Dec 2018 – Bite Size Summit: Emerging technologies for gut-brain research

Speaker: Seongjun Park, Ph.D., Postdoctoral Associate in Dr. Polina Anikeeva’s Bioelectronics Group at Massachusetts Institute of Technology

Title: Bioelectronics for neural engineering

Summary: Dr. Seongjun Park received his Ph.D. in Electrical Engineering and Computer Science from MIT in Dr. Polinia Anikeeva’s lab in June of 2018. His doctoral research, which he has expanded upon in his post-doctoral work, has focused on flexible fiberoptics. In the brain, use of electrodes for long term stimulating and recording has been limited by the intense inflammatory response causing inflammatory cell infiltration and scarring. Dr. Park developed a novel flexible fiberoptic to improve the modulus mismatch between the brain and the electrode material. Using this device, he was able to use optogenetics to probe anxiety behavior associated with the circuit between the ventral hypothalamus and the basolateral amygdala. He also extended his work into the spinal cord. For success in the spinal cord, Dr. Park identified the need for a device that can stretch and deform; so, he engineering a stretchable fiber with excellent light transmission properties. Finally, Dr. Park has sought to further engineering his flexible fiberoptic by using a hydrogel coating. By coupling the hydrogel with the flexible fiberoptic, Dr. Park reduced strain between the device and the brain. Using this device, for the first time in the field, Dr. Park was able to record single unit spikes out to 6 months post-implantation. Dr. Park’s ambition is to be an independent investigator in bioengineering, with the goal of engineering devices to improve human health.

Speaker: David Hildebrand, Ph.D., Postdoctoral Associate in Dr. Winrich Freiwald’s Laboratory of Neural Systems at Rockefeller University

Title: High throughput TEM

Summary: Dr. David Hildebrand received his Ph.D. in Neuroscience from Harvard University in the Engert Laboratory. In his doctoral work, Dr. Hildebrand related anatomy, physiology, and behavior in the zebrafish nervous system. In particular, he used developed electron microscopy techniques to image the zebrafish brain at nanoresolution. Transmission electron microscopy is a fast, high signal to noise ratio, and inexpensive way to obtain high resolution images. However, the tissue processing is extremely challenging—nanometer thin samples must be placed by hand on a clear surface for imaging. Scanning transmission electron microscopy, however, can image with intact samples, but it sacrifices speed, resolution, and signal to noise ratio. Dr. Hildebrand merged the benefits of both systems by engineering a automated serial sections to tape transmission electron microscopy system. In his system, tissue is automatically sectioned and mounted to clear tape for transmission imaging. Using this system, he was able to obtain exquisite images of both the zebrafish brain as well as the mouse gastrointestinal tract.

Speaker: Ian Williamson, Ph.D., Postdoctoral Associate in Dr. Xiling Shen’s and Dr. John Rawls Laboratories at Duke University

Title: Nanofeeding human miniguts

Summary: Dr. Williamson received his Ph.D. in Biomedical Engineering from UNC/NCSU in the laboratory of Dr. Scott Magness. Early in his doctoral work, he was struck by how understudied the intestinal epithelium is. In particular, he was interested in how the microbiome interacts with the epithelial layer. He identified several techniques to better study the epithelial layer with the microbiome intact: culture with bacteria, microinjections of bacteria into organoids, or 2-D culture. Microinjection techniques were limited by the use of conventional technology, so Dr. Williamson developed a system for high throughout injection of fecal microbiome directly into the lumen of organoids. He identified that after injection into the lumen, the organoids live healthily in culture for up to 96 hours. During that time, the number of species in the microbiome increases with minor changes in species representation. Using this system, he further went on to demonstrate that organoids are able to reproducible metabolize fatty acids injected into their lumen. Dr. Williamson hopes to expand upon these techniques to study the gut epithelium in his post doctoral work at Duke University.

Speaker: Meg Younger, Ph.D., Kavli Fellow in Dr. Leslie Vosshall’s Laboratory of Neurogenetics and Behavior at Rockefeller University

Title: Processing human cues in the mosquito brain

Summary: Dr. Meg Younger received her Ph.D. from UCSF studying the homeostatic regulation of neurotransmitter release in the laboratory of Dr. Graeme Davis in 2013. Since joining Dr. Leslie Vosshall’s laboratory for her post-doctoral fellowship, Dr. Younger has focused on studying how mosquitos identify humans by sensory cues. Mosquitos integrate sensory information including body heat, human odor, and carbon dioxide emissions to find a blood meal. The human order code, however, remains unknown. Because mosquitos are not a model system, Dr. Younger began her research by developing a standard reference brain for mosquitoes (mosquitobrains.org). Using this, she identified 50 glomeruli for odor sensation; she targeted 3 specific glomeruli that synapse with sensory neurons from the maxillary palp. Using the CRISPR Q system and calcium imaging, she has been able to identify that the mosquito odorant is quite different that that of other model systems such as drosophila. Some sensory neurons express multiple odorant receptors to synapse on one glomeruli, while other sensory neurons express only one odorant receptor. And, one glomeruli may receive signals from multiple sensory neurons with different receptors. Using this work as a foundation, she hopes to uncover how mosquitos find humans.

