Tuzo

Lisa Beutler, M.D., Ph.D., Assistant Professor of Medicine in Endocrinology, Feinberg School of Medicine, Northwestern University, Chicago, IL

Dissecting the gut-brain dynamics underlying anorexia

Feeding is at the very core of an animal’s survival, so it’s no surprise that the gut and brain are in constant communication to coordinate appropriate food intake and stable bodyweight. However, in the presence of inflammation, this system may break down. One of the hallmarks of inflammation-associated anorexia (not to be confused with anorexia nervosa) is decreased appetite, which can be severe enough to cause malnutrition. Current therapies – including IV-delivered nutrition and intestinal feeding tubes – can reduce quality of life and have significant collateral consequences.

Dr. Beutler aims to use advanced neural observation and manipulation techniques to dissect the underlying mechanisms involved in inflammation-associated anorexia. Beutler’s team will use calcium imaging to reveal the effects individual cytokines (signals released during inflammation) have on specific groups of feeding-related neurons. Her group will also use cutting-edge genetic tools to try to override the inappropriate ‘don’t eat’ signals that result from severe inflammation. Finally, she will study how specific models of inflammatory disease change the neural response to nutrient intake.

Beutler’s research will be the first to study these specific processes at this level of detail in a living organism. By identifying precise neurological targets of cytokine release, and deciphering how this modulates appetite, Beutler hopes to identify therapeutic targets for malnutrition associated with inflammatory diseases. Moreover, her lab aims to create a road map of gut-brain-immune signaling that may have major implications not only for treating inflammation-mediated anorexia, but broadly for future feeding and metabolism research.

Jeremy Day, Ph.D., Associate Professor, Department of Neurobiology, Heersink School of Medicine, University of Alabama – Birmingham; and Ian Maze, Ph.D., Professor – Departments of Neuroscience and Pharmacological Sciences, Director – Center for Neural Epigenome Engineering, Icahn School of Medicine at Mount Sinai, New York City

Leveraging single-cell epigenomics for targeted manipulation of drug-activated ensembles

Drug addiction is a serious problem both for individuals and society as a whole. While there has been significant research into understanding and treating addiction, 60% of those treated will suffer a relapse. In fact, the craving for drugs may actually increase over time, incubating in those who have been addicted even without further drug exposures. Dr. Day and Dr. Maze aim to research addiction at a new level – drilling down to the epigenetic effects of drug use on specific cells at a single-cell level, and how these may predispose a subject to a relapse.

Preliminary research has shown that exposure to drugs over time alters how genes are expressed. In essence, drugs can hijack genetic regulatory elements known as “enhancers,” which when activated cause certain genes to be expressed in brain cells that motivate the subject to seek out these drugs. Day and Maze have designed a project to identify these enhancers in a cell-type specific fashion that are activated (or unsilenced) by cocaine – a well understood and researched stimulant – and then create and insert viral vectors into cells that will only become active in the presence of that unsilenced enhancer. Using this strategy, the viral vector will express its cargo only in cell ensembles that are affected by cocaine and allow researchers to optogenetically or chemogenetically activate or deactivate the affected cells.

With this, Day and Maze will perturb the ensembles to investigate their effects on drug seeking behavior in a rodent model of volitional cocaine self-administration. Their work builds on recent advances in the ability to target individual cells and small groups of cells, rather than entire populations of cells or cell types as has been the focus of earlier research. Now that it is possible to focus on the role specific cells play, the hope is that better treatments may be developed that address the genetic roots of addiction and relapse, and without the negative side effects of manipulating larger, less targeted populations of brain cells.

Stephan Lammel, Ph.D., Associate Professor of Neurobiology, University of California – Berkeley

Neurotensin mediated regulation of hedonic feeding behavior and obesity

The brain is obsessed with finding and consuming food. When calorie-dense food is found – rare in the wild – animals will instinctively consume it rapidly. For humans with ready access to calorie-dense food, the instinct sometimes leads to overeating, obesity, and related health issues. But research has also shown that in some cases, the drive to feed on high-calorie food may diminish when such food is always available. Dr. Lammel seeks to identify the neural processes and brain regions involved in such feeding behavior and its regulation.

