Amygdala GABA Neurons: Gatekeepers of Stress and Reproduction

Abstract

Stress can disrupt menstrual cycles, cause infertility, and lead to other reproductive disorders. The posterodorsal medial amygdala (MePD) processes stress signals and regulates the gonadotropin-releasing hormone (GnRH) pulse generator through GABAergic inhibitory projections to the hypothalamus. However, how stress is processed in the MePD - especially involving its dense GABAergic and Urocortin-3 (UCN3) neurons - remains poorly understood. In this study, we combine in vivo GRadient-INdex (GRIN) lens mini-endoscopic calcium imaging (to track neuronal activity), optogenetics, clustering analysis, and computational modeling to investigate MePD circuitry. Our findings reveal two anti-correlated GABAergic sub-populations in the MePD that dictate responses to both UCN3 neuron stimulation and restraint stress. Our computational modeling suggests that mutual inhibition between these GABAergic groups drives this anti-correlated activity and predicts how these interactions shape downstream responses to stimulation of GABAergic and UCN3 neurons. We test these predictions using optogenetics and confirm that GABAergic neurons operate downstream of the UCN3 population, playing a crucial role in transmitting UCN3 signals to regulate luteinizing hormone (LH) pulse frequency. Our study is the first to show how GABAergic neurons in the amygdala mediate stress effects on reproductive health, uncovering key neural mechanisms linking emotional and reproductive functions.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

* The manuscript has been updated: Figures 1-6 have been modified, Results and Discussion sections have been expanded. We expanded Supplementary Information file.