Evidence for the Integration of Stress-Related Signals by the Rostral Posterior Hypothalamic Nucleus in the Regulation of Acute and Repeated Stress-Evoked Hypothalamo-Pituitary-Adrenal Response in Rat.

A likely adaptive process mitigating the effects of chronic stress is the phenomenon of stress habituation, which frequently reduces multiple stress-evoked responses to the same (homotypic) stressor experienced repeatedly. The current studies investigated putative brain circuits that may coordinate the reduction of stress-related responses associated with stress habituation, a process that is inadequately understood. Initially, two rat premotor regions that respectively regulate neuroendocrine (medial parvicellular region of the paraventricular hypothalamic nucleus [PaMP]) and autonomic (rostral medullary raphe pallidus [RPa]) responses were targeted with distinguishable retrograde tracers. Two to 3 weeks later, injected animals underwent loud noise stress, and their brains were processed for fluorescent immunohistochemical detection of the tracers and the immediate early gene Fos. A rostral region of the posterior hypothalamic nucleus (rPH), and to a lesser extent, the median preoptic nucleus, exhibited the highest numbers of retrogradely labeled cells from both the RPa and PaMP that were colocalized with loud noise-induced Fos expression. Injections of an anterograde tracer in the rPH confirmed these connections and suggested that this region may contribute to the coordination of multiple stress-related responses. This hypothesis was partially tested by posterior hypothalamic injections of small volumes of muscimol, which disrupts normal synaptic functions, before acute and repeated loud noise or restraint exposures. In addition to significantly reduced corticosterone release in response to these two distinct stressors, rPH muscimol disrupted habituation to each stressor modality, suggesting a novel and important contribution of the rostral posterior hypothalamic nucleus in this category of adaptive processes. Significance statement: Habituation to stress is a process that possibly diminishes the detrimental health consequences of chronic stress by reducing the amplitude of many responses when the same challenging conditions are experienced repeatedly. Stress elicits a highly coordinated set of neuroendocrine, autonomic, and behavioral responses that are independently and relatively well defined; however, how the brain achieves coordination of these responses and their habituation-related declines is not well understood. The current studies provide some of the first anatomical and functional results suggesting that a specific region of the hypothalamus, the rostral posterior hypothalamic nucleus, targets multiple premotor regions and contributes to the regulation of acute neuroendocrine responses and their habituation to repeated stress.