Depression is a chronic and debilitating mental illness. Anhedonia, one of the two core symptoms of major depression, is particularly difficult to treat. Individuals can experience one or more types of anhedonia, defined as a loss of interest or a loss of pleasure. However, the neural circuits and molecular substrates underlying anhedonia and other key depressive symptoms remain poorly understood. The arcuate nucleus (ARC) of the hypothalamus contains two distinct neuronal populations expressing proopiomelanocortin (POMC) and agouti-related protein (AgRP) that are well known for their roles in homeostatic and hedonic control of feeding. We demonstrated that chronic unpredictable stress causes different types of anhedonia and behavioral despair and induces opposite changes in spontaneous firing rate of POMC and AgRP neurons. We hypothesize that POMC and AgRP neurons play distinct roles in chronic stress-induced depressive behaviors.
The specific aims of this project are designed to determine 1) how chronic unpredictable stress regulates POMC and AgRP neuronal activity; 2) whether SIRT1 in POMC and AgRP neurons functions as a molecular mediator of chronic stress-induced depressive behaviors and neuronal dysfunction; and 3) whether selective activation or inhibition of POMC and AgRP neurons causes or reverses depressive behaviors.

Public Health Relevance

Depressive disorders affect approximately 17% of people in the U.S. Women are twice as likely as men to develop depression. Only about one-third of patients with major depression can achieve full remission with available treatments. Thus, there is an urgent need for better understanding of the pathogenesis of depression and novel treatments. The goal of this project is to identify the neuronal circuits and molecular substrates underlying the vulnerability to chronic stress and will provide potential novel therapeutic targets for the treatment of depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
High Priority, Short Term Project Award (R56)
Project #
5R56MH119456-02
Application #
9882506
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Winsky, Lois M
Project Start
2019-04-01
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Augusta University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912