| Function and activity dynamics of lateral hypothalamic glutamatergic neurons in obesity The underlying physiological mechanisms contributing to the obese state are largely unknown. Appetitive and consummatory behaviors, which are thought to be dysregulated in obesity, are governed by descending signals from the brain, but how specific neural circuits regulate such behaviors is unclear. One brain area that is hypothesized to be a critical component in the circuitry that orchestrates feeding behavior is the lateral hypothalamic area (LHA), a molecularly and functionally heterogeneous hypothalamic region that is interconnected with limbic and hindbrain structures. Recently developed circuit dissection tools have made it possible to study the function of molecularly defined neuron populations. One population of particular importance to feeding behavior is the putative glutamatergic, Vglut2-expressing neurons of the LHA (LHA-Vglut2), which are known to be involved in controlling food intake and reward seeking. Yet, how these neurons orchestrate feeding behavior and how they might contribute to obesity is unknown. Thus, the objective of this proposal is to use contemporary tools to study the precise neurocircuitry that allows the LHA to control food intake. Here I propose to identify the natural activity dynamics and the function of LHA-Vglut2 neurons in regulating voluntary, consummatory behavior. The natural activity dynamics of LHA-Vglut2 neurons will be measured using in vivo two-photon calcium imaging during consummatory behaviors, and the sufficiency of these neurons to inhibit consumption will be tested using cell-type specific optogenetic stimulation (Aim 1). Furthermore, the activity dynamics of LHA-Vglut2 neurons will be monitored during the gradual transition to obesity induced by chronic consumption of calorie dense food. Following diet-induced obesity, LHA-Vglut2 neurons will be selectively activated with chemogenetic tools to suppress food consumption and mitigate obesity (Aim 2). Based on my preliminary data and published work by my sponsor and others, I hypothesize that LHA-Vglut2 activity represents a negative feeding signal, which serves to suppress food intake. When mice are fasted, basal dynamics are suppressed and consumption-evoked responses are reduced. I predict that activation of these neurons will rapidly abolish consummatory behavior. During high fat diet-induced obesity, the LHA- Vglut2 response will be downregulated. I hypothesize that this downregulation can be reversed by chemogenetic activation of LHA-Vglut2 neurons, thereby restoring normal behavior. Regardless of the results, these experiments will identify, for the first time, natural activity dynamics of LHA-Vglut2 neurons and how they are altered by obesity.

Public Health Relevance

The proposed research is relevant to public health because elucidating the neural circuits that contribute to motivated consummatory behaviors will increase our understanding of the etiology of disorders that are characterized by impairments of motivation, including but not limited to obesity. The proposed research is relevant to the mission of the NIH because it focuses on developing fundamental knowledge that will further our understanding of the neural circuits that underlie normal and pathological motivated behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK112564-02
Application #
9358324
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Densmore, Christine L
Project Start
2016-09-20
Project End
2019-09-19
Budget Start
2017-09-20
Budget End
2018-09-19
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Psychiatry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Rossi, Mark A; Stuber, Garret D (2018) Overlapping Brain Circuits for Homeostatic and Hedonic Feeding. Cell Metab 27:42-56
McHenry, Jenna A; Otis, James M; Rossi, Mark A et al. (2017) Hormonal gain control of a medial preoptic area social reward circuit. Nat Neurosci 20:449-458