Scientists identify new brain circuit in mice that controls body's inflammatory reactions

The brain can direct the immune system to an unexpected degree, capable of detecting, ramping up and tamping down inflammation, shows a new study in mice from researchers at Columbia's Zuckerman Institute.

"The brain is the center of our thoughts, emotions, memories and feelings," said Hao Jin, PhD, a co-first author of the study published online today in Nature. "Thanks to great advances in circuit tracking and single-cell technology, we now know the brain does far more than that. It is monitoring the function of every system in the body."

Future research could identify drugs that can target this newfound brain circuit to help treat a vast range of disorders and diseases in which the immune system goes haywire.

"This new discovery could provide an exciting therapeutic venue to control inflammation and immunity," said Charles S. Zuker, PhD, the study's senior author, a principal investigator at Columbia's Zuckerman Institute and a Howard Hughes Medical Institute investigator.

Recent work from the Zuker lab and other groups is revealing the importance of the body-brain axis, a vital pathway that conveys data between the organs and the brain. For example, Dr. Zuker and his colleagues discovered that sugar and fat entering the gut use the body-brain axis to drive the craving and strong appetite for sugary and fatty foods.

"We found all these ways in which the body is informing the brain about the body's current state," said co-first author Mengtong Li, PhD, a postdoctoral researcher in the Zuker lab. "We wanted to understand how much farther the brain's knowledge and control of the body's biology went."

The scientists looked for connections the brain might have with inflammation and innate immunity, the defense system shared by all animals and the most ancient component of the immune system. Whereas the adaptive immune system remembers previous encounters with intruders to help it resist them if they invade again, the innate immune system attacks anything with common traits of germs. The relative simplicity of innate immunity lets it respond to new insults more quickly than adaptive immunity.

Prior studies in humans revealed that electrically stimulating the vagus nerve -- a bundle of thousands of nerve fibers linking the brain and the body's internal organs -- could reduce the response linked to a specific inflammatory molecule. However, much remained unknown about the nature of this body-brain system: for instance, the generality of the brain's modulation of immunity and the inflammatory response, the selective lines of communication between the body and the brain, the logic of the underlying neural circuit, and the identity of the vagal and brain components that monitor and regulate inflammation.

The Zuker lab turned to a bacterial compound that sets off innate immune responses. The scientists found that giving this molecule to mice activated the caudal nucleus of the solitary tract, or cNST, which is tucked inside the brainstem. The cNST plays a major role in the body-brain axis and is the primary target of the vagus nerve.

The scientists showed that chemically suppressing the cNST resulted in an out-of-control inflammatory response to the immune insult: levels of pro-inflammatory molecules released by the immune system were more than three times higher than usual, and levels of anti-inflammatory immune compounds were roughly three times lower than normal. In contrast, artificially activating the cNST reduced pro-inflammatory molecule levels by nearly 70 percent and increased anti-inflammatory chemical levels almost tenfold.

"Similar to a thermostat, this newfound brain circuit helps increase or decrease inflammatory responses to keep the body responding in a healthy manner," said Dr. Jin, who started this study as a postdoctoral researcher in Dr. Zuker's lab. Dr. Jin is now a tenure track investigator at the National Institute of Allergy and Infectious Diseases. "In retrospect, it makes sense to have a master arbiter controlling this vital response."

Previous vagus nerve stimulation research in humans suggests the findings go beyond mice. The new research may also be in line with thousands of years of thought on the potential importance of the mind on the body.

"A lot of psychosomatic effects could actually be linked to brain circuits telling your body something," Dr. Jin noted.

The scientists identified the specific groups of neurons in the vagus nerve and in the cNST that help detect and control pro- and anti-inflammatory activity. "This opens up a new window into how the brain monitors and modulates body physiology," said Dr. Zuker, a professor of biochemistry, molecular biophysics and neuroscience at Columbia's Vagelos College of Physicians and Surgeons.

Discovering ways to control this newfound brain circuit may lead to novel therapies for common auto-immune diseases such as rheumatoid arthritis, type I diabetes, multiple sclerosis, neurodegenerative diseases, lupus, inflammatory bowel disease and Crohn's disease, as well as conditions such as long COVID syndrome, immune rejection of transplanted organs, and the potentially deadly outbursts known as cytokine storms that COVID infections can trigger.

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Researchers identify the link between memory and appetite in the human brain to explain obesity

Disrupted connections between memory and appetite regulating brain circuits are directly proportional to body mass index (BMI), notably in patients who suffer from disordered or overeating that can lead to obesity, such as binge eating disorder (BED), according to new research from the Perelman School of Medicine at the University of Pennsylvania. Published today in Nature, the research notes that individuals who are obese have impaired connections between the dorsolateral hippocampus (dlHPC) and the lateral hypothalamus (LH), which may impact their ability to control or regulate emotional responses when anticipating rewarding meals or treats.

