Identification of Novel Cross-Talk between the Neuroendocrine and Autonomic Stress Axes Controlling Blood Pressure

• Published in: The Journal of neuroscience Vol. 41; no. 21; pp. 4641 - 4657
• Main Authors: Elsaafien, Khalid, Kirchner, Matthew K, Mohammed, Mazher, Eikenberry, Sophia A, West, Chloe, Scott, Karen A, de Kloet, Annette D, Stern, Javier E, Krause, Eric G
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 26-05-2021
• Subjects: Anatomy; Angiotensin; Angiotensin II; Animals; Autonomic nervous system; Autonomic Nervous System - physiology; Axes (reference lines); Blood pressure; Blood Pressure - physiology; Calcium imaging; Calcium ions; Corticotropin-releasing hormone; Crosstalk; Electrophysiology; Excitation; Fibers; Genetics; Hypertension; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - physiology; Hypothalamus; Information processing; Liquid oxygen; Male; Males; Medulla oblongata; Mice; mRNA; Nervous system; Neurons; Neurons - physiology; Optics; Paraventricular Hypothalamic Nucleus - physiology; Paraventricular nucleus; Pituitary; Pituitary-Adrenal System - physiology; Pressure dependence; Receptors; Stress (physiology); Stress response; Sympathetic nervous system; Synthesis; Vasoconstriction; Vasoconstriction - physiology; autonomic; stress; HPA axis; glucocorticoids; cardiovascular; hypertension
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.0251-21.2021

The hypothalamic paraventricular nucleus (PVN) controls neuroendocrine axes and the autonomic nervous system to mount responses that cope with the energetic burdens of psychological or physiological stress. Neurons in the PVN that express the angiotensin Type 1a receptor (PVN
) are implicated in neuroendocrine and autonomic stress responses; however, the mechanism by which these neurons coordinate activation of neuroendocrine axes with sympathetic outflow remains unknown. Here, we use a multidisciplinary approach to investigate intra-PVN signaling mechanisms that couple the activity of neurons synthesizing corticotropin-releasing-hormone (CRH) to blood pressure. We used the Cre-Lox system in male mice with
optogenetics and cardiovascular recordings to demonstrate that excitation of PVN
promotes elevated blood pressure that is dependent on the sympathetic nervous system. Next, neuroanatomical experiments found that PVN
synthesize CRH, and intriguingly, fibers originating from PVN
make appositions onto neighboring neurons that send projections to the rostral ventrolateral medulla and express CRH type 1 receptor (CRHR1) mRNA. We then used an
preparation that combined optogenetics, patch-clamp electrophysiology, and Ca
imaging to discover that excitation of PVN
drives the local, intra-PVN release of CRH, which activates rostral ventrolateral medulla-projecting neurons via stimulation of CRHR1(s). Finally, we returned to our
preparation and found that CRH receptor antagonism specifically within the PVN lowered blood pressure basally and during optogenetic activation of PVN
Collectively, these results demonstrate that angiotensin II acts on PVN
to conjoin hypothalamic-pituitary-adrenal axis activity with sympathetically mediated vasoconstriction in male mice.
The survival of an organism is dependent on meeting the energetic demands imposed by stressors. This critical function is accomplished by the CNS's ability to orchestrate simultaneous activities of neurosecretory and autonomic axes. Here, we unveil a novel signaling mechanism within the paraventricular nucleus of the hypothalamus that links excitation of neurons producing corticotropin-releasing-hormone with excitation of neurons controlling sympathetic nervous system activity and blood pressure. The implication is that chronic stress exposure may promote cardiometabolic disease by dysregulating the interneuronal cross-talk revealed by our experiments.