A closed-loop approach to monitor and manipulate the neural control of blood pressure.

Background: Arterial baroreceptors are mechanosensitive nerve endings that detect blood pressure deviations and transmit this information to the central nervous system via vagal afferent neurons. Vagal afferent neuron cell bodies reside in the nodose ganglion (NG) and they terminate in the nucleus of the solitary tract (NTS) within the brainstem, thus serving as a critical component of the baroreflex circuitry. We previously found that specific angiotensin-sensitive vagal afferent nerve terminals within the NTS (referred to as NTS afferents) are sufficient to initiate baroreflex responses in both normotensive and hypertensive conditions.

Neurons of the Central Nucleus of the Amygdala That Express Angiotensin Type 2 Receptors Couple Lowered Blood Pressure with Anxiolysis in Male Mice.

Relief from psychological stress confers cardio-protection by altering brain activity and lowering blood pressure; however, the neuronal circuits orchestrating these effects are unknown. Here, we used male mice to discern neuronal circuits conferring stress relief and reduced blood pressure. We found that neurons residing in the central nucleus of the amygdala (CeA) expressing angiotensin type 2 receptors (ATR), deemed CeA, innervate brain nuclei regulating stress responding.

Mechanosensation of the heart and gut elicits hypometabolism and vigilance in mice.

Interoception broadly refers to awareness of one's internal milieu. Although the importance of the body-to-brain communication that underlies interoception is implicit, the vagal afferent signalling and corresponding brain circuits that shape perception of the viscera are not entirely clear. Here, we use mice to parse neural circuits subserving interoception of the heart and gut.

Optical perturbation of Agtr1a-containing neurons and afferents within the caudal nucleus of the solitary tract modulates sodium intake.

Angiotensin-II (Ang-II) production is driven by deviations in blood volume and osmolality, and serves the role of regulating blood pressure and fluid intake to maintain cardiovascular and hydromineral homeostasis. These actions are mediated by Ang-II acting on its type 1a receptor (AT1aR) within the central nervous system and periphery. Of relevance, AT1aR are expressed on sensory afferents responsible for conveying cardiovascular information to the nucleus of the solitary tract (NTS).

Angiotensin-(1-5) is a Potent Endogenous Angiotensin AT -Receptor Agonist.

Background: The renin-angiotensin system involves many more enzymes, receptors and biologically active peptides than originally thought. With this study, we investigated whether angiotensin-(1-5) [Ang-(1-5)], a 5-amino acid fragment of angiotensin II, has biological activity, and through which receptor it elicits effects.

Methods: The effect of Ang-(1-5) (1µM) on nitric oxide release was measured by DAF-FM staining in human aortic endothelial cells (HAEC), or Chinese Hamster Ovary (CHO) cells stably transfected with the angiotensin AT -receptor (AT R) or the receptor Mas.

Alleviating Hypertension by Selectively Targeting Angiotensin Receptor-Expressing Vagal Sensory Neurons.

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NG) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using -Cre mice and Cre-dependent AAVs to direct tdTomato to NG, neuroanatomical studies revealed that NG receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, To evaluate the functionality of NG, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to -containing neurons.

ACE2 overexpression in corticotropin-releasing-hormone cells offers protection against pulmonary hypertension.

Background: Pulmonary hypertension (PH), characterized by elevated pulmonary pressure and right heart failure, is a systemic disease involving inappropriate sympathetic activation and an impaired gut-brain-lung axis. Global overexpression of angiotensin converting enzyme 2 (ACE2), a cardiopulmonary protective enzyme of the renin-angiotensin system, attenuates PH induced by chronic hypoxia. Neurons within the paraventricular nucleus of the hypothalamus (PVN) that synthesize corticotropin-releasing hormone (CRH) are activated by stressors, like hypoxia, and this activation augments sympathetic outflow to cardiovascular tissues.

Mechanosensation of the heart and gut elicits hypometabolism and vigilance in mice.

Interoception broadly refers to awareness of one's internal milieu. Vagal sensory afferents monitor the internal milieu and maintain homeostasis by engaging brain circuits that alter physiology and behavior. While the importance of the body-to-brain communication that underlies interoception is implicit, the vagal afferents and corresponding brain circuits that shape perception of the viscera are largely unknown.

Sodium Intake and Disease: Another Relationship to Consider.

Sodium (Na) is crucial for numerous homeostatic processes in the body and, consequentially, its levels are tightly regulated by multiple organ systems. Sodium is acquired from the diet, commonly in the form of NaCl (table salt), and substances that contain sodium taste salty and are innately palatable at concentrations that are advantageous to physiological homeostasis. The importance of sodium homeostasis is reflected by sodium appetite, an "all-hands-on-deck" response involving the brain, multiple peripheral organ systems, and endocrine factors, to increase sodium intake and replenish sodium levels in times of depletion.

Fecal matter transplant from Ace2 overexpressing mice counteracts chronic hypoxia-induced pulmonary hypertension.

Recent evidence suggests pulmonary hypertension (PH), a disease of the pulmonary vasculature actually has multiorgan pathophysiology and perhaps etiology. Herein, we demonstrated that fecal matter transplantation from angiotensin-converting enzyme 2 overexpressing mice counteracted the effects of chronic hypoxia to prevent pulmonary hypertension, neuroinflammation, and gut dysbiosis in wild type recipients.

Oxytocin and cardiometabolic interoception: Knowing oneself affects ingestive and social behaviors.

