic signals
Authors: Kaoru Beppu, Naoko Kubo, and Ko Matsui*
Journal: Journal of Physiology
DOI: 10.1113/JP280857


Provided by Tohoku University

Seeing Schizophrenia: X-rays Shed Light on Neural Differences, Point Toward Treatment (Psychiatry)

An international research team used the ultrabright X-rays of the Advanced Photon Source to examine neurons in the brains of schizophrenia patients. What they learned may help neurologists treat this harmful brain disorder.

Schizophrenia, a chronic, neurological brain disorder, affects millions of people around the world. It causes a fracture between a person’s thoughts, feelings and behavior. Symptoms include delusions, hallucinations, difficulty processing thoughts and an overall lack of motivation. Schizophrenia patients have a higher suicide rate and more health problems than the general population, and a lower life expectancy.

There is no cure for schizophrenia, but the key to treating it more effectively is to better understand how it arises. And that, according to Ryuta Mizutani, professor of applied biochemistry at Tokai University in Japan, means studying the structure of brain tissue. Specifically, it means comparing the brain tissues of schizophrenia patients with those of people in good mental health, to see the differences as clearly as possible.

“There are only a few places in the world where you can do this research. Without 3D analysis of brain tissues this work would not be possible.”

— Ryuta Mizutani, professor, Tokai University

“The current treatment for schizophrenia is based on many hypotheses we don’t know how to confirm,” Mizutani said. ​“The first step is to analyze the brain and see how it is constituted differently.”

To do that, Mizutani and his colleagues from several international institutions collected eight small samples of brain tissue — four from healthy brains and four from those of schizophrenia patients, all collected post-mortem — and brought them to beamline 32-ID of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at DOE’s Argonne National Laboratory.

At the APS, the team used powerful X-rays and high-resolution optics to capture three-dimensional images of those tissues. (Researchers collected similar images at the Super Photon Ring 8-GeV [SPring-8] light source facility in Japan.) The resolution of the X-ray optics used at the APS can be as high as 10 nanometers. That’s about 700 times smaller than the width of the average red blood cell, and there are five million of those cells in a drop of blood.

“There are only a few places in the world where you can do this research,” Mizutani said. ​“Without 3D analysis of brain tissues this work would not be possible.”

According to Vincent De Andrade, physicist in Argonne’s X-ray Science Division, capturing images at high resolution presents a challenge, since the neurons being imaged can be centimeters long. The neuron is the basic working unit of the brain, a cell within the nervous system that transmits information to other cells to control body functions. The human brain has roughly 100 billion of these neurons, in various sizes and shapes.

“The sample has to move through the X-ray beam to trace the neurons through the sample,” De Andrade explained. ​“The field of view of our X-ray microscope is about 50 microns, about the width of a human hair, and you need to follow these neurons over several millimeters.”

What these images showed is that the structures of these neurons are uniquely different in each schizophrenia patient, which Mizutani said is evidence that the disease is associated with those structures. Images of healthy neurons were relatively similar, while neurons from schizophrenia patients showed far more deviation, both from the healthy brains and from each other.

More study is needed, Mizutani said, to figure out exactly how the structures of neurons are related to the onset of the disease and to devise a treatment that can alleviate the effects of schizophrenia. As X-ray technology continues to improve — the APS, for example, is scheduled to undergo a massive upgrade that will increase its brightness up to 500 times — so will the possibilities for neuroscientists.

“The APS upgrade will allow for better sensitivity and resolution for imaging, making the process of mapping neurons in the brain faster and more precise,” De Andrade said. ​“We would need resolutions of better than 10 nanometers to capture synaptic connections, which is the holy grail for a comprehensive mapping of neurons, and those should be achievable with the upgrade.”

De Andrade also noted that while electron microscopy has been used to map the brains of small animals — fruit flies, for instance — that technique would take a long time to image the brain of a larger animal, such as a mouse, let alone a full human brain. Ultrabright, high energy X-rays like those at the APS, he said, could speed up the process, and advances in technology will help scientists get a more complete picture of brain tissue.

For neuroscientists like Mizutani, the end goal is fewer people suffering with brain diseases like schizophrenia.

“The differences in brain structure between healthy and schizophrenic people must be linked to mental disorders,” he said. ​“We must find some way to make people healthy.”

Mizutani and his team reported their results in Translational Psychiatry.

Featured image: These 3D images of neurons in the brain of a schizophrenia patient show wavy, distorted neurites, which indicate that the condition may be linked to the shape of the neurons. X-ray images were taken at the Advanced Photon Source. (Image by Ryuta Mizutani.)


