Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity

Xing Fang, Shujun Jiang, Jiangong Wang, Yu Bai, Chung Sub Kim, David Blake, Neal L. Weintraub, Yun Lei, Xin Yun Lu

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Previous studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.

Original languageEnglish (US)
Pages (from-to)2299-2315
Number of pages17
JournalMolecular Psychiatry
Issue number6
StatePublished - Jun 2021

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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