Researchers discover a specific brain circuit damaged by social isolation during childhood

Study in mice shows long-lasting effects and points the way to potential treatments

August 31, 2020

Science Daily/The Mount Sinai Hospital / Mount Sinai School of Medicine

Loneliness is recognized as a serious threat to mental health. Even as our world becomes increasingly connected over digital platforms, young people in our society are feeling a growing sense of isolation. The COVID-19 pandemic, which forced many countries to implement social distancing and school closures, magnifies the need for understanding the mental health consequences of social isolation and loneliness. While research has shown that social isolation during childhood, in particular, is detrimental to adult brain function and behavior across mammalian species, the underlying neural circuit mechanisms have remained poorly understood.

A research team from the Icahn School of Medicine at Mount Sinai has now identified specific sub-populations of brain cells in the prefrontal cortex, a key part of the brain that regulates social behavior, that are required for normal sociability in adulthood and are profoundly vulnerable to juvenile social isolation in mice. The study findings, which appear in the August 31 issue of Nature Neuroscience, shed light on a previously unrecognized role of these cells, known as medial prefrontal cortex neurons projecting to the paraventricular thalamus, the brain area that relays signals to various components of the brain's reward circuitry. If the finding is replicated in humans, it could lead to treatments for psychiatric disorders connected to isolation.

"In addition to identifying this specific circuit in the prefrontal cortex that is particularly vulnerable to social isolation during childhood, we also demonstrated that the vulnerable circuit we identified is a promising target for treatments of social behavior deficits," says Hirofumi Morishita, MD, PhD, Associate Professor of Psychiatry, Neuroscience, and Ophthalmology at the Icahn School of Medicine at Mount Sinai, a faculty member of The Friedman Brain Institute and the Mindich Child Health and Development Institute, and senior author of the paper. "Through stimulation of the specific prefrontal circuit projecting to the thalamic area in adulthood, we were able to rescue the sociability deficits caused by juvenile social isolation."

Specifically, the team found that, in male mice, two weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the paraventricular thalamus during social exposure in adulthood. Researchers found that juvenile isolation led to both reduced excitability of the prefrontal neurons projecting to the paraventricular thalamus and increased inhibitory input from other related neurons, suggesting a circuit mechanism underlying sociability deficits caused by juvenile social isolation. To determine whether acute restoration of the activity of prefrontal projections to the paraventricular thalamus is sufficient to ameliorate sociability deficits in adult mice that underwent juvenile social isolation, the team employed a technique known as optogenetics to selectively stimulate the prefrontal projections to paraventricular thalamus. The researchers also used chemogenetics in their study. While optogenetics enables researchers to stimulate particular neurons in freely moving animals with pulses of light, chemogenetics allows non-invasive chemical control over cell populations. By employing both of these techniques, the researchers were able to quickly increase social interaction in these mice once light pulses or drugs were administered to them.

"We checked the presence of social behavior deficits just prior to stimulation and when we checked the behavior while the stimulation was ongoing, we found that the social behavior deficits were reversed," said Dr. Morishita.

Given that social behavior deficits are a common dimension of many neurodevelopmental and psychiatric disorders, such as autism and schizophrenia, identification of these specific prefrontal neurons will point toward therapeutic targets for the improvement of social behavior deficits shared across a range of psychiatric disorders. The circuits identified in this study could potentially be modulated using techniques like transcranial magnetic stimulation and/or transcranial direct current stimulation.

https://www.sciencedaily.com/releases/2020/08/200831112345.htm

REM sleep tunes eating behavior

August 6, 2020

Science Daily/University of Bern

Despite our broad understanding of the different brain regions activated during rapid-eye-movement sleep, little is known about what this activity serves for. Researchers at the University of Bern and the Inselspital have now discovered that the activation of neurons in the hypothalamus during REM sleep regulates eating behaviour: suppressing this activity in mice decreases appetite.

While we are asleep, we transition between different phases of sleep each of which may contribute differently to us feeling rested. During (rapid eye movement) REM sleep, a peculiar sleep stage also called paradoxical sleep during which most dreaming occurs, specific brain circuits show very high electrical activity, yet the function of this sleep-specific activity remains unclear.

Among the brain regions that show strong activation during REM sleep are areas that regulate memory functions or emotion, for instance. The lateral hypothalamus, a tiny, evolutionarily well conserved brain structure in all mammals also shows high activity during REM sleep. In the awake animals, neurons from this brain region orchestrate appetite and the consumption of food and they are involved in the regulation of motivated behaviours and addiction.