"These findings underscore that some individual's brains can be fundamentally different in regions that increase the risk for obesity," senior author, Casey Halpern, MD, an associate professor of Neurosurgery and Chief of Stereotactic and Functional Neurosurgery at Penn Medicine and the Corporal Michael J. Crescenz Veterans Affairs Medical Center. "Conditions like disordered eating and obesity are a lot more complicated than simply managing self-control and eating healthier. What these individuals need is not more willpower, but the therapeutic equivalent of an electrician that can make right these connections inside their brain."

The dlHPC is located in the region of the brain that processes memory, and the LH is in the region of the brain that is responsible for keeping the body in a stable state, called homeostasis. Previous research has found an association with loss of function in the human hippocampus in individuals with obesity and related disordered eating, like BED. However, outside of imaging techniques such as magnetic resonance imaging (MRI), the role of the hippocampus has been difficult to study in humans with obesity and related eating disorders.

In this study, researchers were able to evaluate patients whose brains were already being monitored electrically in the Epilepsy Monitoring Unit. Researchers monitored brain activity as patients anticipated and then received a sweet treat (a chocolate milkshake). They found that both the dlHPC and the LH activated simultaneously when participants anticipated receiving the rewarding meal. These researchers confirmed using stimulation techniques pioneered by coauthors, Kai Miller, MD, PhD, and Dora Hermes Miller, PhD, from Mayo Clinic, that this specific zone of the hippocampus, the dlHPC, and LH exhibited extremely strong connectivity, as well.

In individuals with obesity, researchers found that the impairment of this hypothalamus-hippocampus circuit was directly proportional to their BMI. That is, in participants with a high BMI, the connection was even more disturbed.

To further validate the connection, Halpern's team used a technique called "brain clearing," to analyze brain tissue. The technique revealed melanin-concentrating hormone, a hormone known to regulate feeding behavior that is produced in the LH. They found the presence of MCH in the dlHPC, and nowhere else, confirming a link between the two regions.

"The hippocampus has never been targeted to treat obesity, or the disordered eating that can sometimes cause obesity," said Halpern. "We hope to be able to use this research to both identify which individuals who are likely to develop obesity later in life, and to develop novel therapies -- both invasive and not -- to help improve function of this critical circuit that seems to go awry in patients who are obese."

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How the brain generates rhythmic behavior

Many of our bodily functions, such as walking, breathing, and chewing, are controlled by brain circuits called central oscillators, which generate rhythmic firing patterns that regulate these behaviors.

MIT neuroscientists have now discovered the neuronal identity and mechanism underlying one of these circuits: an oscillator that controls the rhythmic back-and-forth sweeping of tactile whiskers, or whisking, in mice. This is the first time that any such oscillator has been fully characterized in mammals.

The MIT team found that the whisking oscillator consists of a population of inhibitory neurons in the brainstem that fires rhythmic bursts during whisking. As each neuron fires, it also inhibits some of the other neurons in the network, allowing the overall population to generate a synchronous rhythm that retracts the whiskers from their protracted positions.

"We have defined a mammalian oscillator molecularly, electrophysiologically, functionally, and mechanistically," says Fan Wang, an MIT professor of brain and cognitive sciences and a member of MIT's McGovern Institute for Brain Research. "It's very exciting to see a clearly defined circuit and mechanism of how rhythm is generated in a mammal."

Wang is the senior author of the study, which appears today in Nature. The lead authors of the paper are MIT research scientists Jun Takatoh and Vincent Prevosto.

Rhythmic behavior

Most of the research that clearly identified central oscillator circuits has been done in invertebrates. For example, Eve Marder's lab at Brandeis University found cells in the stomatogastric ganglion in lobsters and crabs that generate oscillatory activity to control rhythmic motion of the digestive tract.

Characterizing oscillators in mammals, especially in awake behaving animals, has proven to be highly challenging. The oscillator that controls walking is believed to be distributed throughout the spinal cord, making it difficult to precisely identify the neurons and circuits involved. The oscillator that generates rhythmic breathing is located in a part of the brain stem called the pre-Bötzinger complex, but the exact identity of the oscillator neurons is not fully understood.

"There haven't been detailed studies in awake behaving animals, where one can record from molecularly identified oscillator cells and manipulate them in a precise way," Wang says.