Reference: Mizutani, R., Saiga, R., Yamamoto, Y. et al. Structural diverseness of neurons between brain areas and between cases. Transl Psychiatry 11, 49 (2021). https://www.nature.com/articles/s41398-020-01173-x https://doi.org/10.1038/s41398-020-01173-x


Provided by Argonne National University

Tiny Population of Neurons May Have Big Role In Depression (Psychiatry)

A tiny population of neurons known to be important to appetite appear to also have a significant role in depression that results from unpredictable, chronic stress, scientists say.

These AgRP neurons reside exclusively in the bottom portion of the hypothalamus called the arcuate nucleus, or ARC, and are known to be important to energy homeostasis in the body as well prompting us to pick up a fork when we are hungry and see food.

Now Medical College of Georgia scientists and their colleagues report the first evidence that, not short-term stress, like a series of tough college exams, rather chronic, unpredictable stress like that which erupts in our personal and professional lives, induces changes in the function of AgRP neurons that may contribute to depression, they write.

The small number of AgRP neurons likely are logical treatment targets for depression, says Dr. Xin-Yun Lu, chair of the Department of Neuroscience and Regenerative Medicine at MCG at Augusta University and Georgia Research Alliance Eminent Scholar in Translational Neuroscience.

While it’s too early to say if the shift in neuron activity prompted by chronic stress and associated with depression starts with these neurons, they are a definite and likely key piece of the puzzle, says Lu, corresponding author of the study in the journal Molecular Psychiatry.

“It is clear that when we manipulate these neurons, it changes behavioral reactions,” she says, but many questions remain, like how these AgRP neurons in the human brain help us cope with and adapt to unpredictable chronic stress over time.

They have shown this type of stress, which results in an animal model of depression, decreases the activity of AgRP, or agouti-related protein, neurons, decreasing the neurons’ ability to spontaneously fire, increasing firing irregularities and otherwise altering the usual firing properties of AgRP neurons in both their male and female mouse model of depression.

Additionally, when they used a small molecule to directly inhibit the neurons, it increased their susceptibility to chronic, unpredictable stress, inducing depression-like behavior in the mice, including reducing usual desires for rewards like consuming palatable sucrose and sex. When they activated the neurons, it reversed classic depressive behaviors like despair and the inability to experience pleasure.

“We can remotely stimulate those neurons and reverse depression,” Lu says, using a synthetic small molecule agonist that binds to an also manmade chemogenetic receptor in their target neurons — a common method for studying the relationship between behavior and particular neurons — delivered directly to those neurons via a viral vector.

As in life, unpredictability can increase stress’ impact, Lu says, so they also used that approach in their studies, with techniques like social isolation and switching light and dark cycles, and found that mice began exhibiting depressive behavior by 10 days.

The scientists found that the stress-related decrease in AgRP neuron activity seems to produce an increase in the activity of other nearby neuron types in the ARC, and are pursuing that observation further. They also are looking at adjustments that may happen to other neurons that respond to stress and reward in other subregions of the hypothalamus as well as other parts of the brain to help define the circuitry involved.

They also already are looking at the more time-consuming process of assessing whether removing the chronic stressors alone will also eventually result in the AgRP neurons resuming more normal activity.

Major depression is one of the most common mental health disorders in the United States, according to the National Institute of Mental Health, with an estimated 17.3 million adults experiencing at least one episode. Prevalence rates are highest among 18-25 year olds, females having about twice the risk of men, and depression can run in families.

Only about one-third of patients achieve full remission with existing treatments and anhedonia, the inability to experience pleasure, which increases suicide risk, typically is the last symptom to resolve. However, mechanisms behind depression’s effects remain poorly understood, the scientists say.

“We want to find better ways to treat it, including more targeted treatments that may reduce side effects, which often are significant enough to prompt patients to stop taking them,” Lu says. Undesirable effects can include weight gain and insomnia.

Prozac, for example, reduces the uptake of serotonin, a neurotransmitter involved in mood regulation, but serotonin also has important functions like regulating the sleep cycle, and sleep disturbances are an established side effect of selective serotonin-reuptake inhibitors.

While it’s unknown if some of the existing antidepressants happen to impact AgRP neurons, it’s possible that new therapies designed to target the neurons could also produce weight gain because of the neurons’ role in feeding behavior and metabolism, Lu notes.

Lu was among the scientists who earlier characterized the network of AgRP neurons in the brain, and was the first to show fluctuations in the production of AgRP over the course of the day and that a surge of glucocorticoid stress hormones comes before peak expression of AgRP and feeding.

The new study shows that AgRP neurons are a key component to the neural circuitry underlying depression-like behavior, they write, and chronic stress causes AgRP dysfunction. They suspect one reason for the reduced excitability of the neurons is increased sensitivity to the inhibitory neurotransmitter GABA.

AgRP neurons are stimulated by hunger signals and inhibited by satiety. Previous studies have shown that when activated, AgRP neurons can produce significant increases in eating that can result in significant weight gain. Activating these neurons in mice, in fact, increases their eating and food seeking. Just the presence of food increases the firing of AgRP neurons, reinforcing that you are hungry and driving you to pick up that fork, Lu says of the neuron sometimes dubbed the hanger neuron.

