Stress-related mental health disorders, such as post-traumatic stress disorder (PTSD) promote susceptibility to hypertension and cardiovascular disease (CVD), with PTSD increasing the risk of developing CVD and cardiac-related death by over 60%. The central amygdala (CeA), a region critical for coordinating behavioral and physiological threat responses, contains the angiotensin II, type 2 receptor (AT2R). Our laboratory has shown that neurons that express AT2R in the CeA (CeA-AT2R) regulate both blood pressure and anxiety-like behavior. The goal of the current studies is to extend these findings by utilizing Pavlovian fear conditioning, immunohistochemistry, chemogenetic manipulations, optogenetic manipulations, and radiotelemetry recordings. Mice expressing cre-recombinase in AT2R neurons (AT2Cre), were injected with a cre-inducible excitatory chemogenetic virus, hM3Dq or a control mCherry virus into the CeA. Three-weeks later, mice underwent Pavlovian cued fear conditioning. Chemogenetic activation of CeA-AT2R neurons promoted a form of contextual fear generalization that occurred rapidly, while conditioned fear responses to the tone were not significantly altered. AT2Cre mice were also used to optogenetically stimulate CeA-AT2R neurons while recording blood pressure, heart rate and temperature. Mice were injected with a cre-inducible ChR2 or EYFP control virus and three weeks later, they were implanted with radiotelemetry devices and allowed to recover for an additional two weeks. After habituation to optogenetic tethering, the mice were subjected to various optogenetic stimulation protocols while awake and freely moving. In all cases, optogenetic activation of CeA-AT2R neurons produced a robust increase in systolic blood pressure. Overall, these data suggest that CeA-AT2R activation is sufficient to facilitate the generalization of fear responses which may result from activation of these neurons increasing systolic blood pressure. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Obesity is highly prevalent worldwide and is driven by reduced energy expenditure and increased food intake. Consequently, there is growing interest in pharmacological interventions that can mitigate this global burden. Glucagon-like peptide-1 (GLP-1) agonists, such as semaglutide, induce substantial weight loss; however, adverse effects, including loss of lean mass and weight regain following treatment cessation remain poorly understood. We hypothesized that dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis contributes to these adverse effects. Here, we tested whether targeting the HPA axis with a novel corticotropin-releasing hormone (CRH) neutralizing immunotherapy (anti-CRH) could improve the quality and durability of semaglutide-induced weight loss. Male and female C57BL/6J mice were made diet-induced obese, housed in an indirect calorimetry system, and assigned to one of four groups: (1) saline control, (2) semaglutide (40 µg/kg/day, s.c.), (3) anti-CRH (25 mg/kg, i.p., followed by weekly 12.5 mg/kg, i.p.), or (4) semaglutide + anti-CRH. Metabolic outcomes, plasma corticosterone, and glucose tolerance were monitored before, during, and after the 3-week semaglutide treatment period. As anticipated, anti-CRH consistently lowered plasma corticosterone. Semaglutide alone or with anti-CRH reduced body weight and fat mass. Notably, semaglutide induced a marked decrease in lean mass, an effect that was blunted when anti-CRH was co-administered. Following semaglutide withdrawal, mice displayed robust hyperphagia accompanied by rapid recovery of adipose tissue; both of which were attenuated in the combination-treated group and corresponded with increase POMC neuron number and reduced AgRP mRNA in the arcuate nucleus. While studies defining the hypothalamic circuits involved are ongoing, taken together, these findings suggest that dampening HPA axis activity can alleviate key adverse effects of GLP-1R agonists and may offer a strategy to improve both the quality and long-term maintenance of weight loss by reducing circulating corticosterone. