Excitation-inhibition imbalance in medial preoptic area circuits underlies chronic stress-induced depression-like states

Nat Commun. 2024 Oct 3;15(1):8575. doi: 10.1038/s41467-024-52727-2.

Abstract

Dysregulation of brain homeostasis is associated with neuropsychiatric conditions such as major depressive disorder. However, underlying neural-circuit mechanisms remain not well-understood. We show in mice that chronic restraint stress (CRS) and social defeat stress (SDS) are both associated with disruption of excitation (E)-inhibition (I) balance, with increased E/I ratios, in medial preoptic area (MPOA) circuits, but through affecting different neuronal types. CRS results in elevated activity in glutamatergic neurons, and their suppression mitigates CRS-induced depressive-like behaviors. Paraventricular hypothalamic input to these neurons contributes to induction but not expression of depressive-like behaviors. Their projections to ventral tegmental area and periaqueductal gray/dorsal raphe suppress midbrain dopaminergic and serotonergic activity, respectively, and mediate expression of divergent depressive-like symptoms. By contrast, SDS results in reduced activity of GABAergic neurons, and their activation alleviates SDS-induced depressive-like behaviors. Thus, E/I imbalance with relatively increased excitation in MPOA circuits may be a general mechanism underlying depression caused by different etiological factors.

MeSH terms

  • Animals
  • Behavior, Animal
  • Depression* / etiology
  • Depression* / metabolism
  • Depression* / physiopathology
  • Disease Models, Animal
  • GABAergic Neurons* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Pathways / physiopathology
  • Neurons / metabolism
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Preoptic Area* / metabolism
  • Restraint, Physical
  • Social Defeat
  • Stress, Psychological* / complications
  • Stress, Psychological* / physiopathology
  • Ventral Tegmental Area / physiopathology