Studies over the years have linked feeding to the hypothalamus, an ancient and deep part of the brain. However, evidence also points to a role for the reward and pleasure centers of the brain. Lammel’s preliminary research found that links from the lateral nucleus accumbens (NAcLat) to the ventral tegmental area (VTA) are central to hedonistic feeding – activating that link optogenetically led to increased feeding of calorie-rich foods, but not regular food. Other research identified the amino acid neurotensin (NTS) as a player in the regulation of feeding, in addition to other roles.

Lammel’s research seeks to map out the circuitry and roles of the various parts of the brain that lead animals to eat hedonistically as well as the role of NTS, which is expressed in the NAcLat. Subjects are presented with a normal diet or a calorie-rich jelly diet, and activity on the NAcLat-to-VTA pathway is recorded and mapped to feeding behaviors. He will also track changes over time with prolonged exposure to hedonistic food. Further research will look at changes in NTS presence in cells, and how its presence in different amounts affects cell function. By understanding the pathways and molecular mechanics involved in feeding and obesity, this work may contribute to future efforts help manage obesity.

Lindsay Schwarz, Ph.D., Assistant Professor in Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN

Identifying brain circuits that connect respiration and cognitive state

Breathing is automatic in animals, but unlike other comparably essential functions – heartbeat, digestion, etc. – animals can consciously control breathing. Breathing is also tied to emotional and mental state in a two-way manner: emotional triggers can cause changes in breathing, but consciously changing breathing has also been shown to influence state of mind. In her research, Dr. Schwarz aims to identify which breathing-related neurons are selectively activated by physiological and cognitive cues and map the brain regions they connect with. This research may prove helpful in studying a variety of neurological disorders where breathing is impacted, such as sudden infant death syndrome (SIDS), central sleep apnea, and anxiety disorders.

Schwarz aims to take advantage of advances in neural tagging to study these neurons which, located deep in the brain stem, have traditionally been difficult to isolate and record in vivo. But with activity tagging, Schwarz can identify the neurons activated during innate vs. active respiration. For the latter, subjects are conditioned to a stressful stimulus that causes them to freeze and alter their breathing. Researchers then can examine the tagged neurons to identify which were active in the conditioned subjects, and address whether these overlap with neurons active during innate respiration.

A second aim is to identify the molecular identity of the breathing-related neurons that were activated during conditioning to more precisely understand which cells are part of the breathing circuit. Finally, having identified those neurons, Schwarz will use viral vector approaches developed by other researchers to determine what parts of the brain those activated cells connect to. Identifying the links between brain states and breathing, the overlap of conscious and unconscious breathing circuits, and the connection between breathing and certain diseases may lay the groundwork for better therapies as well as a fuller understanding of how our most fundamental functions are wired.

Rui Chang, Ph.D., Assistant Professor, Departments of Neuroscience and of Cellular and Molecular Physiology, Yale University School of Medicine

Sreeganga Chandra, Ph.D. Associate Professor, Departments of Neurology and Neuroscience, Yale University School of Medicine

From gut to brain: Understanding the propagation of Parkinson’s Disease

Parkinson’s Disease is a widely known but still mysterious neurological degenerative disease that dramatically affects quality of life. Exactly how the disease initiates is unknown, but recent research indicates that at least some Parkinson’s cases originate in the gut and propagate to the brain via the vagus nerve, a long, complex, multifaceted nerve connecting many organs to the brain.

Dr. Chang and Dr. Chandra are taking this gut-to-brain propagation insight to the next level with their research. Their first two aims seek to identify exactly which vagal neuron populations transmit Parkinson’s and the process by which the gut and these neurons interact. The experiment uses a mouse model, injections of proteins that can induce Parkinson’s, and a novel process to tag and selectively ablate (shut down) specific types of neurons. Through experiments in which certain neurons are ablated, the protein introduced, and the mice examined for Parkinson’s, the team will narrow in on specific candidates. In the third aim, the team hopes to uncover the mechanism by which the disease is transported at the molecular level within neurons.

