Despite its long-recognized effects in relieving pain, the neural substrates of auricular stimulation remain elusive. Here, we show that trans-auricular vagus nerve stimulation (taVNS), i.e., electrical stimulation of the auricular concha, effectively induces analgesia in a mouse model of neuropathic pain. Viral tracing, microendoscopic calcium imaging, and multi-electrode recordings reveal that auricular vagal signals travel to the jugular-nodose ganglia (JNG), which in turn connect to pro-opiomelanocortinergic neurons in nucleus tractus solitarius (NTS), subsequently activating glutamatergic neurons in ventrolateral periaqueductal gray (vlPAG). Optogenetic stimulation of central vagus terminals, JNG-derived auricular peripheral fibers, or vlPAG-projecting NTS neurons mimics taVNS-induced analgesia, whereas chemogenetic silencing of central vagus terminals or NTS neurons abolishes this effect. This study identifies an auricle-to-brain circuit underlying taVNS-driven analgesia in mice, with potential for facilitating taVNS optimization for pain management and other neurological conditions.

The lower brainstem is a key hub linking visceral physiology with the regulation of brain states. This review synthesizes recent findings demonstrating how several nuclei within this region—including the nucleus of the solitary tract (NST), parabrachial nucleus (PBN), and other medullary circuits—function as an integrated network that couples sleep-wake regulation to the body's homeostatic demands. The NST serves as a central gateway, translating cardiovascular, immune, and digestive signals into a sleep drive, whereas the PBN plays a pivotal role in processing threat-related inputs to promote arousal. Several populations of GABAergic neurons in the medulla induce both motor suppression and sleep. In addition, cholinergic neurons in the nucleus ambiguus and catecholaminergic cells in the ventrolateral medulla and locus coeruleus regulate sleep-wake states together with somatic and autonomic motor activity. Collectively, these findings establish the brainstem not merely as a collection of reflex centers but as a master coordinator aligning global brain states with peripheral bodily functions.

Cortical neurons in sensory areas undergo a protracted process of postnatal maturation that includes changes in membrane properties, synaptic drive and connectivity. The completion of this process is associated with the closure of critical periods for experience-dependent plasticity in visual, auditory and somatosensory cortices. Whether these findings extend to the postnatal development of cortical circuits for taste is currently unknown. Taste receptor cells in the taste buds reliably fire action potentials in response to taste stimuli by the third postnatal week and show extended refinement of membrane excitability into adulthood. Taste responsive neurons in the nucleus of the solitary tract show reorganization of peripheral nerve terminals (NTS) over a timeline comparable to taste buds. However, no study to date investigated the postnatal development of neurons in the gustatory cortex (GC). Here, we focused on pyramidal neurons in the deep layers of GC in acute slices from male and female mice and compared their membrane properties from the third to the eighth postnatal week. We report changes in intrinsic excitability and a shift of the excitation/inhibition (E/I) balance toward inhibition as pyramidal neurons reach their young adult properties. The increase in inhibitory drive accompanied a protracted process of postnatal maturation of inhibitory circuits mediated by parvalbumin expressing neurons (PV+ neurons) that showed an increase in their association with perineuronal nets (PNNs) as well as refinement of their connectivity onto pyramidal neurons. Together, our results indicate that GC neurons undergo protracted postnatal maturation that may influence taste response properties.Significance Statement We show that the circuit in the gustatory cortex (GC) undergoes a protracted maturation process extending into adulthood that shifts the excitability of GC toward inhibition through changes in pyramidal neurons membrane properties, increased inhibitory synaptic drive and refinement of parvalbumin neurons connectivity. GC circuit refinement extends beyond the developmental windows previously reported for other sensory cortical circuits and overlaps with the window of maturation for taste receptor cells and with the critical period for the development of taste preferences. As finding nutritious food sources may require the integration of vision, audition, somatosensation and olfaction, an extended maturation of GC may facilitate the integration of sensory information for the identification of food and the decision to ingest it.