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Vagal sensory neurons play a critical role in the maintenance of physiological functions, including digestion, satiety, respiration, blood pressure, and heart rate. These sensory neurons innervate several organs, reside within the nodose ganglion (NDG) of the vagus nerve, and terminate within the nucleus of the solitary tract (NTS). Sensory neurons innervating the aortic arch are “aortic baroreceptors” that maintain blood pressure at homeostatic levels by engaging the baroreflex. Although the baroreflex was described more than 80 years ago, the specific molecular, structural, and functional phenotype of aortic baroreceptors remains to be fully elucidated. To this end, we utilized a novel approach to selectively target aortic baroreceptors. Age-matched male and female C57BL/6J mice were anesthetized with isoflurane, intubated, and artificially ventilated. Following sternotomy, the aortic arch was exposed, and a retrograde adeno-associated virus was applied to the aortic arch to direct the expression of tdTomato (tdTom) in aortic baroreceptors. Consistent with the structural characteristics of aortic baroreceptors, robust tdTom expression was observed in nerve endings surrounding the aortic arch, within the fibers of the aortic depressor and vagus nerves, cell bodies within the NDG, and neural projections to the caudal NTS. The tdTom labeled cell bodies within the NDG did not express mRNAs coding for chemoreception or airway control. These results validate that our approach selectively labels aortic baroreceptors. Surprisingly, about ~50% of labeled neurons expressed mRNAs coding for the mechanically gated ion channels, PIEZO-1 and/or PIEZO-2. Interestingly, we found aortic baroreceptors expressing PIEZO channels to co-express estrogen receptor-1. This suggests a possible interaction between estrogen and stretch sensors expressed on aortic baroreceptors that may contribute to sex differences in baroreflex sensitivity. To address this possibility, we locally applied Yoda-1 (PIEZO-1 agonist; 20 mM) to the aortic arch and observed depressor responses in both anaesthetized male and female mice. Interestingly, the magnitude of the depressor responses was 2-3 times greater in female mice. Taken together, PIEZO channels containing aortic baroreceptors that co-express estrogen receptors may play a role in sex differences observed in baroreflex sensitivity. Funding: NHLBI K99HL175100 and R00HL175100 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Iron overload disrupts endocrine function and metabolic health, while iron chelation and phlebotomy enhance metabolic fitness in humans and mice. However, the working mechanism of iron-lowering strategies remains largely undefined, and it is unclear whether dietary iron restriction can serve as a new strategy to treat metabolic syndrome. Here we show that 20-ppm iron (i.e., iron moderately restricted) diet increased insulin sensitivity, adipose mitochondrial biogenesis, and energy expenditure compared to 50-ppm iron (i.e., iron adequate) diet in mice. By contrast, severe iron restriction (4-ppm iron diet) caused anemia, underweight and metabolic disorder. Mechanistically, moderate iron restriction induced a condition of subcellular "iron deficiency" due to iron redistribution into mitochondria in adipose tissues, which augmented H3K4 methylation possibly by suppressing iron-dependent histone demethylase like JARID. Enriched H3K4 methylation upregulated the expression of GDF15, a nutrient sensor that promotes adipose browning and metabolic enhancement. Pharmacological inhibition of H3K4 methylation or knockdown of GDF15 prevented iron restriction-induced enhancement of insulin sensitivity. Our study reveals a potential strategy targeting dietary iron to prevent metabolic disorder. It provides the first line of evidence of epigenetic regulation of GDF15 via an iron restriction-H3K4 methylation cascade. Future studies of the H3K4 methylation-GDF15 axis may fuel developing therapeutic options or dietary interventions for metabolic disease.