The research is a collaborative, interdisciplinary effort drawing upon Dr. Chang’s experience researching the vagal nerve and enteric system and Dr. Chandra’s expertise in Parkinson’s Disease and its pathology. It is hoped that with a better, more precise understanding of how the disease reaches the brain, new targets farther from the brain can be identified for treatment that are more precise, allowing treatment to delay or diminish the onset of Parkinson’s without harming the brain or affecting the many other important functions of the extraordinarily complex vagal nerve or the enteric system.

Rainbo Hultman, Ph.D., Assistant Professor, Department of Molecular Physiology and Biophysics, Iowa Neuroscience Institute – Carver College of Medicine, University of Iowa

Brain-wide electrical connectivity in migraine: Toward the development of network-based therapeutics

Migraine is a widespread, often debilitating disorder. It is complex and notoriously difficult to treat; sufferers have differing symptoms, often triggered by sensory hypersensitivity, that may include pain, nausea, visual impairment, and other effects. Migraine affects multiple interconnected parts of the brain, but not always in the same way, and treatments often won’t have the same effect from person to person. Dr. Hultman’s research proposes to examine migraines using new tools with the aim of illuminating new paths for treatment.

The research builds upon her team’s discovery of electome factors, measurements of electrical activity patterns in the brain tied to specific brain states. Using implants to measure brain activity in mouse models representing both acute and chronic migraine, her team will observe which parts of a mouse brain are activated and in what sequence on a millisecond scale for the first time. Machine learning will help organize the collected data, and the electome maps created can be used to help identify the parts of the brain affected, and how the electome changes over time, particularly through the onset of chronicity. The experiment also examines electrical activity patterns tied to behavioral response; for example, the electrical signals observed in the brain of a subject who seeks to avoid bright lights may offer a way to predict more severe responses to migraine.

A second part of Dr. Hultman’s research will then use the same tools to look at how available therapeutics and prophylactics work. Electome factors of subjects treated with these therapeutics will be collected and compared with controls to identify what parts of the brain are affected and in what way, helping reveal the effect of each therapeutic/prophylactic, as well as the effects of medication overuse headache, a common side effect experienced by migraine sufferers who seek to manage their condition.

Gregory Scherrer, Ph.D., Associate Professor, Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina

Elucidating the neural basis of pain unpleasantness: Circuits and new therapeutics to end the dual epidemic of chronic pain and opioid addiction

Pain is how our brain perceives potentially harmful stimuli, but it’s not a single experience. It’s multidimensional, involving transmissions from nerves to the spinal cord and brain, processing of the signal, triggering of reflexive action, and then follow-up neural activity involved in actions to soothe the pain in the near term and complex learning processes to avoid it in the future.

Pain is also at the core of what Dr. Scherrer sees as two interrelated epidemics: the epidemic of chronic pain, affecting some 116 million Americans, and the opioid epidemic that results from the misuse of powerful and often addictive drugs to treat it. In his research, Dr. Scherrer is looking to find out exactly how the brain encodes the unpleasantness of pain. Many drugs seek to affect that sense of unpleasantness but are often overbroad and also trigger the reward and breathing circuits, leading to addiction (and by extension overuse) and the respiratory shutdown responsible for opioid-related deaths.

Dr. Scherrer’s team will generate a brain-wide map of pain emotional circuits using genetic trapping and labelling of neurons activated by pain with fluorescent markers. Second, activated brain cells will be separated out and their genetic code will be sequenced, looking for common receptors on those cells that may be targets for therapeutics. Finally, the research will investigate compounds in chemical libraries designed to interact with any of those identified target receptors; the effects those compounds have on the unpleasantness of pain; and whether these compounds also carry risk of overuse or affect the respiratory system. Ultimately, the intention is to help find better ways to relieve all types of pain and to improve the well-being and quality of life of patients who experience it.