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Poster Highlight: Bidirectional control of depression through hypothalamic feeding circuits


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Stress-induced depression and feeding circuits in the arcuate nuclei

During the day 2 poster sessions, one that caught my eye was titled “Chronic unpredictable stress modulates neuronal activity of AgRP and POMC neurons in hypothalamic arcuate nucleus” presented by Xing Fang in the Xin-yun Lu lab at the Medical College of Georgia at Augusta University

Agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons in the arcuate nucleus strongly regulate feeding behavior and food intake. Broadly, AgRP neurons promote feeding (orexigenic), while POMC neurons work in a reciprocal manner to suppress feeding (anorexigenic).

AgRP neurons in the arcuate promote food intake while POMC neurons inhibit food intake via their actions on downstream MC4R- expressing neurons in the paraventricular nucleus (Credit: Carol A. Rouzer, Vanderbilt University)

Depression is characterized by aberrant responses to environmental stimuli. For example, chronic psychological stress can promote depression in humans and animal models. Stress-induced depression is characterized by anhedonia (not enjoying what you used to love), lethargy and despair, and changes in feeding behavior and appetite. How does stress cause these behaviors to come about?

Using in vivo electrophysiology, behavioral assays, and DREADDs, Fang and colleagues investigated the role of hypothalamic AgRP and POMC neurons (two populations that powerfully control appetite) in mediating these behaviors.

This work builds on previous studies by the group, long linking depressive-like behavior to alterations in feeding and satiety hormones such as leptin.

To induce depression in mice, the researchers used a technique called ‘chronic unpredictable stress’ (CUS). This model strongly promotes a depression-like state after 10 days of unpredictable stress where mice go through a gamut of constant light exposure, tail pinches, restraint, and shock stimuli, among others.

Viral injections into the arcuate nucleus of POMC-Cre mice (left panels; projections in red) shows their wide axonal distribution throughout the brain. Similarly, injections into the arcuate nucleus of AgRP-cre mice demonstrate that they also project throughout the brain, although in a different pattern (right panels, projections in green) (Credit: Wang et al., 2015; Frontiers in Neuroanatomy)

Through their electrophysiological recordings, the researchers demonstrated that CUS decreased the firing rate of AgRP neurons but increased the firing rate of POMC neurons. When they tested the role of AgRP neurons in depressive-like behavior using stimulatory (Gq) or inhibitory (Gi) DREADDs, they were able to elicit opposite responses. Stimulation of these neurons improved depressive-like behavior, while inhibition promoted it.

Together, these studies suggest that AgRP and POMC neurons play an important role in stress-related adaptive behavior. Importantly, they provide a novel circuit related to depression which may be targetable for the treatment of the disease through pharmacological agents or lifestyle changes.

Jeremy C Borniger, PhD
Department of Psychiatry & Behavioral Sciences
Stanford University SoM
Twitter: @jborniger
Website: www.jeremyborniger.com

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