Whisking is a prominent rhythmic exploratory behavior in many mammals, which use their tactile whiskers to detect objects and sense textures. In mice, whiskers extend and retract at a frequency of about 12 cycles per second. Several years ago, Wang's lab set out try to identify the cells and the mechanism that control this oscillation.

To find the location of the whisking oscillator, the researchers traced back from the motor neurons that innervate whisker muscles. Using a modified rabies virus that infects axons, the researchers were able to label a group of cells presynaptic to these motor neurons in a part of the brainstem called the vibrissa intermediate reticular nucleus (vIRt). This finding was consistent with previous studies showing that damage to this part of the brain eliminates whisking.

The researchers then found that about half of these vIRt neurons express a protein called parvalbumin, and that this subpopulation of cells drives the rhythmic motion of the whiskers. When these neurons are silenced, whisking activity is abolished.

Next, the researchers recorded electrical activity from these parvalbumin-expressing vIRt neurons in brainstem in awake mice, a technically challenging task, and found that these neurons indeed have bursts of activity only during the whisker retraction period. Because these neurons provide inhibitory synaptic inputs to whisker motor neurons, it follows that rhythmic whisking is generated by a constant motor neuron protraction signal interrupted by the rhythmic retraction signal from these oscillator cells.

"That was a super satisfying and rewarding moment, to see that these cells are indeed the oscillator cells, because they fire rhythmically, they fire in the retraction phase, and they're inhibitory neurons," Wang says.

"New principles"

The oscillatory bursting pattern of vIRt cells is initiated at the start of whisking. When the whiskers are not moving, these neurons fire continuously. When the researchers blocked vIRt neurons from inhibiting each other, the rhythm disappeared, and instead the oscillator neurons simply increased their rate of continuous firing.

This type of network, known as recurrent inhibitory network, differs from the types of oscillators that have been seen in the stomatogastric neurons in lobsters, in which neurons intrinsically generate their own rhythm.

"Now we have found a mammalian network oscillator that is formed by all inhibitory neurons," Wang says.

The MIT scientists also collaborated with a team of theorists led by David Golomb at Ben-Gurion University, Israel, and David Kleinfeld at the University of California at San Diego. The theorists created a detailed computational model outlining how whisking is controlled, which fits well with all experimental data. A paper describing that model is appearing in an upcoming issue of Neuron.

Wang's lab now plans to investigate other types of oscillatory circuits in mice, including those that control chewing and licking.

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Sprint then stop? Brain is wired for the math to make it happen

Your new apartment is just a couple of blocks down the street from the bus stop but today you are late and you see the bus roll past you. You break into a full sprint. Your goal is to get to the bus as fast as possible and then to stop exactly in front of the doors (which are never in exactly the same place along the curb) to enter before they close. To stop quickly and precisely enough, a new MIT study in mice finds, the mammalian brain is niftily wired to implement principles of calculus.

One might think that coming to a screeching halt at a target after a flat out run would be as simple as a reflex, but catching a bus or running right up to a visually indicated landmark to earn a water reward (as the mice did), is a learned, visually guided, goal-directed feat. In such tasks, which are a major interest in the lab of senior author Mriganka Sur, Newton Professor of Neuroscience in The Picower Institute for Learning and Memory at MIT, the crucial decision to switch from one behavior (running) to another (stopping) comes from the brain's cortex, where the brain integrates the learned rules of life with sensory information to guide plans and actions.

"The goal is where the cortex comes in," said Sur, a faculty member of MIT's Department of Brain and Cognitive Sciences. "Where am I supposed to stop to achieve this goal of getting on the bus."

And that's also where it gets complicated. The mathematical models of the behavior that postdoc and study lead author Elie Adam developed predicted that a "stop" signal going directly from the M2 region of the cortex to regions in the brainstem, which actually control the legs, would be processed too slowly.

"You have M2 that is sending a stop signal, but when you model it and go through the mathematics, you find that this signal, by itself, would not be fast enough to make the animal stop in time," said Adam, whose work appears in the journal Cell Reports.

So how does the brain speed up the process? What Adam, Sur and co-author Taylor Johns found was that M2 sends the signal to an intermediary region called the subthalamic nucleus (STN), which then sends out two signals down two separate paths that re-converge in the brainstem. Why? Because the difference made by those two signals, one inhibitory and one excitatory, arriving one right after the other turns the problem from one of integration, which is a relatively slow adding up of inputs, to differentiation, which is a direct recognition of change. The shift in calculus implements the stop signal much more quickly.

Adam's model employing systems and control theory from engineering -- accurately -- predicted the speed needed for a proper stop and that differentiation would be necessary to achieve it, but it took a series of anatomical investigations and experimental manipulations to confirm the model's predictions.

