A Hypothalamic Inhibitory Circuit Encoding the Scalability of Stress Responses

An appropriate stress response is essential for properly responding to, coping with, and subsequently recovering from disturbing environmental stimuli. However, how the brain dynamically encodes the scalability of stress responses remains poorly understood. Here, we found that, GABAergic neurons in the arcuate nucleus (Arc, denoted as Arc^GABA neurons) send direct inputs to corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH, denoted as PVH^CRH neurons), the primary regulators of the hypothalamic-pituitary-adrenal (HPA) axis. Although PVH^CRH neurons exhibited time-locked activation in response to various environmental stressors, both GABA release onto PVH^CRH neurons and the activity of PVH^CRH-projecting Arc^GABA neurons were selectively reduced during exposure to prolonged, high-intensity stressors, but not following exposure to transient, low-intensity stressors. Notably, GABA release onto PVH^CRH neurons was positively correlated with PVH^CRH-projecting Arc^GABA neuron activity, yet anticorrelated with PVH^CRH neuronal activity in response to the same prolonged, high-intensity stressors. Selective silencing of PVH^CRH- projecting Arc^GABA neurons was sufficient to elevate HPA axis activity and stress levels, phenocopying the effect of direct of PVH^CRH neuron activation. Conversely, selective activation of PVH^CRH-projecting Arc^GABA neurons reduced both HPA axis activity and stress levels, this effect was completely abolished by concurrent excitation of PVH^CRH neurons. Molecular identity screening further revealed that these PVH^CRH-projecting Arc^GABA neurons are not subsets expressing agouti-related peptide (AgRP) and tyrosine hydroxylase (TH) markers. Collectively, these findings indicate that the non-AgRP/TH Arc^GABA→PVH^CRH neurocircuit serves as a critical neural substrate that directly encodes the scalability of stress responses to environmental stressors by modulating inhibitory GABA release in a stimulus intensity-dependent manner.