Neuroanatomical characterization of angiotensin‐sensitive neurons within the paraventricular nucleus of the hypothalamus reveals an access point for controlling behavioral and physiological responses to stress.

Stressors perceived in the environment or those arising from the internal milieu create neural signals that converge on the paraventricular nucleus of the hypothalamus (PVN). The PVN contains distinct neuronal phenotypes that integrate and transduce these signals into cardiovascular, neuroendocrine and behavioral responses that cope with the impact of psychological and physiological stress. Accumulating evidence implicates angiotensin receptors within the PVN as mediators of the stress response; however, the neuroanatomical mechanisms underlying these effects are not completely understood. Here, we use the Cre‐LoxP system in mice with virally‐mediated gene transfer and optogenetics to characterize the structure and function of neurons in the PVN that express the angiotensin type 1a receptor (Agtr1a). Neuroanatomical experiments discovered that Agtr1a(s) were expressed on neurons in the PVN that synthesize mRNAs for corticotropin‐releasing‐hormone (CRH) or thyroid‐releasing‐hormone (TRH). These CRH and TRH neurons were found to send direct axonal projections to the median eminence and their optogenetic excitation increased, but inhibition decreased, circulating levels of corticosterone and thyroxine, indicating that Agtr1a‐expressing neurons in the PVN control the activity of neuroendocrine axes. To investigate how angiotensin signaling may affect stress responding, we engineered mice with Agtr1a specifically deleted from the PVN (Agtr1a‐PVN KO). Under basal conditions, no effect of the deletion was observed; however, maintenance on high fat diet, a metabolic stressor, revealed a gene x environment interaction whereby Agtr1a‐PVN KO mice had increased adiposity and body weight but lower blood pressure relative to controls. In psychogenic stress paradigms, Agtr1a‐PVN KO mice were found to have slight but significant decreases in anxiety‐like behavior and cardiovascular reactivity. Collectively, these results suggest that stimulation of Agtr1a(s) in the PVN contribute to activation of neuroendocrine axes that mediate behavioral and physiological responses to metabolic and psychogenic stressors. Support or Funding Information NIH: HL122494, HL139868, HL136595