Hypoxia can be classified into two types based on its temporal characteristics: acute hypoxia and chronic hypoxia, posing a severe threat to the physiological homeostasis of the body. Hypoxia stimulates peripheral chemoreceptors and activates compensatory responses in the autonomic nervous system and cardiopulmonary functions. These responses rely on coordinated regulation by the carotid body and multiple nuclei in the central nervous system. Through specific neural pathways and molecular mechanisms, the body adapts to hypoxia and sustains survival. However, severe hypoxia may lead to irreversible damage or asphyxiation. In this review, we discuss recent research on central neural circuits and molecular changes in nuclei induced by hypoxia. It focuses on key regions associated with hypoxia, including the nucleus of the solitary tract, retrotrapezoid nucleus, rostral ventral lateral medulla, parabrachial nucleus, and hypothalamic paraventricular nucleus. From a neuroscience perspective, it elaborates on the effects of hypoxia on respiratory, cardiovascular, and other bodily functions. This understanding may help guide the treatment of hypoxia-related clinical diseases. JOURNAL/mgres/04.03/01612956-990000000-00093/figure1/v/2026-04-11T111231Z/r/image-tiff.

Sleep apnea syndrome (SAS) is a prevalent disorder characterized by recurrent respiratory pauses during sleep; however, the neural mechanisms governing respiratory stability remain poorly understood. In this study, we identify the ratio of sigh expiratory volume to eupneic expiratory volume as a potential predictor of post-sigh apnea in susceptible C57BL/6J mice. We demonstrate that leptin signaling within the nucleus tractus solitarius (NTS) is critical for maintaining respiratory drive and suppressing apnea. Chemogenetic activation of Leptin receptor b-expressing NTS (NTSLepRb) neurons significantly reduced apnea incidence, whereas their ablation exacerbated respiratory dysfunction. Moreover, NTSLepRb neurons mediate these effects through anatomically and functionally segregated projections to the dorsomedial hypothalamus and the lateral parabrachial nucleus. These findings define a specific leptin-mediated brainstem circuit that stabilizes respiratory output, providing new mechanistic insights and potential therapeutic targets for sleep-disordered breathing.

This study aimed to investigate the potential of ononin in alleviating mild cognitive impairment (MCI) and to determine whether its effects depend on the functional recovery of neurons in the nucleus tractus solitarius (NTS). Four-month-old APP/PS1 mice were treated with 30-mg/kg ononin via oral gavage for 8 consecutive days. Cognitive behavior was assessed using the novel object recognition test, Y-maze test, and open field test. Cortical perfusion was measured by laser speckle contrast imaging. The activation of NTS neurons was detected using c-Fos immunofluorescence staining, while dendritic complexity and neuronal firing frequency were evaluated via Golgi staining and patch-clamp electrophysiology, respectively. Ononin treatment significantly improved the novel object recognition index and spontaneous alternation rate in the Y-maze test in APP/PS1 mice. It also enhanced cerebral blood flow perfusion and increased the number of c-Fos-positive cells in the NTS, hippocampal CA1 region, and cortex. Furthermore, ononin increased dendritic intersections and restored dendritic spine density in NTS neurons to normal levels, along with significantly elevating their firing frequency. Ononin may ameliorate MCI-like cognitive deficits in APP/PS1 mice by activating NTS neurons, restoring synaptic plasticity, and improving cerebral perfusion. These findings suggest that the NTS could serve as a potential target for early intervention in Alzheimer's disease.

Granular motivational interaction and behavioral choice during feeding.

HF-rTMS improves swallowing function in rats with poststroke dysphagia by increasing nucleus tractus solitarius excitability through the NMDAR1-Npas4-Nav1.1 pathway.

Validates blood pressure control for seizure management: Jujuboside B exerts antiseizure effects via blood pressure reduction and activation of NTS-VGLUT2+ neurons.

Pharmacological administration of FGF21 reverses obesity through a parabrachial-projecting neuron population in the hindbrain.

FGF21 signals through hindbrain neurons to alter food intake and energy expenditure during dietary protein restriction.