Nov 2018 – Randy Seeley

Reinventing Bariatric Surgery

Dr. Randy Seeley is the Henry K. Ransom Endowed Professor of Surgery at the University of Michigan School of Medicine. He also serves as the director of the NIH-funded Michigan Nutrition Obesity Research Center (MNORC). His scientific work has focused on the actions of various peripheral hormones in the CNS that serve to regulate food intake, body weight and the levels of circulating fuels. His work has also focused on new treatment strategies for obesity and diabetes. He has published over 310 peer-reviewed articles including articles in Science, Nature, Nature Medicine, Nature Neuroscience, Science Translational Medicine, Cell Metabolism, The Journal of Clinical Investigation and the New England Journal of Medicine. Collectively, this work has been cited more than 28,000 times and Dr. Seeley has a scopus h-index of 82. Dr. Seeley has received numerous awards including the 2009 Outstanding Scientific Achievement Award from the American Diabetes Association. This award is presented to an individual medical researcher under age 45 who has made an outstanding contribution to diabetes research that demonstrates both originality and independence of thought. Dr. Seeley has also served on numerous review panels for the NIH and was Chair of the Integrative Physiology of Obesity and Diabetes review panel and on the Board of Reviewing Editors for Science. He is currently Senior Associate Editor for Diabetes. See his work here.

Oct 2018 – Will de Lartigue

Will de Lartigue is an Assistant Professor in Pharmacodynamics at the University of Florida. His lab studies the neurobiology of feeding. They are specifically interested in an understudied set of peripheral neurons that make up the sensory arm of the vagus nerve. These neurons form a direct anatomical link between the gut and the brain and provide a rapid neural mechanism for conveying information about the gastrointestinal environment to the brain. Although electrical stimulation of the vagus nerve is proving effective in treating a number of diseases, a lack of tools available to study the role of specific subsets of vagal neurons in physiological and disease states has led to an incomplete understanding of this pathway. They make use of molecular and genetic tools to target, image, and trace projections from subpopulations of sensory vagal neurons that innervate the gut to study the signals that active them and the circuits they recruit. In combination with behavioral, physiologic, and neurochemical techniques we study the role of vagal sensory neurons in the control feeding behaviors.

See more of his work here .

Sep 2018 – Subhash Kulkarni

Adult enteric neurogenesis: Implications for gut and brain health and disease

Dr. Subhash Kulkarni, M.S., Ph.D., is an Assistant Professor of Medicine at the Johns Hopkins University School of Medicine. His research focuses on the origin and development of the enteric nervous system (ENS). The ENS is maintained despite significant and continuous insults, and chronic dysmotility can result from dysregulation of the ENS. However, there is significant conflicting data on the stability of the ENS over a lifetime, with research disputing the occurrence of apoptosis and neurogenesis of enteric neurons. Dr. Kulkarni’s laboratory’s research has focused on investigating three central hypotheses: 1) the ENS is maintained by a balance of apoptosis and neurogenesis, 2) ENS turnover contributes to recovery from insult, and 3) issues with the autocorrect mechanisms regulating the ENS can cause adult onset dysmotility. In work published in PNAS in 2017, Dr. Kulkarni and colleagues showed that apoptosis and neurogenesis occur in balance to maintain a steady number of enteric neurons over time. Further, they showed that Nestin+ cells are the enteric neuron precursor cells that proliferate and generate adult neurons, replacing 88% of the adult ENS in two weeks. To address their second hypothesis, Dr. Kulkarni and his laboratory considered the intestinal insult of antibiotics. After exposure to the antibiotic ampicillin, intestinal dysbiosis changes ganglionic diversity, and over time, increased neurogenesis restores neuronal numbers to pre-ampicillin levels in a TLR2 mediated mechanism. Finally, Dr. Kulkarni and colleagues studied how ENS neurogenesis from precursor cells could contribute to disease. Knocking out PTEN in enteric neuron precursor cells caused unchecked proliferation and significantly increased neuronal numbers, size, and whole-gut transit time— an intestinal phenotype that resembled ganglioneuromatosis, a disorder of adult onset dysmotility. Dr. Kulkarni and his lab will continue to study how the ENS originates and develops and how it affects diseases of dysmotility.

