The direct regulation of feeding-driving hypothalamic GABAergic neurons on stress responses

An appropriate stress response is essential for proper responding to, coping with, and subsequently recover from disturbing environmental stressors. However, the dysregulated responses to stress stimuli can result in abnormal psychiatric and behavioral outcomes, and if severe, can lead to stress-related mental disorders such as the posttraumatic stress disorder (PTSD). To develop effective therapies for treating these disorders, it is of utmost importance to fully understand the brain neural bases and mechanisms regulating stress responses. Emerging evidence indicates that stress-related emotional modalities are equally implicated in feeding regulation by hypothalamic neurons, suggesting that common neurocircuits co-regulate stress and feeding. Our tracing studies indicate that non-AgRP GABAergic neurons in the arcuate nucleus (Arc, denoted as ArcGABA neurons) send direct inputs to corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH, denoted as PVHCRH neurons). While PVHCRH neurons exhibit time-locked activation in response to various environmental stressors, we found that both GABA release onto PVHCRH neurons and ArcGABA neuron activity decrease under chronic stress conditions (e.g., tail suspension and restraint), but not under acute stressors (e.g., water spray and air puff). Specifically, ArcGABA neuronal activity correlates with GABA release onto PVHCRH neurons, but it is anticorrelated with PVHCRH neuronal activity in response to the same stressor. Furthermore, chemogenetic inhibition of PVHCRH-projecting ArcGABA neurons enhances PVHCRH neuronal activity and elevates stress levels, phenocopying the direct activation of PVHCRH neurons. Conversely, chemogenetic activation of PVHCRH-projecting ArcGABA neurons reduces both PVHCRH neuronal activity and stress levels, and this phenotype can be completely abolished by concurrent excitation of PVHCRH neurons. Altogether, our findings indicate that non-AgRP ArcGABA neurons play a critical role in encoding the scalability of stress responses to environmental stressors by modulating inhibitory GABA release onto PVHCRH neurons in a stimulus strength-dependent manner.