Norepinephrine neurons in the locus coeruleus and the nucleus of the solitary tract drive different stress-related behavioral outputs in mice

A large body of data indicate that the aminergic, cholinergic and hypocretin/orexin neurons are responsible for inducing wakefulness. However, recent data showed that other systems might also play a key role. Further, wakefulness induced by different drugs versus non-pharmacological means could be generated by different populations of neurons. To address these questions, we evaluated at the whole brain level in the same mice using TRAP2 model whether the same neurons were activated by the wake-inducing drugs modafinil and solriamfetol versus non-pharmacological wake. Our results show that nine subcortical structures namely the oval part of the bed nucleus of the stria terminalis, lateral part of the central amygdalar nucleus, paraventricular hypothalamic and thalamic and supraoptic nuclei, external part of the lateral parabrachial nucleus, caudal part of the nucleus of the solitary tract and the area postrema are significantly more activated by solriamfetol than modafinil and non-pharmacological wakefulness. In contrast, a second category of structures including the orexin neurons, the parasubthalamic and laterodorsal tegmental nucleus are strongly activated in all types of induced wake. Further, some classical wake systems like the dopaminergic neurons of the ventral tegmental area or the dorsal raphe nucleus and the noradrenergic neurons of the locus coeruleus are either very poorly or not strongly activated. These results reveal that many structures not previously involved in wakefulness might play a key role in regulating the state and that some structures might be more recruited by solriamfetol than modafinil or non-pharmacological wakefulness. Our results are particularly relevant for pathologies such as hypersomnia. They open a new era in the study of the mechanisms responsible for inducing wakefulness.

A large body of data indicate that the aminergic, cholinergic and hypocretin/orexin neurons are responsible for inducing wakefulness. However, recent data showed that other systems might also play a key role. Further, wakefulness induced by different drugs versus non-pharmacological means could be generated by different populations of neurons. To address these questions, we evaluated at the whole brain level in the same mice using TRAP2 model whether the same neurons were activated by the wake-inducing drugs modafinil and solriamfetol versus non-pharmacological wake. Our results show that nine subcortical structures namely the oval part of the bed nucleus of the stria terminalis, lateral part of the central amygdalar nucleus, paraventricular hypothalamic and thalamic and supraoptic nuclei, external part of the lateral parabrachial nucleus, caudal part of the nucleus of the solitary tract and the area postrema are significantly more activated by solriamfetol than modafinil and non-pharmacological wakefulness. In contrast, a second category of structures including the orexin neurons, the parasubthalamic and laterodorsal tegmental nucleus are strongly activated in all types of induced wake. Further, some classical wake systems like the dopaminergic neurons of the ventral tegmental area or the dorsal raphe nucleus and the noradrenergic neurons of the locus coeruleus are either very poorly or not strongly activated. These results reveal that many structures not previously involved in wakefulness might play a key role in regulating the state and that some structures might be more recruited by solriamfetol than modafinil or non-pharmacological wakefulness. Our results are particularly relevant for pathologies such as hypersomnia. They open a new era in the study of the mechanisms responsible for inducing wakefulness.

Vagus nerve stimulation offers a promising strategy for seizure control but remains limited by its invasive delivery. Here, we reveal electroacupuncture (EA), an ancient neuromodulatory technique rooted in traditional Chinese medicine, at specific somatic acupoints linked to the vagal-brain axis to treat epilepsy and delineate the precise underlying neural mechanisms. We demonstrate that EA at the Dazhui (GV14) acupoint exhibits broad-spectrum antiseizure efficacy across multiple seizure models. Anatomical and functional analyses reveal that GV14 activates the vagal afferents and recruits neurons in the caudal nucleus of the solitary tract (cNTS), which are essential for seizure suppression. Using targeted recombination in active populations and chemogenetic manipulation, we show that GV14 EA suppresses seizures via the recruitment of a defined cNTS-locus coeruleus-amygdala circuit. Furthermore, through vagal afferent activity screening, we identify Yaoqi (EXB9) as an alternative therapeutic acupoint that activates a shared neural pathway to robustly attenuate seizures. Importantly, thread-embedding acupuncture at GV14 or EXB9 produces sustained seizure reduction in a chronic epilepsy model. Together, these findings elucidate a functional vagal-brain circuit underlying EA-induced seizure control and support its translational potential as a minimally invasive neuromodulatory strategy to replace vagal stimulation for epilepsy treatment.