In a new study, researchers headed by Prof. Dr. Antoine Adamantidis at the University of Bern set out to investigate the function of the activity of hypothalamic neurons in mice during REM sleep. They aimed at better understanding how neural activation during REM sleep influences our day-to-day behaviour. They discovered that suppressing the activity of these neurons decreases the amount of food the mice consume. "This suggests that REM sleep is necessary to stabilize food intake," says Adamantidis. The results of this study have been published in the journal Proceedings of the National Academy of Sciences (PNAS).

Long-lasting effect on neuronal activity and feeding behavior

The researcher discovered that specific activity patterns of neurons in the lateral hypothalamus that usually signal eating in the awake mouse are also present when the animals were in the stage of REM sleep. To assess the importance of these activity patterns during REM sleep the research group used a technique called optogenetics, with which they used light pulses to precisely shut down the activity of hypothalamic neurons during REM sleep. As a result, the researchers found that the activity patterns for eating were modified and that the animals consumed less food.

"We were surprised how strongly and persistently our intervention affected the neural activity in the lateral hypothalamus and the behaviour of the mice," says Lukas Oesch, the first author of the study. He adds: "The modification in the activity patterns was still measurable after four days of regular sleep." These findings suggest that electrical activity in hypothalamic circuits during REM sleep are highly plastic and essential to maintain a stable feeding behaviour in mammals.

It is a question of quality

These findings point out that sleep quantity alone is not solely required for our well-being, but that sleep quality plays a major role in particular to maintain appropriate eating behaviour. "This is of particular relevance in our society where not only sleep quantity decreases but where sleep quality is dramatically affected by shift work, late night screen exposure or social jet-lag in adolescents," explains Adamantidis.

The discovered link between the activity of the neurons during REM sleep and eating behaviour may help developing new therapeutical approaches to treat eating disorders. It might also be relevant for motivation and addiction. "However, this relationship might depend on the precise circuitry, the sleep stage and other factors yet to be uncovered," adds Adamantidis.

https://www.sciencedaily.com/releases/2020/08/200806111820.htm

Blue light triggers memory and emphatic fear in mice via a non-invasive approach

January 21, 2020

Science Daily/Institute for Basic Science

Researchers at the Center for Cognition and Sociality, within the Institute for Basic Science (IBS) in South Korea, have engineered an improved biological tool that controls calcium (Ca2+) levels in the brain via blue light. Published in Nature Communications, this optogenetic construct, called monster-OptoSTIM1 or monSTIM1 for short, causes a change in mice's fear learning behavior without the need of optic fiber implants in the brain.

The brain utilizes Ca2+ signaling to regulate a variety of functions, including memory, emotion, and movement. Several evidences show correlation between abnormally regulated Ca2+ levels in certain brain cells and neurodegenerative diseases, but the details still remain obscure. For understanding the precise role of Ca2+ signaling, the IBS team is studying Ca2+-specific modulators that can be triggered in different parts of the brain at a designated time.

Optogenetics uses light to control Ca2+ signaling in the mouse brain. Since the brain is surrounded by hair, skin and skull, which prevent light from reaching deep tissues, optic fiber insertion in the brain used to be the norm in optogenetics. However, these implants can cause inflammation, morphological changes of neurons and disconnection of neural circuits. In this study, the research team improved their optogenetic tool so that it works with an external source of blue light, shone from the ceiling of the mouse cage, and without the need of brain implants.

MonSTIM1 is made of a part (CRY2) that responds to blue light and another part (STIM1) that activates calcium channels. Compared to the previously developed optogenetic techniques, the researchers were able to enhance CRY2's light-sensitivity approximately 55-fold and also avoid the increase of basal Ca2+ levels. The monSTIM1 construct was injected into the mouse brain through a virus, and was shown to activate Ca2+ signals in the cortex as well as in the deeper hippocampus and thalamus regions.

The team observed behavioral changes in mice with monSTIM1 expressed in excitatory neurons in the anterior cingulate cortex, a brain region that has a central function in empathic emotions. Mice with activated monSTIM1 froze with fear by looking at other mice, which experienced a mild electric foot shock. Twenty-four hours later the same mice remembered about it and showed again an enhanced fear response, indicating that Ca2+ signaling contributed to both short- and long-term social fear responses.

"MonSTIM1 can be applied to a wide range of brain calcium research and brain cognitive science research, because it allows easy manipulation of intracellular calcium signals without damaging the brain," says Won Do Heo (KAIST professor), leading author of this research.

https://www.sciencedaily.com/releases/2020/01/200121123953.htm

How stress can curb the desire to eat in an animal model

August 16, 2019

Science Daily/University of Texas Health Science Center at Houston

Eating disorder researchers at The University of Texas Health Science Center at Houston (UTHealth) have discovered a neurocircuit in mice that, when activated, increased their stress levels while decreasing their desire to eat. Findings appear in Nature Communications.