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 NTSAT1aR afferents) are sufficient to initiate baroreflex responses in both normotensive and hypertensive conditions. NEW METHOD:Here, we developed a closed-loop system in mice to monitor blood pressure and target NTSAT1aR afferents with optogenetic stimulation. To determine the efficacy of the system, mice were subjected to acute pressor stimuli, including restraint or subcutaneous delivery of Ang-II, and delivered optical stimulation by the system until blood pressure returned below threshold. RESULTS:The closed-loop system is effective in attenuating acute elevations in blood pressure induced by physiological or psychological stressors. by initiating compensatory mechanisms to reduce heart rate and blood pressure. However, blood pressure did return to below threshold levels within similar time frames in stimulated and in stimulation-paired control mice. COMPARISON WITH EXISTING METHODS:While some existing approaches that lower blood pressure target similar neural pathways, they do not take such a closed-loop tactic. CONCLUSION:The implication is that this closed-loop system, coupled with the optogenetic targeting of NTSAT1aR afferents, may be exploited to understand and alleviate hypertension.

The brain maintains blood pressure, in part, via arterial baroreceptors that innervate the aortic arch. Arterial baroreceptors 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 arterial baroreceptors remain uncharacterized. This is due to the lack of tools that provide the genetic and target organ specificity that is required to selectively characterize arterial baroreceptors. Here, we use a novel approach to selectively target arterial baroreceptors that innervate the aortic arch. Male C57BL/6J mice were anesthetized with isoflurane, intubated, and artificially ventilated. Following sternotomy, the aortic arch was exposed, and a retrograde adeno-associated virus was applied to the aortic arch to direct the expression of channelrhoropsin-2 (ChR2) and/or tdTomato (tdTom) to arterial baroreceptors. Consistent with the structural characteristics of arterial baroreceptors, robust tdTom expression was observed in nerve endings surrounding the aortic arch, within the fibers of the aortic depressor and vagus nerves, cell bodies of the nodose ganglia (NDG), and neural projections to the caudal NTS (cNTS). Additionally, the tdTom labeled cell bodies within the NDG also expressed mRNAs coding for the mechanically gated ion channels, PIEZO-1 and PIEZO-2. In vivo optogenetic stimulation of the cell bodies of arterial baroreceptors produced robust depressor responses. These results validate that our approach selectively targets arterial baroreceptors innervating the aortic arch. Utilizing this approach, we found subsets of tdTom labeled cell bodies within the NDG that expressed mRNAs coding for epithelial sodium channels (ENaC) and transient potential ankyrin 1 (TRPA1) channels. To ascertain the functionality of these channels, we locally applied 2M sodium chloride or 4-ethyl-2-methyl-2-thiazoline (4E2MT; TRPA1 agonist) to the aortic arch and observed depressor responses in anaesthetized mice. Taken together, we utilized a novel approach to selectively label arterial baroreceptors and found that activation of ENaC and TRPA1channels is sufficient to evoke baroreception. AHA 23POST1020034 and NHLBI K99HL175100 to KE. NHLBI R01HL136595, R35HL150750, R01HL145028 and NCCIH R65AT012142 to ADK & EGK. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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 (AT2R), deemed CeAAT2R, innervate brain nuclei regulating stress responding. In vivo optogenetic excitation of CeAAT2R lowered blood pressure, and this effect was abrogated by systemic hexamethonium or antagonism of GABA receptors within the CeA. Intriguingly, in vivo optogenetic excitation of CeAAT2R was also potently anxiolytic. Delivery of an AT2R agonist into the CeA recapitulated the hypotensive and anxiolytic effects, but ablating AT2R(s) from the CeA was anxiogenic. The results suggest that the excitation of CeAAT2R couples lowered blood pressure with anxiolysis. The implication is that therapeutics targeting CeAAT2R may provide stress relief and protection against cardiovascular disease.

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.

Social adversity, such as that which occurs during subjugation to a lower social status, has profound psychological and cardiometabolic consequences that are conserved across species. Clinically, such adversity often arises from being of a lower socioeconomic status and may contribute to health disparities in cardiometabolic and affective disorders. To develop a better understanding of the cardiometabolic consequences of social adversity, we employ chronic social defeat stress (CSDS) in adult male mice. CSDS results in increases in body mass, that are accompanied by elevated lean and fluid mass, as well as several somatic indices of chronic stress. Moreover, mice exposed to CSDS exhibit increased anxiety-like behavior, spending more time in the closed arms of the elevated plus maze and less time in the center of an open field arena. Regarding cardiovascular parameters, initial social defeat sessions result in increases in blood pressure, activity, and temperature in comparison with control mice. Interestingly, while blood pressure returns to basal levels by the start of the light cycle for the first few days of defeat, 14 days of CSDS results in sustained elevations in blood pressure, lower activity and lower body temperature. Finally, the results of heart rate variability, spontaneous baroreflex sensitivity and adrenal transcriptome analyses were consistent with CSDS-induced autonomic dysfunction, effects that may contribute to the hypertension observed. Collectively, these data suggest that CSDS may be useful for modeling hypertension induced by chronic social stress, thereby enabling us to better understand the mechanisms that contribute to stress-induced cardiometabolic disease.

