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 NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2 To evaluate the functionality of NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a-containing neurons. Two-photon intravital imaging in Agtr1a-GCaMP6s mice revealed that NGAT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aR at their soma or axon terminals within the caudal NTS of Agtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension.

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. Here, we use mice to parse neural circuits subserving interoception of the heart and gut. We determine vagal sensory afferents expressing the oxytocin receptor, hereafter referred to as NDGOxtr, send projections to the aortic arch or stomach and duodenum with molecular and structural features indicative of mechanosensation. Chemogenetic excitation of NDGOxtr significantly decreases food and water consumption, and remarkably, produces a torpor-like phenotype characterized by reductions in cardiac output, body temperature, and energy expenditure. Chemogenetic excitation of NDGOxtr also creates patterns of brain activity associated with augmented hypothalamic-pituitary-adrenal axis activity and behavioral indices of vigilance. Recurrent excitation of NDGOxtr suppresses food intake and lowers body mass, indicating that mechanosensation of the heart and gut can exert enduring effects on energy balance. These findings suggest that the sensation of vascular stretch and gastrointestinal distention may have profound effects on whole body metabolism and mental health.

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. Visceral sensory information and endocrine signals are integrated by the brain to regulate sodium intake. Dysregulation of the systems involved can lead to sodium overconsumption, which numerous studies have considered causal for the development of diseases, such as hypertension. The purpose here is to consider the inverse-how disease impacts sodium intake, with a focus on stress-related and cardiometabolic diseases. Our proposition is that such diseases contribute to an increase in sodium intake, potentially eliciting a vicious cycle toward disease exacerbation. First, we describe the mechanism(s) that regulate each of these processes independently. Then, we highlight the points of overlap and integration of these processes. We propose that the analogous neural circuitry involved in regulating sodium intake and blood pressure, at least in part, underlies the reciprocal relationship between neural control of these functions. Finally, we conclude with a discussion on how stress-related and cardiometabolic diseases influence these circuitries to alter the consumption of sodium.

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. Specialized sensory afferent nerve endings of Oxtr-expressing nodose ganglia cells transmit cardiometabolic signals via the Vagus nerve to integrative regions in the brain that also express Oxtr(s). These brain regions are influenced by vagal sensory pathways and coordinate with external events such as those demanding attention to social stimuli, thus the sensations related to cardiometabolic function and social interactions are influenced by oxytocin signaling. This review investigates the literature supporting the idea that oxytocin mediates the interoception of cardiovascular and gastrointestinal systems, and that the modulation of this awareness likewise influences social cognition. These concepts are then considered in relation to Autism Spectrum Disorder, exploring how atypical social behavior is comorbid with cardiometabolic dysfunction.

Optogenetic Stimulation of Type I GAD65+ Cells in Taste Buds Activates Gustatory Neurons and Drives Appetitive Licking Behavior in Sodium-Depleted Mice.

Mammalian taste buds are comprised of specialized neuroepithelial cells that act as sensors for molecules that provide nutrition (e.g., carbohydrates, amino acids, and salts) and those that are potentially harmful (e.g., certain plant compounds and strong acids). Type II and III taste bud cells (TBCs) detect molecules described by humans as "sweet," "bitter," "umami," and "sour." TBCs that detect metallic ions, described by humans as "salty," are undefined. Historically, type I glial-like TBCs have been thought to play a supportive role in the taste bud, but little research has been done to explore their role in taste transduction. Some evidence implies that type I cells may detect sodium (Na+) via an amiloride-sensitive mechanism, suggesting they play a role in Na+ taste transduction. We used an optogenetic approach to study type I TBCs by driving the expression of the light-sensitive channelrhodopsin-2 (ChR2) in type I GAD65+ TBCs of male and female mice. Optogenetic stimulation of GAD65+ TBCs increased chorda tympani nerve activity and activated gustatory neurons in the rostral nucleus tractus solitarius. "N neurons," whose NaCl responses were blocked by the amiloride analog benzamil, responded robustly to light stimulation of GAD65+ TBCs on the anterior tongue. Two-bottle preference tests were conducted under Na+-replete and Na+-deplete conditions to assess the behavioral impact of optogenetic stimulation of GAD65+ TBCs. Under Na+-deplete conditions GAD65-ChR2-EYFP mice displayed a robust preference for H2O illuminated with 470 nm light versus nonilluminated H2O, suggesting that type I glial-like TBCs are sufficient for driving a behavior that resembles Na+ appetite.SIGNIFICANCE STATEMENT This is the first investigation on the role of type I GAD65+ taste bud cells (TBCs) in taste-mediated physiology and behavior via optogenetics. It details the first definitive evidence that selective optogenetic stimulation of glial-like GAD65+ TBCs evokes neural activity and modulates behavior. Optogenetic stimulation of GAD65+ TBCs on the anterior tongue had the strongest effect on gustatory neurons that responded best to NaCl stimulation through a benzamil-sensitive mechanism. Na+-depleted mice showed robust preferences to "light taste" (H2O illuminated with 470 nm light vs nonilluminated H2O), suggesting that the activation of GAD65+ cells may generate a salt-taste sensation in the brain. Together, our results shed new light on the role of GAD65+ TBCs in gustatory transduction and taste-mediated behavior.