The scientists believe their research could aid efforts to develop treatments for a serious eating disorder called anorexia nervosa, which has the highest mortality rate of any mental disorder, according to the National Institute of Mental Health. People with anorexia nervosa avoid food, severely restrict food, or eat very small quantities of only certain foods. Even when they are dangerously underweight, they may see themselves as overweight.

"We have identified a part of the brain in a mouse model that controls the impact of emotions on eating," said Qingchun Tong, PhD, the study's senior author and an associate professor in the Center for Metabolic and Degenerative Disease at McGovern Medical School at UTHealth.

Because mice and humans have similar nervous systems, Tong, the Cullen Chair in Molecular Medicine at UTHealth, believes their findings could shed light on the part of the human brain that regulates hunger.

The investigators believe they are among the first to demonstrate the role of this neurocircuit in the regulation of both stress and hunger.

While previous research has established that stress can both reduce and increase a person's desire to eat, the neural mechanisms that act on the regulation of eating by stress-related responses largely remain a mystery.

Tong's team focused on a neurocircuit connecting two parts of the mouse brain: the paraventricular hypothalamus, an eating-related zone in the brain, and the ventral lateral septum, an emotional zone in the brain. The neurocircuit acts as an on/off switch.

When researchers activated the neurocircuit, there was an increase in anxiety levels and a decrease in appetite. Conversely, when the investigators inhibited the neurocircuit, anxiety levels dropped and hunger increased.

The scientists used a research technique called optogenetics to turn the neurons in question on and off.

https://www.sciencedaily.com/releases/2019/08/190816191450.htm

Manipulating specific brain waves in sleep shifts balance between learning or forgetting a new skill

October 3, 2019

Science Daily/University of California - San Francisco

Distinct patterns of electrical activity in the sleeping brain may influence whether we remember or forget what we learned the previous day, according to a new study by UC San Francisco researchers. The scientists were able to influence how well rats learned a new skill by tweaking these brainwaves while animals slept, suggesting potential future applications in boosting human memory or forgetting traumatic experiences, the researchers say.

In the new study, published online October 3 in the journal Cell, a research team led by Karunesh Ganguly, MD, PhD, an associate professor of neurology and member of the UCSF Weill Institute for Neurosciences, used a technique called optogenetics to dampen specific types of brain activity in sleeping rats at will.

This allowed the researchers to determine that two distinct types of slow brain waves seen during sleep, called slow oscillations and delta waves, respectively strengthened or weakened the firing of specific brain cells involved in a newly learned skill -- in this case how to operate a water spout that the rats could control with their brains via a neural implant.

"We were astonished to find that we could make learning better or worse by dampening these distinct types of brain waves during sleep," Ganguly said. "In particular, delta waves are a big part of sleep, but they have been less studied, and nobody had ascribed a role to them. We believe these two types of slow waves compete during sleep to determine whether new information is consolidated and stored, or else forgotten."

"Linking a specific type of brain wave to forgetting is a new concept," Ganguly added. "More studies have been done on strengthening of memories, fewer on forgetting, and they tend to be studied in isolation from one another. What our data indicate is that there is a constant competition between the two -- it's the balance between them that determines what we remember."

Some Sleep to Remember, Others to Forget

Over the past two decades the centuries-old human hunch that sleep plays a role in the formation of memories has been increasingly supported by scientific studies. Animal studies show that the same neurons involved in forming the initial memory of a new task or experience are reactivated during sleep to consolidate these memory traces in the brain. Many scientists believe that forgetting is also an important function of sleep -- perhaps as a way of uncluttering the mind by eliminating unimportant information.

Slow oscillations and delta waves are hallmarks of so-called non-REM sleep, which -- in humans, at least -- makes up half or more of a night's sleep. There is evidence that these non-REM sleep stages play a role in consolidating various kinds of memory, including the learning of motor skills. In humans, researchers have found that time spent in the early stages of non-REM sleep is associated with better learning of a simple piano riff, for instance.

Ganguly's team began studying the role of sleep in learning as part of their ongoing efforts to develop neural implants that would allow people with paralysis to more reliably control robotic limbs with their brain. In early experiments in laboratory animals, he had noted that the biggest improvements in the animals' ability to operate these brain-computer interfaces occurred when they slept between training sessions.

