The motivation to eat depends on the relative balance of activity between orexigenic (appetite inducing) and anorexigenic (appetite suppressing) brain systems. An abnormal balance of activity in these systems can lead to substantial health problems with high associated economic costs. In the United States, over half the population is considered overweight, and the aggregate economic cost is estimated in excess of $60 billion per year. Undernourishment is also a substantial problem: abnormal appetite suppression, as can occur during infection, old age, and cancer, can lead to severely low body weight and malnutrition. However, despite obvious importance, the neural basis of hunger and appetite suppression continues to be poorly understood at a neuronal or circuit level, and is currently an important focus of investigation. We recently discovered that a population of neurons in the parasubthalamic nucleus (PSTN) sends substantial monosynaptic axonal projections to neurons in the parabrachial nucleus (PBN) that express calcitonin gene related peptide (?PBN CGRP neurons?) and are well known to be necessary and sufficient for normal appetite suppression following a meal, during gastrointestinal distress, and during infection. Previous studies investigating the PSTN are minimal, but they suggest that these neurons may play a role in appetite suppression. Therefore, the purpose of this proposal is to characterize the role of PSTN neurons in food intake behavior.
In Aim 1, we will test the hypothesis that multiple forms of appetite suppression cause an increase in activity in PSTN neurons.
In Aim 2, we will test the hypothesis that stimulation of PSTN neurons is sufficient to decrease food intake. We will also test the hypothesis that stimulation of projections from the PSTN to the PBN is sufficient to decrease food intake.
In Aim 3, we will test the hypothesis that inhibition of PSTN neurons will increase food intake during baseline conditions and during conditions of appetite suppression. To pursue these Aims, we will use cutting edge viral gene delivery tools and genetically encoded neuronal actuators to provide new insights into how the brain regulates appetite.

Public Health Relevance

The motivation to eat depends on the relative balance of activity in distinct brain regions that individually induce or suppress appetite. An abnormal amount of activity in appetite suppression neurons, as can occur during infection, inflammation, and illnesses such as cancer, can cause malnutrition and a severe reduction in body weight. The purpose of this proposal is to investigate the role of a relatively unexplored population of neurons in the parasubthalamic nucleus (PSTN) in appetite suppression. Our results will provide new insights into how the brain regulates food intake and potentially yield novel therapeutic targets for the re-establishment of hunger in conditions of extreme loss of appetite.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15DK105510-02
Application #
9590735
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Stoeckel, Luke
Project Start
2018-09-20
Project End
2021-09-19
Budget Start
2018-09-20
Budget End
2021-09-19
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Williams College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
020665972
City
Williamstown
State
MA
Country
United States
Zip Code
Iyer, Manasi; Essner, Rachel A; Klingenberg, Bernhard et al. (2018) Identification of discrete, intermingled hypocretin neuronal populations. J Comp Neurol 526:2937-2954
Goldstein, Nitsan; Levine, Brian J; Loy, Kelsey A et al. (2018) Hypothalamic Neurons that Regulate Feeding Can Influence Sleep/Wake States Based on Homeostatic Need. Curr Biol 28:3736-3747.e3
Essner, Rachel A; Smith, Alison G; Jamnik, Adam A et al. (2017) AgRP Neurons Can Increase Food Intake during Conditions of Appetite Suppression and Inhibit Anorexigenic Parabrachial Neurons. J Neurosci 37:8678-8687