Eliminating AgRP neurons conversely suppresses feeding and has been shown to enhance anorexia.

The new study’s first author is Dr. Xing Fang, who completed graduate studies in the neurosciences at MCG and The Graduate School at AU and is now a postdoctoral scholar at the University of Southern California.

The hypothalamus is a small region — about the size of an almond — located just above the brainstem and involved in essentials like body temperature, blood pressure and heart rate, emotion and sleep cycles, as well as appetite and weight control.

The research was supported by the National Institutes of Health.

Read the full study.

Featured image: Dr. Xin-Yun Lu © Phil Jones, freelance photographer


Reference: Fang, X., Jiang, S., Wang, J. et al. Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-020-01004-x


Provided by Medical College of Georgia at Augusta University

Study Reveals Neurons Responsible for Rapidly Stopping Behaviors, Actions (Neuroscience)

First-Ever Study in People Describes ‘Stop Signal Neurons’ in Patients with Parkinson’s Disease

For the first time in humans, investigators at Cedars-Sinai have identified the neurons responsible for canceling planned behaviors or actions—a highly adaptive skill that when lost, can lead to unwanted movements.

Known as “stop signal neurons,” these neurons are critical in powering someone to stop or abort an action they have already put in process.

“We have all had the experience of sitting at a traffic stop and starting to press the gas pedal but then realizing that the light is still red and quickly pressing the brake again,” said Ueli Rutishauser, PhD, professor of Neurosurgery, Neurology and Biomedical Sciences at Cedars-Sinai and senior author of the study published online in the peer-reviewed journal Neuron. “This first-in-human study of its kind identifies the underlying brain process for stopping actions, which remains poorly understood.”

The findings, Rutishauser said, reveals that such neurons exist in an area of the brain called the subthalamic nucleus, which is a routine target for treating Parkinson’s disease with deep brain stimulation.

Ueli Rutishauser, PhD © Cedars sinai

Patients with Parkinson’s disease, a motor system disorder affecting nearly 1 million people in the U.S., suffer simultaneously from both the inability to move and the inability to control excessive movements. This paradoxical mix of symptoms has long been attributed to disordered function in regions of the brain that regulate the initiation and halting of movements. How this process occurs and what regions of the brain are responsible have remained elusive to define despite years of intensive research.

Now, a clearer understanding has emerged.

Jim Gnadt, PhD, program director for the NIH Brain Research through Advancing Innovative Technologies® (BRAIN) Initiative, which funded this project, explained that this study helps us understand how the human brain is wired to accomplish rapid movements.

“It is equally important for motor systems designed for quick, fast movements to have a ‘stop control’ available at a moment’s notice—like a cognitive change in plan—and also to keep the body still as one begins to think about moving but has yet to do so.”

To make their discovery, the Cedars-Sinai research team studied patients with Parkinson’s disease who were undergoing brain surgery to implant a deep brain stimulator—a relatively common procedure to treat the condition. Electrodes were lowered into the basal ganglia, the part of the brain responsible for motor control, to precisely target the device while the patients were awake.

The researchers discovered that neurons in one part of the basal ganglia region—the subthalamic nucleus—indicated the need to “stop” an already initiated action. These neurons responded very quickly after the appearance of the stop signal.

“This discovery provides the ability to more accurately target deep brain stimulation electrodes, and in return, target motor function and avoid stop signal neurons,” said Adam Mamelak, MD, professor of Neurosurgery and co-first author of the study.

Mamelak notes that many patients with Parkinson’s disease have issues with impulsiveness and the inability to stop inappropriate actions. As a next step, Mamelak and the research team will build on this discovery to investigate whether these neurons also play a role in these more cognitive forms of stopping.

“There is strong reason to believe that they do, based on significant literature linking inability to stop to impulsiveness,” said Mamelak. “This discovery will enable investigating whether the neurons we discovered are the common mechanisms that link the two phenomena.”

Clayton Mosher, PhD, co-first author of the study and a project scientist in the Rutishauser lab, says while it has long been hypothesized that such neurons exist in a particular brain area, such neurons had never been observed “in action” in humans.

“Stop neurons responded very quickly following the onset of the stop cue on the screen, a key requirement to be able to suppress an impending action,” said Mosher. “Our result is the first single-neuron demonstration in humans of signals that are likely carried by this particular pathway.”

Funding: Research reported in this publication was supported by the NIH Brain Research through Advancing Innovative Technologies® (BRAIN) Initiative Awards U01NS098961 and U01NS103792.

DOI: Distinct roles of dorsal and ventral subthalamic neurons in action selection and cancellation

Featured image: A coronal view of a human brain with Parkinson’s disease. Image by Getty.


Provided by Cedars Senai