"We realized that we needed to understand how learning and forgetting occur during sleep to understand how to truly integrate artificial systems into the brain," Ganguly said.

Brain Waves Compete to Determine Learning During Sleep

In the new study, a dozen rats were implanted with electrodes that monitor firing among a small group of selected neurons in their brains' motor cortex, which is involved in conceiving and executing voluntary movements. Producing a particular pattern of neural firing allowed the rats to control a water-dispensing tube in their cages. In essence, the rats were performing a kind of biofeedback -- each rat learned how to fire a small ensemble of neurons together in a unique new pattern in order to move the spigot and get the water.

Ganguly's team observed the same unique new firing pattern replaying in animals' brains as they slept. The strength of this reactivation during sleep determined how well rats were able to control the water spout the next day. But the researchers wanted to go further -- to understand how the brain controls whether rats learn or forget while they slumber.

To manipulate the effect of brain waves during non-REM sleep, the researchers genetically modified rat neurons to express a light-sensitive optogenetic control switch, allowing the team to use lasers and fiber optics to instantaneously dampen brain activity associated with the transmission of specific brain waves. With precise, millisecond timing of the laser, the scientists in separate experiments specifically dampened either slow oscillating waves or delta waves in a tiny patch of the brain around the new memory circuit.

Disruption of delta waves strengthened reactivation of the task-associated neural activity during sleep and was associated with better performance upon waking. Conversely, disruption of slow oscillations resulted in poor performance upon waking. "Slow oscillations seem to be protecting new patterns of neural firing after learning, while delta waves tend to erase them and promote forgetting," Ganguly said.

Further analysis showed that in order to protect learning, slow oscillations had to occur at the same time as a third, well-studied brain wave phenomenon, called sleep spindles. A sleep spindle is a high-frequency, short-duration burst of activity that originates in a region called the thalamus and then propagates to other parts of the brain. They have been linked to memory consolidation, and a lack of normal sleep spindles is associated with brain maladies including schizophrenia and developmental delay, and also with aging.

"Our work shows that there is a strong drive to forget during sleep," Ganguly said. "Very brief pairings of sleep spindles and slow oscillations can overcome delta wave-driven forgetting and preserve learning, but the balance is very delicate. Even small disturbances in these events lead to forgetting."

It's not yet known what tips the scales between delta wave-driven forgetting and slow oscillation-driven learning, but it's clear that better understanding the process could have profound impacts on the study of human learning and memory, Ganguly said. "Sleep is truly driving profound changes in the brain. Understanding these changes will be critical for brain integration of artificial interfaces and may one day allow us to modify neural circuits to aid in movement rehabilitation, such as after stroke, where previous studies have shown that sleep plays an important role in successful recovery."

Funding: The study was funded by the Department of Veterans Affairs, the National Institutes of Health, the National Research Foundation of Korea, and the Burroughs Wellcome Fund. Ganguly designed the study with postdoctoral fellows Jaekyung Kim and Tanuj Gulati, who conducted the experiments.

https://www.sciencedaily.com/releases/2019/10/191003114039.htm

New research provides hope for people living with chronic pain

September 9, 2019

Science Daily/University of Calgary

Researchers have been investigating which brain circuits are changed by injury, in order to develop targeted therapies to reset the brain to stop chronic pain.

When you experience severe pain, like breaking or shattering a bone, the pain isn't just felt at the sight of the injury. There is an entire network of receptors in your body running from the site of the injury, through your nervous system, along the spine and into the brain that reacts to tell you how much pain you are feeling. This system goes into high alert when the injury occurs, and then usually resets as you heal. However, sometimes, the system doesn't reset, and even though the injury has mended, nerve damage has caused your brain to be permanently altered. It means you still feel the pain, even though the injury has fully healed.

Dr. Gerald Zamponi, PhD, and a team with the Cumming School of Medicine's Hotchkiss Brain Institute (HBI) and researchers at Stanford University, California, have been investigating which brain circuits are changed by injury, in order to develop targeted therapies to reset the brain to stop chronic pain.

"It's a terrible situation for many people living with chronic pain, because there is often very little that works for them to control their pain," says Zamponi, senior associate dean (research) and a professor in the departments of Physiology & Pharmacology and Cell Biology & Anatomy at the CSM. "This doesn't just impact people who have experienced peripheral nerve damage. There are cases of people having a stroke and are experiencing severe pain afterward in another part of their body. It may also explain why some people who have lost a limb can still feel pain in the limb even though it's no longer there."