ABSTRACT 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 2 -receptor (AT 2 R) or the receptor Mas. A potential vasodilatory effect of Ang-(1-5) was tested in mouse mesenteric and human renal arteries by wire myography; the effect on blood pressure was evaluated in normotensive C57BL/6 mice by Millar catheter. These experiments were performed in the presence or absence of a range of antagonists or inhibitors or in AT 2 R-knockout mice. Binding of Ang-(1-5) to the AT 2 R was confirmed and the preferred conformations determined by in silico docking simulations. The signaling network of Ang-(1-5) was mapped by quantitative phosphoproteomics. Results Key findings included: (1) Ang-(1-5) induced activation of eNOS by changes in phosphorylation at Ser1177 eNOS and Tyr657 eNOS and thereby (2) increased NO release from HAEC and AT 2 R-transfected CHO cells, but not from Mas-transfected or non-transfected CHO cells. (3) Ang-(1-5) induced relaxation of preconstricted mouse mesenteric and human renal arteries and (4) lowered blood pressure in normotensive mice – effects which were respectively absent in arteries from AT 2 R-KO or in PD123319-treated mice and which were more potent than effects of the established AT 2 R-agonist C21. (5) According to in silico modelling, Ang-(1-5) binds to the AT 2 R in two preferred conformations, one differing substantially from where the first five amino acids within angiotensin II bind to the AT 2 R. (6) Ang-(1-5) modifies signaling pathways in a protective RAS-typical way and with relevance for endothelial cell physiology and disease. Conclusions Ang-(1-5) is a potent, endogenous AT 2 R-agonist.

Oxytocin is a neuropeptide in clinical trials for mental health disorders that is also reported to have beneficial effects on cardiovascular function. Arterial baroreceptors contribute to cardiovascular function by relaying information pertaining to perfusion pressure to the brain. Neurons that give rise to arterial baroreceptors reside in the nodose ganglion (NG). These neurons utilize Piezo2, a mechanosensitive ion channel, to convert pressure and stretch exerted on the vascular wall of the aortic arch into action potentials that are carried by the vagus nerve to the brain. Upon receiving this information, the brain initiates the baroreflex which adjusts cardiac output and vasculature resistance to maintain blood pressure at optimal levels. Interestingly, we have determined that a subpopulation of NG neurons express both the oxytocin receptor (Oxtr) and Piezo2. Here, we test the overall hypothesis that Piezo2 synthesized by Oxtr-expressing neurons mediate cardiovascular function in male and female mice. Mice that express Cre-recombinase at the Oxtr locus were bred to mice with LoxP sites flanking the Piezo2 gene. This resulted in offspring with the Piezo2 gene selectively deleted from cells that express the Oxtr gene (Oxtr Piezo2 KO) or littermates only harboring LoxP sites flanking the Piezo2 gene (controls). To validate the selective deletion of Piezo2 from neurons that express Oxtr, we used RNAscope in situ hybridization to label Oxtr and Piezo2 mRNAs within the NG. In control mice, we frequently observed NG neurons double-labeled for Oxtr and Piezo2 mRNAs. In contrast, colocalization of these mRNAs was not observed in NG neurons obtained from OxtrPiezo2 KO mice. Cardiovascular recordings were performed in anesthetized mice administered the vasoactive drug phenylephrine (PE; i.v.) to determine whether deletion of Piezo2 from Oxtr-expressing neurons affects blood pressure, heart rate, and the baroreflex. Baseline systolic blood pressure was lower in male OxtrPiezo2 KO mice compared to controls but resting heart rate was similar amongst the groups. Pressor and bradycardic responses to PE were not different between male OxtrPiezo2 KO mice and controls, suggesting that deletion of Piezo2 from Oxtr-expressing neurons has no effect on the baroreflex in male mice. Female OxtrPiezo2 KO mice had baseline systolic blood pressure and heart rate that were similar to controls. In females, delivery of PE similarly increased systolic blood pressure in OxtrPiezo2 KO mice and controls, but remarkably, the significant bradycardia that was observed in control mice was completely absent in female OxtrPiezo2 KO mice. Collectively, these results suggest that Piezo2 expression in neurons that synthesize Oxtr is necessary to evoke the baroreflex specifically in female mice. AHA 23POST1020034 to KE. NHLBI R01HL136595, R35HL150750, R01HL145028 and NCCIH R65AT012142 to ADK & EGK. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