Maintaining homeostasis while navigating one's environment involves accurately assessing and interacting with external stimuli while remaining consciously in tune with internal signals such as hunger and thirst. Both atypical social interactions and unhealthy eating patterns emerge as a result of dysregulation in factors that mediate the prioritization and attention to salient stimuli. Oxytocin is an evolutionarily conserved peptide that regulates attention to exteroceptive and interoceptive stimuli in a social environment by functioning in the brain as a modulatory neuropeptide to control social behavior, but also in the periphery as a hormone acting at oxytocin receptors (Oxtr) expressed in the heart, gut, and peripheral ganglia.

A Novel Organ-Specific Approach to Selectively Target Sensory Afferents Innervating the Aortic Arch.

The brain maintains cardiovascular homeostasis, in part, the arterial baroreflex which senses changes in blood pressure (BP) at the level of the aortic arch. Sensory afferents innervating the aortic arch employ baroreceptors to convert stretch exerted on the arterial wall into action potentials carried by the vagus nerve to second order neurons residing within the nucleus of the solitary tract (NTS). Although the baroreflex was described more than 80 years ago, the specific molecular, structural, and functional phenotype of the baroreceptors remain uncharacterized.

Conditioned social preference and reward value of activating oxytocin-receptor-expressing ventral tegmental area neurons following repeated daily binge ethanol intake.

Background: Individuals with alcohol use disorder (AUD) exhibit a disruption of social behavior and dysregulation of oxytocin signaling in the brain, possibly reflecting decreased activation of oxytocin receptors (OxTRs) in reward pathways in response to social stimuli. We hypothesize that daily binge ethanol intake causes a deficit in social reward and oxytocin signaling in the ventral tegmental area (VTA).

Methods: After 9 weeks of daily binge ethanol intake (blood ethanol concentration >80 mg%), OxTR-cre mice underwent conditioned place preference for social reward.

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

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.

Targeting angiotensin type-2 receptors located on pressor neurons in the nucleus of the solitary tract to relieve hypertension in mice.

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.

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

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 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.

Brain Angiotensin Type-1 and Type-2 Receptors in Physiological and Hypertensive Conditions: Focus on Neuroinflammation.

Purpose Of Review: To review recent data that suggest opposing effects of brain angiotensin type-1 (ATR) and type-2 (ATR) receptors on blood pressure (BP). Here, we discuss recent studies that suggest pro-hypertensive and pro-inflammatory actions of ATR and anti-hypertensive and anti-inflammatory actions of ATR. Further, we propose mechanisms for the interplay between brain angiotensin receptors and neuroinflammation in hypertension.

Overexpression of angiotensin converting enzyme 2 reduces anxiety-like behavior in female mice.

Accumulating evidence has revealed an intricate role for the renin-angiotensin system (RAS) in the progression or alleviation of stress-related disorders. Along these lines, the 'pro-stress' actions of angiotensin-II (Ang-II) are largely thought to be mediated by the angiotensin type-1a receptor (AT1aR). On the other hand, a counter regulatory limb of the RAS that depends on the conversion of Ang-II to angiotensin-(1-7) by angiotensin-converting enzyme 2 (ACE2) has been postulated to exert stress-dampening actions.

Gut Pathology and Its Rescue by ACE2 (Angiotensin-Converting Enzyme 2) in Hypoxia-Induced Pulmonary Hypertension.

Therapeutic advances for pulmonary hypertension (PH) have been incremental because of the focus on the pulmonary vasculature in PH pathology. Here, we evaluate the concept that PH is, rather, a systemic disorder involving interplay among multiorgan systems, including brain, gut, and lungs. Therefore, the objective of this study was to evaluate the hypothesis that PH is associated with a dysfunctional brain-gut-lung axis and that global overexpression of ACE2 (angiotensin-converting enzyme 2) rebalances this axis and protects against PH.

Endogenous oxytocin inhibits hypothalamic corticotrophin-releasing hormone neurones following acute hypernatraemia.

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.

Brain angiotensin type-1 and type-2 receptors: cellular locations under normal and hypertensive conditions.

Brain angiotensin-II (Ang-II) type-1 receptors (AT1Rs), which exert profound effects on normal cardiovascular, fluid, and metabolic homeostasis, are overactivated in and contribute to chronic sympathoexcitation and hypertension. Accumulating evidence indicates that the activation of Ang-II type-2 receptors (AT2Rs) in the brain exerts effects that are opposite to those of AT1Rs, lowering blood pressure, and reducing hypertension. Thus, it would be interesting to understand the relative cellular localization of AT1R and AT2R in the brain under normal conditions and whether this localization changes during hypertension.

An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes.

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis.

Oxytocin Receptors Are Expressed by Glutamatergic Prefrontal Cortical Neurons That Selectively Modulate Social Recognition.

Social recognition, the ability to recognize individuals that were previously encountered, requires complex integration of sensory inputs with previous experience. Here, we use a variety of approaches to discern how oxytocin-sensitive neurons in the PFC exert descending control over a circuit mediating social recognition in mice. Using male mice with Cre-recombinase directed to the oxytocin receptor gene (), we revealed that oxytocin receptors (OXTRs) are expressed on glutamatergic neurons in the PFC, optogenetic stimulation of which elicited activation of neurons residing in several mesolimbic brain structures.

Top-down and bottom-up control of stress-coping.

In this 30th anniversary issue review, we focus on the glucocorticoid modulation of limbic-prefrontocortical circuitry during stress-coping. This action of the stress hormone is mediated by mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) that are co-expressed abundantly in these higher brain regions. Via both receptor types, the glucocorticoids demonstrate, in various contexts, rapid nongenomic and slower genomic actions that coordinate consecutive stages of information processing.

Macrophage angiotensin II type 2 receptor triggers neuropathic pain.

Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor (AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene () expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism.