An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice

Abstract

Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.

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

“…In this regard, the subfornical organ and the median preoptic nucleus are brain regions that express Agtr1a(s) that send axonal projections into the PVN (Bains et al, 1992;Z. Li and Ferguson, 1993;Krause et al, 2011;Leib et al, 2017;Frazier et al, 2021). Thus, the optogenetic approach implemented in the prior experiment likely excites these axonal projections, as well as the soma of PVN Agtr1a .…”

Preoptic BRS3 neurons increase body temperature and heart rate via multiple pathways

“…The PVH also originates sympathetic signaling to other organs, including the heart (Nunn et al, 2011). The POA/PVH pathway has been implicated in autonomic cardiovascular and renal regulation (Frazier et al, 2021;Llewellyn et al, 2012;Marciante et al, 2020;McKinley et al, 2015;Sawchenko and Swanson, 1983;Stocker and Toney, 2005), but less in Tb regulation. We now show that POA BRS3 /PVH neurons regulate Tb, HR, and MAP through the sympathetic nervous system.…”

Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension

“…Activation of the brain RAS, particularly AT 1a Rs, has been shown in several types of hypertension models, including DOCA-salt hypertension [ 25 , 57 , 58 , 59 , 60 , 61 , 62 ]. Here, we sought to understand whether part of the mechanism underlying the actions of renin-a deletion reflects altered regulation of the angiotensin receptors, AT 1a R and AT 2 R, in the SFO.…”