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.

Significant prior evidence indicates that centrally acting oxytocin robustly modulates stress responsiveness and anxiety‐like behaviour, although the neural mechanisms behind these effects are not entirely understood. A plausible neural basis for oxytocin‐mediated stress reduction is via inhibition of corticotrophin‐releasing hormone (CRH) neurones in the paraventricular nucleus of the hypothalamus (PVN) that regulate activation of the hypothalamic‐pituitary‐adrenal axis. Previously, we have shown that, following s.c. injection of 2.0 mol L−1 NaCl, oxytocin synthesising neurones are activated in the rat PVN, an oxytocin receptor (Oxtr)‐dependent inhibitory tone develops on a subset of parvocellular neurones and stress‐mediated increases in plasma corticosterone levels are blunted. In the present study, we utilised transgenic male CRH‐reporter mice to selectively target PVN CRH neurones for whole‐cell recordings. These experiments reveal that acute salt loading produces tonic inhibition of PVN CRH neurones through a mechanism that is largely independent of synaptic activity. Further studies reveal that a subset of CRH neurones within the PVN synthesise mRNA for Oxtr(s). Salt induced Oxtr‐dependent inhibitory tone was eliminated in individual PVN CRH neurones filled with GDP‐β‐S. Additional electrophysiological studies suggest that reduced excitability of PVN CRH neurones in salt‐loaded animals is associated with increased activation of inwardly rectifying potassium channels. Nevertheless, substantial effort to recapitulate the core effects of salt loading by activating Oxtr(s) with an exogenous agonist produced mixed results. Collectively, these results enhance our understanding of how oxytocin receptor‐mediated signalling modulates the function of CRH neurones in the PVN.

Aims These studies evaluate whether angiotensin type-2 receptors (AT2Rs) that are expressed on γ-aminobutyric acid (GABA) neurons in the nucleus of the solitary tract (NTS) represent a novel endogenous blood pressure lowering mechanism. Methods and Results Experiments combined advanced genetic and neuroanatomical techniques, pharmacology, electrophysiology and optogenetics in mice to define the structure and cardiovascular-related function of NTS neurons that contain AT2R. Using mice with Cre-recombinase directed to the AT2R gene, we discovered that optogenetic stimulation of AT2R-expressing neurons in the NTS increases GABA release and blood pressure. To evaluate the role of the receptor, per se, in cardiovascular regulation, we chronically delivered C21, a selective AT2R agonist, into the brains of normotensive mice and found that central AT2R activation reduces GABA-related gene expression and blunts the pressor responses induced by optogenetic excitation of NTS AT2R neurons. Next, using in situ hybridization, we found that the levels of Agtr2 mRNAs in GABAergic NTS neurons rise during experimentally-induced hypertension, and we hypothesized that this increased expression may be exploited to ameliorate the disease. Consistent with this, final experiments revealed that central administration of C21 attenuates hypertension, an effect that is abolished in mice lacking AT2R in GABAergic NTS neurons. Conclusions These studies unveil novel hindbrain circuits that maintain arterial blood pressure, and reveal a specific population of AT2R that can be engaged to alleviate hypertension. The implication is that these discrete receptors may serve as an access point for activating an endogenous depressor circuit. Translational perspective Hypertension is a widespread health problem and risk factor for cardiovascular disease and stroke. Although treatment options exist, many patients suffer from resistant hypertension, which is associated with enhanced sympathetic drive. Thus, many available therapeutics focus on dampening pressor mechanisms. The present studies take the alternative approach of treating hypertension by exploiting an endogenous depressor mechanism.

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