Working closely with Dr. Junting Huang, PhD, and Dr. Vinicius Gadotti, PhD, co-first authors on the study, along with Dr. Zizhen Zhang, PhD, the team utilized optogenetics to study the neuron connections in the brains of mice. Optogenetics allow scientists to use light to target and control individual neurons in the brain. With this tool, researchers are able to map a pathway showing which neurons are communicating with each other to process a pain signal and then communicate this information all the way back through the spine where painful stimuli are first processed.

"We've known that certain parts of the brain are important for pain, but now we've been able to identify a long range circuit in the brain that carries the message and we've been able to show how it is altered during chronic pain states," says Zamponi who is also a member of the CSM's Alberta Children's Hospital Research Institute.

Much of the research for chronic pain has been focused on the spinal cord and targeting nerve fibres where the pain response is processed. Treatment with current pain relief medications is often ineffective and can have serious side effects. This new understanding of the pain signaling circuit may allow scientists to develop new drug therapies and targeted brain stimulation treatments to address chronic nerve pain, and hopefully provide relief for pain sufferers. Working with mice, Zamponi's lab has proven that targeting certain pathways in the brain can interfere with the pain signal and stop pain sensation.

"If you understand how the brain rewires itself, you can interfere with that and you can restore it. That's important," says Zamponi. "If you think about it, there are some drugs you don't want to give to kids who have chronic pain. What if you could non-invasively stimulate certain brain regions or inhibit them, and bring pain relief that way? I think it would be a tremendous, alternative approach to taking drugs."

Zamponi expects the results the lab has seen in mice will be comparable in humans. While the human brain is very complex, the communication network is similar in the animal brain. Findings are published in Nature Neuroscience.

The Zamponi lab is already applying this research to investigate how this brain circuit interacts with other parts of the brain involved in more complex behaviours like the interaction between pain pathways and addiction, depression, and anxiety.

https://www.sciencedaily.com/releases/2019/09/190909113027.htm

How the brain fights off fears that return to haunt us

April 1, 2019

Science Daily/University of Texas at Austin

Neuroscientists at The University of Texas at Austin have discovered a group of cells in the brain that are responsible when a frightening memory re-emerges unexpectedly, like Michael Myers in every "Halloween" movie. The finding could lead to new recommendations about when and how often certain therapies are deployed for the treatment of anxiety, phobias and post-traumatic stress disorder (PTSD).

In the new paper, out today in the journal Nature Neuroscience, researchers describe identifying "extinction neurons," which suppress fearful memories when they are activated or allow fearful memories to return when they are not.

Since the time of Pavlov and his dogs, scientists have known that memories we thought we had put behind us can pop up at inconvenient times, triggering what is known as spontaneous recovery, a form of relapse. What they didn't know was why it happened.

"There is frequently a relapse of the original fear, but we knew very little about the mechanisms," said Michael Drew, associate professor of neuroscience and the senior author of the study. "These kinds of studies can help us understand the potential cause of disorders, like anxiety and PTSD, and they can also help us understand potential treatments."

One of the surprises to Drew and his team was finding that brain cells that suppress fear memories hid in the hippocampus. Traditionally, scientists associate fear with another part of the brain, the amygdala. The hippocampus, responsible for many aspects of memory and spatial navigation, seems to play an important role in contextualizing fear, for example, by tying fearful memories to the place where they happened.

The discovery may help explain why one of the leading ways to treat fear-based disorders, exposure therapy, sometimes stops working. Exposure therapy promotes the formation of new memories of safety that can override an original fear memory. For example, if someone becomes afraid of spiders after being bitten by one, he might undertake exposure therapy by letting a harmless spider crawl on him. The safe memories are called "extinction memories."

"Extinction does not erase the original fear memory but instead creates a new memory that inhibits or competes with the original fear," Drew said. "Our paper demonstrates that the hippocampus generates memory traces of both fear and extinction, and competition between these hippocampal traces determines whether fear is expressed or suppressed."

Given this, recommended practices around the frequency and timing of exposure therapy may need revisiting, and new pathways for drug development may be explored.

In experiments, Drew and his team placed mice in a distinctive box and induced fear with a harmless shock. After that, when one of the mice was in the box, it would display fear behavior until, with repeated exposure to the box without a shock, the extinction memories formed, and the mouse was not afraid.

Scientists were able to artificially activate the fear and suppress the extinction trace memories by using a tool called optogenetics to turn the extinction neurons on and off again.

"Artificially suppressing these so-called extinction neurons causes fear to relapse, whereas stimulating them prevents fear relapse," Drew said. "These experiments reveal potential avenues for suppressing maladaptive fear and preventing relapse."

https://www.sciencedaily.com/releases/2019/04/190401115757.htm