First, Adam confirmed that indeed M2 was producing a surge in neural activity only when the mice needed to achieve their trained goal of stopping at the landmark. He also showed it was sending the resulting signals to the STN. Other stops for other reasons did not employ that pathway. Moreover, artificially activating the M2-STN pathway compelled the mice to stop and artificially inhibiting it caused mice overrun the landmark somewhat more often.

The STN certainly then needed to signal the brainstem -- specifically the pedunculopontine nucleus (PPN) in the mesenecephalic locomotor region. But when the scientists looked at neural activity starting in the M2 and then quickly resulting in the PPN, they saw that different types of cells in the PPN responded with different timing. Particularly, before the stop, excitatory cells were active and their activity reflected the speed of the animal during stops. Then, looking at the STN, they saw two kinds of surges of activity around stops -- one slightly slower than the other -- that were conveyed either directly to PPN through excitation or indirectly via the substantia nigra pars reticulata (SNr) through inhibition. The net result of the interplay of these signals in the PPN was an inhibition sharpened by excitation. That sudden change could be quickly found by differentiation to implement stopping.

"An inhibitory surge followed by excitation can create a sharp [change of] signal," Sur said.

The study dovetails with other recent papers. Working with Picower Institute investigator Emery N. Brown, Adam recently produced a new model of how deep brain stimulation in the STN quickly corrects motor problems that result from Parkinson's disease. And last year members of Sur's lab, including Adam, published a study showing how the cortex overrides the brain's more deeply ingrained reflexes in visually guided motor tasks. Together such studies contribute to understanding how the cortex can consciously control instinctually wired motor behaviors but also how important deeper regions, such as the STN, are to quickly implementing goal-directed behavior. A recent review from the lab expounds on this.

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A brain circuit in the thalamus helps us hold information in mind

As people age, their working memory often declines, making it more difficult to perform everyday tasks. One key brain region linked to this type of memory is the anterior thalamus, which is primarily involved in spatial memory -- memory of our surroundings and how to navigate them.

In a study of mice, MIT researchers have identified a circuit in the anterior thalamus that is necessary for remembering how to navigate a maze. The researchers also found that this circuit is weakened in older mice, but enhancing its activity greatly improves their ability to run the maze correctly.

This region could offer a promising target for treatments that could help reverse memory loss in older people, without affecting other parts of the brain, the researchers say.

"By understanding how the thalamus controls cortical output, hopefully we could find more specific and druggable targets in this area, instead of generally modulating the prefrontal cortex, which has many different functions," says Guoping Feng, the James W. and Patricia T. Poitras Professor in Brain and Cognitive Sciences at MIT, a member of the Broad Institute of Harvard and MIT, and the associate director of the McGovern Institute for Brain Research at MIT.

Feng is the senior author of the study, which appears today in the Proceedings of the National Academy of Sciences. Dheeraj Roy, a NIH K99 Awardee and a McGovern Fellow at the Broad Institute, and Ying Zhang, a J. Douglas Tan Postdoctoral Fellow at the McGovern Institute, are the lead authors of the paper.

Spatial memory

The thalamus, a small structure located near the center of the brain, contributes to working memory and many other executive functions, such as planning and attention. Feng's lab has recently been investigating a region of the thalamus known as the anterior thalamus, which has important roles in memory and spatial navigation.

Previous studies in mice have shown that damage to the anterior thalamus leads to impairments in spatial working memory. In humans, studies have revealed age-related decline in anterior thalamus activity, which is correlated with lower performance on spatial memory tasks.

The anterior thalamus is divided into three sections: ventral, dorsal, and medial. In a study published last year, Feng, Roy and Zhang studied the role of the anterodorsal (AD) thalamus and anteroventral (AV) thalamus in memory formation. They found that the AD thalamus is involved in creating mental maps of physical spaces, while the AV thalamus helps the brain to distinguish these memories from other memories of similar spaces.

In their new study, the researchers wanted to look more deeply at the AV thalamus, exploring its role in a spatial working memory task. To do that, they trained mice to run a simple T-shaped maze. At the beginning of each trial, the mice ran until they reached the T. One arm was blocked off, forcing them to run down the other arm. Then, the mice were placed in the maze again, with both arms open. The mice were rewarded if they chose the opposite arm from the first run. This meant that in order to make the correct decision, they had to remember which way they had turned on the previous run.

As the mice performed the task, the researchers used optogenetics to inhibit activity of either AV or AD neurons during three different parts of the task: the sample phase, which occurs during the first run; the delay phase, while they are waiting for the second run to begin; and the choice phase, when the mice make their decision which way to turn during the second run.