Gamma-aminobutyric acid (GABA) and its receptors play a critical role in maintaining the balance between excitatory and inhibitory neurotransmission in the central nervous system, including autonomic regulatory regions that control cardiometabolic function. Vagal circuits facilitate bidirectional communication between peripheral organs and the brain to elicit autonomic reflexes and modulate complex adaptive behavior to preserve cardiometabolic homeostasis. Dampened vagal activity can lead to the development of cardiometabolic diseases. Emerging evidence over the past decade identifies inhibitory GABAergic signaling in key vagal regulatory regions as a potential mechanism underlying vagal dysfunction linked to cardiometabolic disease. In this review, we discuss recent studies exploring GABAergic signaling modulation in vagal circuits, focusing on the regulation of food intake, cardiac function, and glucose metabolism-critical physiological processes that are often disrupted in cardiometabolic disease. We outline GABAergic signaling properties within key vagal reflex circuits, namely, vagal sensory afferents, nucleus tractus solitarius, and vagal motor neurons, and discuss how cardiometabolic stressors, as well as disease states, remodel vagal GABAergic signaling.

The cardiac-cerebral reflex (CCR) is a bidirectional neural loop that continuously links cardiac sensory input with central autonomic control, and thereby governs heart rate, conduction, and myocardial excitability. Once thought of mainly as a homeostatic feedback mechanism, the CCR is now recognized as a key actor in the genesis of malignant arrhythmias and some forms of sudden cardiac death. This narrative review synthesizes current understanding of the CCR from cellular mechanisms to clinical syndromes. We highlight the Central Autonomic Network-with emphasis on the nucleus tractus solitarius and the insular cortex-and trace how aberrant autonomic signaling (excess sympathetic discharge, vagal imbalance) creates both the "spark" and the "substrate" for arrhythmogenesis. We review diagnostic approaches (heart rate variability, baroreflex testing, cardiac 123I-metaiodobenzylguanidine imaging, prolonged ECG/EEG monitoring), summarize therapeutic options with a focus on neuromodulation (cardiac sympathetic denervation, stellate blockade, vagus nerve stimulation), and propose practical steps for clinicians caring for patients in whom brain-heart interactions are central. Moving from a cardiocentric to a neurocardiac perspective can improve risk stratification and open new management avenues for arrhythmias that resist conventional approaches.

Glucagon-like peptide-1 receptor (GLP-1R) activation in the brain strongly reduces appetite, but most brain GLP-1Rs are not accessible for systemically administered GLP-1R agonists. Acute activation of nucleus tractus solitarius (NTS) GLP-1 neurons, known as preproglucagon (PPG) neurons, strongly suppresses food intake separate from GLP-1R agonists. However, it is unknown if chronic stimulation of PPG neurons is a viable strategy for appetite suppression, or if obesity disrupts their function. Here we demonstrate that PPG neurons in the NTS and intermediate reticular nucleus (IRT) determine meal size, and that their total number is inversely correlated with bodyweight gain. We report that PPGNTS and PPGIRT neurons receive distinct monosynaptic inputs, but have convergent efferent projection targets throughout the brain, and that combined ablation of both populations delays the onset of physiological satiation to a degree sufficient to promote weight gain under ad libitum chow fed conditions. Crucially, chronic daily chemogenetic activation of PPGNTS+IRT neurons drives robust and sustained hypophagia and weight loss in obese mice without notable adverse effects, demonstrating their value as targets for obesity pharmacotherapy.

According to the 2023 National Survey on Drug Use and Health (NSDUH), 28.9 million people ages 12 and older in the United States had alcohol use disorder (AUD) in the past year. Although chronic alcohol use contributes to numerous health disorders as well as being an economic burden, there are few medications approved for treatment of AUD, and these medications are not uniformly effective and are not widely used. We now describe studies of a small molecule, novel chemical entity called Nezavist, which shows promise as a medication to treat AUD and possibly other addictive disorders. Nezavist acts as a positive allosteric modulator at a novel site on the GABAA receptor, but pharmacokinetic analysis demonstrates that Nezavist does not enter the CNS. However, Nezavist effectively reduces relapse to chronic alcohol consumption in alcohol-dependent animals in two widely used models. An important goal of the current studies is to provide evidence for the hypothesis that Nezavist acts in the intestine to stimulate vagus nerve afferents that project to the brainstem (nucleus tractus solitarius), leading to reduced inflammation in the brain that may alleviate alcohol 'craving' during abstinence from alcohol. It is hoped that the presentation of the current results will stimulate interest in further confirmation of the mechanism of action of Nezavist, with the intent of developing a new and effective medication for treatment for AUD.

Physical activity promotes gut adaptation, nutrient responsiveness, and sensitivity to gut peptides in male mice.