Specific Neurons Responsible for Depression, Anhedonia in Times of Chronic Stress

A group of neurons in the arcuate nucleus (ARC) become hyperactive during chronic stress, causing behavioral issues such as depression and anhedonia in mice. When the activity of these neurons is reduced, the behaviors are also reduced. Results were published in Molecular Psychiatry. 

The ARC contains 2 types of neurons—agouti-related protein (AgRP) and proopiomelanocortin neurons (POMC)—that innervate brain regions involved in neuroendocrine control and adaptive behaviors related to stress.

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“Our findings indicate that activation of POMC neurons in the ARC is both necessary and sufficient to mediate stress susceptibility and induce anhedonia and behavioral despair,” lead authors Xing Fang, PhD, and Yuting Chen, PhD, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, and co-authors noted. “These results suggest that POMC neurons act in opposition to AgRP neurons in behavioral and neural plasticity to chronic stress. Thus, hypothalamic POMC and AgRP neurons can be viewed as Yin-Yang partners in modulating responses and adaptations to stress.”

“Importantly, POMC gene variants in humans have been reported to interact with stress life events and associate with antidepressant treatment responses.”

The mice were exposed to 10 days of chronic unpredictable stress (CUS). Stressors included 2 hours in restraints, a 15-minute tail pinch, constant light for 24 hours, wet bedding with 45° angle cage tilt for 24 hours, 10 minutes of foot shocks, 30 minutes on an elevated platform, and social isolation.

Both male and female mice showed increased firing rates after CUS exposure, indicating that chronic stress makes these neurons hyperactive. When the neurons began firing more rapidly and regularly, it led to behavioral effects such as PTSD, depression, and loss of interest or pleasure in doing things. Conversely, purposely inhibiting these neurons reversed the behavioral problems. 

“Further studies investigating the mechanisms underlying the synaptic disinhibition and intrinsic hyperexcitability of POMC neurons will provide insight into how POMC neurons modulate stress-related behaviors,” researchers concluded. “Whether efferent projections from these neurons converge on the same downstream targets to control behavioral susceptibility to stress, and whether their influences require melanocortin receptor signaling, need to be investigated.”

Fang X, Chen Y, Wang J, et al. Increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits. Mol Psychiatry. 2023;28(3):1365–1382. doi.org/10.1038/s41380-022-01872-5