The researchers found that inhibiting AV neurons during the sample or choice phases had no effect on the mice's performance, but when they suppressed AV activity during the delay phase, which lasted 10 seconds or longer, the mice performed much worse on the task.

This suggests that the AV neurons are most important for keeping information in mind while it is needed for a task. In contrast, inhibiting the AD neurons disrupted performance during the sample phase but had little effect during the delay phase. This finding was consistent with the research team's earlier study showing that AD neurons are involved in forming memories of a physical space.

"The anterior thalamus in general is a spatial learning region, but the ventral neurons seem to be needed in this maintenance period, during this short delay," Roy says. "Now we have two subdivisions within the anterior thalamus: one that seems to help with contextual learning and the other that actually helps with holding this information."

Age-related decline

The researchers then tested the effects of age on this circuit. They found that older mice (14 months) performed worse on the T-maze task and their AV neurons were less excitable. However, when the researchers artificially stimulated those neurons, the mice's performance on the task dramatically improved.

Another way to enhance performance in this memory task is to stimulate the prefrontal cortex, which also undergoes age-related decline. However, activating the prefrontal cortex also increases measures of anxiety in the mice, the researchers found.

"If we directly activate neurons in medial prefrontal cortex, it will also elicit anxiety-related behavior, but this will not happen during AV activation," Zhang says. "That is an advantage of activating AV compared to prefrontal cortex."

If a noninvasive or minimally invasive technology could be used to stimulate those neurons in the human brain, it could offer a way to help prevent age-related memory decline, the researchers say. They are now planning to perform single-cell RNA sequencing of neurons of the anterior thalamus to find genetic signatures that could be used to identify cells that would make the best targets.

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Scientists can control brain circuits, behavior, and emotion using light

Controlling signal transmission and reception within the brain circuits is necessary for neuroscientists to achieve a better understanding of the brain's functions. Communication among neuron and glial cells is mediated by various neurotransmitters being released from the vesicles through exocytosis. Thus, regulating vesicular exocytosis can be a possible strategy to control and understand brain circuits.

However, it has been difficult to freely control the activity of brain cells in a spatiotemporal manner using pre-existing techniques. One is an indirect approach that involves artificially controlling the membrane potential of cells, but it comes with problems of changing the acidity of the surrounding environment or causing unwanted misfiring of neurons. Moreover, it is not applicable for use in cells that do not respond to the membrane potential changes, such as glial cells.

To address this problem, South Korean researchers led by Director C. Justin LEE at the Center for Cognition and Sociality within the Institute for Basic Science (IBS) and professor HEO Won Do at Korea Advanced Institute of Science and Technology (KAIST) developed Opto-vTrap, a light-inducible and reversible inhibition system that can temporarily trap vesicles from being released from brain cells. Opto-vTrap directly targets transmitters containing vesicles, and it can be used in various types of brain cells, even the ones that do not respond to membrane potential changes.

In order to directly control the exocytotic vesicles, the research team applied a technology they previously developed in 2014, called light-activated reversible inhibition by assembled trap (LARIAT). This platform can inactivate various types of proteins when illuminated under blue light by instantly trapping the target proteins, like a lariat. Opto-vTrap was developed by applying this LARIAT platform to vesicle exocytosis. When the Opto-vTrap expressing cells or tissues are shined under blue light, the vesicles form clusters and become trapped within the cells, inhibiting the release of transmitters.

Most importantly, the inhibition triggered using this new technique is temporary, which is very important for neuroscience research. Other previous techniques that target vesicle fusion proteins damage them permanently and disable the target neuron for up to 24 hours, which is not appropriate for many behavioral experiments with short time constraints. By comparison, vesicles that were inactivated using Opto-vTrap decluster in about 15 minutes, and the neurons regain their full functions within an hour.

Opto-vTrap directly controls the signal transmitters' release, enabling the researchers to freely control brain activity. The research team verified the usability of Opto-vTrap in cultured cells and brain tissue slices. Furthermore, they tested the technique in live mice, which enabled them to temporarily remove fear memory from fear-conditioned animals.

In the future, Opto-vTrap will be used to uncover complex interactions between multiple parts of the brain. It will be a highly useful tool for studying how certain brain cell types affect brain function in different circumstances.

Professor Heo stated, "Since Opto-vTrap can be used in various cell types, it is expected to be helpful in various fields of brain science research," He explained, "We plan to conduct a study to figure out the spatiotemporal brain functions in various brain cell types in a specific environment using Opto-vTrap technology."

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