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). We have previously determined that optical excitation of neurons and vagal afferents within the NTS that express AT1aR (referred to as NTSAT1aR) mimics the perception of increased vascular stretch and induces compensatory responses to restore blood pressure. Here, we test whether NTSAT1aR are also involved in the modulation of water and sodium intake. We directed the light-sensitive excitatory channelrhodopsin-2 (ChR2) or inhibitory halorhodopsin (Halo) to Agtr1a-containing neurons and measured water and sodium chloride (NaCl) intake in the presence and absence of optical stimulation within the NTS during various challenges to fluid homeostasis. Optical perturbation of NTSAT1aR modulates NaCl intake, such that excitation attenuates, whereas inhibition increases intake. This effect is only observed in the water-deprived condition, suggesting that NTSAT1aR are involved in the regulation of sodium intake during an imbalance in both the intracellular and extracellular fluid compartments. Furthermore, optical excitation of NTSAT1aR increases c-Fos expression within oxytocinergic neurons of the paraventricular nucleus of the hypothalamus (PVN), indicating that the regulation of sodium intake by NTSAT1aR may be mediated by oxytocin. Collectively, these results reveal that NTSAT1aR are sufficient and necessary to modulate sodium intake relative to perceived changes in vascular stretch.

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. These data coupled with our observations that ACE2 overexpression in CRH cells (CRH-ACE2KI mice) decreases anxiety-like behavior via suppression of hypothalamic–pituitary–adrenal (HPA) axis activity by decreasing CRH synthesis, led us to hypothesize that selective ACE2 overexpression in CRH neurons would protect against hypoxia-induced PH. Methods CRH-ACE2KI and WT male and female mice were exposed to chronic hypoxia (10%O2) or normoxia (21%O2) for 4 weeks in a ventilated chamber with continuous monitoring of oxygen and carbon dioxide concentrations (n = 7–10/group). Pulmonary hemodynamics were measured with Millar pressure catheters then tissues were collected for histological analyses. Results Chronic hypoxia induced a significant increase (36.4%) in right ventricular (RV) systolic pressure (RVSP) in WT mice, which was not observed in CRH-ACE2KI mice. No significant differences in RVSP were observed between male and female mice in any of the groups. Conclusion Overexpression of ACE2 in CRH cells was protective against hypoxia-induced PH. Since the majority of expression of CRH is in brain nuclei such as paraventricular nucleus of the hypothalamus (PVN) and/or central nucleus of the amygdala (CeA) these data indicate that the protective effects of ACE2 are, at least in part, centrally mediated. This contributes to the systemic nature of PH disease and that CRH neurons may play an important role in PH.

We investigated the lateralization of gut-innervating vagal sensory neurons and their roles in feeding behavior. Using genetic, anatomical, and behavioral analyses, we discovered a subset of highly lateralized vagal sensory neurons with distinct sensory responses to intestinal stimuli. Our results demonstrated that left vagal sensory neurons (LNG) are crucial for distension-induced satiety, while right vagal sensory neurons (RNG) mediate preference for nutritive foods. Furthermore, these lateralized neurons engage different central circuits, with LNG neurons recruiting brain regions associated with energy balance and RNG neurons activating areas related to salience, memory, and reward. Altogether, our findings unveil the diverse roles of asymmetrical gut-vagal-brain circuits in feeding behavior, offering new insights for potential therapeutic interventions targeting vagal nerve stimulation in metabolic and neuropsychiatric diseases. One Sentence Summary Lateralized gut-brain circuits respond to different sensory modalities and control distinct feeding behaviors.