Jun 2018 – Robert Heuckeroth

Dr. Robert Heuckeroth, M.D. Ph.D. is a Professor of Pediatrics and practicing pediatric gastroenterologist at The Children’s Hospital of Philadelphia- Research Institute. His research aims to better understand enteric nervous system anatomy and development to translate into clinical pathology. One of the diseases he studies is Hirschsprung’s disease, a disease in which the distal portion of the bowel is aganglionic due to defective nerve cell migration. This lack of nerve cells prevents the bowel from working correctly causing significant obstruction. Dr. Heuckeroth has provided insight into how the enteric nervous system develops and what external factors affect its development. Hirschsprung’s disease is commonly associated with RET mutations, as RET signaling is critical for enteric nervous system proliferation, migration, and network formation. Dr. Heuckeroth’s work has identified glial cell line-derived neurotrophic factor (GDNF) as an important molecule in establishing enteric nervous system structure and function. His lab has also identified external, prenatal factors that promote proper enteric nervous system development. Vitamin A is essential for enteric nervous system development. Additionally, they have shown that maternal usage of ibuprofen slows migration of enteric nervous system precursor cells and predisposes for Hirschsprung’s disease. They will continue to investigate the internal and external factors that contribute to enteric nervous system development with hopes of both preventing childhood bowel motility disorders.

Apr 2018 – Sean Adams

Metabolomics and xenometabolomics: Applications to study metabolic health

Dr. Sean Adams is the Director of the Arkansas Children’s Nutrition Center where his research aims to understand the molecular processes that underlie metabolic disease and obesity. Although it is well known that health status affects the microbiome and that the microbiome affects health status, molecular signals linking gut microbes and host pathophysiology remain largely unknown. His lab applies metabolomics to gut microbiome metabolism, which they call xenometabolomics. During his talk, Dr. Adams focused on two topics. Firstly, how does microbial metabolism impact host physiology? To investigate this question, they have studied nitrogen, kidney, and liver metabolism in the context of an altered microbiome. They have found that dietary manipulation of the gut microbiome alters the host liver metabolome; there are reduced hepatic amino acids and urea cycle metabolites in mice feed a high starch diet. The same diet fed to experimental mice in a chronic kidney disease model ameliorates the kidney disease. They believe that the high starch diet increases the density of beneficial bacteria which then act as a nitrogen sink to reduce the nitrogen load on the kidney. Further, they reason that the changed metabolites from the changed microbiome reduces uremic solutes. Second, Dr. Adams discussed how host physiological states impact the microbe population and biochemistry. In a study of adult human women, they found that xenometabolites—specifically, cis-3,4-methylene heptanoyl carnitine and aminomalonic acid— change with both acute exercise and with weight loss. They have also found the microbiome and xenometabolomics distinctively change during diabetes progression in a rat model. In fact, performing a “xenoscan” of the cecal metabolites can discriminate severity of disease in a rat model. Knowing this, his group hopes to investigate how we can use these altered metabolites to treat or identify disease. In summary, Dr. Adam’s group has shown that host microbiome cross talk involves a two-way street. They will continue to investigate the molecular factors involved in this communication and work towards improving our metabolic health by studying microbiota ecology and xenometabolism.

May 2017 – Steve Liberles

Dr. Liberles is a Professor of Cell Biology at Harvard University. His lab is interested in understanding how the brain processes external sensory and internal homeostatic signals to initiate behavioral and physiological responses. They study how our senses of smell and taste process different environmental cues (like pheromones, food cues, predator odors) to elicit innate mating, foraging, and avoidance responses. In recent efforts, they are also investigating internal sensory modalities of the vagus nerve.

See more of Dr. Liberles's work: Liberles Lab

Apr 2017 – William Parker

Dr. Parker is an Associate Professor of Surgery at Duke University. The primary focus of his laboratory deals with the concept of “evolutionary mismatch” and how that affects immune function in the modern world. An evolutionary mismatch is simply described as a condition in which an organism’s current environment leads to disease because it does not match the environment which drove the evolution of that organism’s genes. Evolutionary mismatches in Western countries lead to a variety of consequences, including sedentary lifestyles, vitamin D deficiency, chronic psychological stress, and inflammatory diets, which in turn lead to inflammatory diseases. We are interested in normalizing immune function in Western society, in particular by dealing with one of the most profound and impactful consequences of evolutionary mismatch, “biome depletion”. Their lab was instrumental in understanding the role of the human appendix.

See more of Dr. Parker’s work: Parker Lab

Mar 2017 – Laurianne Van Landeghem

Dr. Van Landeghem is an Assistant Professor at NC State College of Veterinary Medicine. Her laboratory focuses on understanding how signals emanating from the microenvironment impact normal and cancer intestinal stem cells with an emphasis on enteric glia. Her group aims to define the molecular crosstalk between intestinal stem cells and their neighboring cells such as enteric glial cells in healthy intestines, and to assess whether alterations of this crosstalk induced by chronic stress occurring during intestinal pathologies may lead to the malignant transformation of normal stem cells into cancer stem cells and promote tumor development using genetic mouse models and primary co-culture systems.

See more of Dr. Lendeghem’s work: Van Landeghem

Feb 2017 – Meenakshi Rao

Dr. Rao is a pediatric gastroenterologist at Columbia University. Her research interest is in the enteric nervous system (ENS). Specifically, she is utilizing mouse genetic models in the laboratory to investigate the role of glial cells in the ENS and determine how they regulate normal digestive function. In addition, she is studying how enteric glial cells participate in ENS neurogenesis, which may have important implications for intestinal injury and repair.

See more of Dr. Raos work here: Rao Scholar