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A novel network analysis method is demonstrated for applications with functional magnetic resonance imaging (fMRI) data. The method is based on structural equation modeling (SEM) plus modeling of physiological responses in order to explain blood oxygenation‐level dependent (BOLD) responses across interconnected regions. The method, termed structural and physiological modeling (SAPM) aims to overcome a weakness of previous analysis methods by estimating both input and output signaling of every region of a network. The results also provide weighting factors (B) which describe the influence of each input signal to a region on its output signaling to another region. The SAPM method is demonstrated by applying it to fMRI data from the brainstem and spinal cord in 55 healthy participants undergoing repeated applications of a heat pain stimulation paradigm. Data are also analyzed using our established SEM method for comparison. The results with both methods indicate that individual differences in nociceptive processing are mediated by differences in descending regulation of spinal cord neurons under the influence of both the nucleus tractus solitarius and periaqueductal gray region. The SAPM results show that BOLD responses in the entire network can be explained during all periods of the stimulation paradigm based on two latent (unobserved) input signaling sources, and a model of the predicted BOLD responses to the heat stimulus. The results demonstrate the concept of our novel SAPM method and provide evidence for its validity. Additional studies are needed to further develop the method and its applications to investigations of complex neural processes across networks. [ABSTRACT FROM AUTHOR]

Analysis of ex vivo Per2 bioluminescent rhythm previously recorded in the mouse dorsal vagal complex reveals a characteristic phase relationship between three distinct circadian oscillators. These signals represent core clock gene expression in the area postrema (AP), the nucleus of the solitary tract (NTS) and the ependymal cells surrounding the 4th ventricle (4Vep). Initially, the data suggests a consistent phasing in which the AP peaks first, followed shortly by the NTS, with the 4Vep peaking 8–9 h later. Wavelet analysis reveals that this pattern is not consistently maintained throughout a recording, however, the phase dynamics strongly imply that oscillator interactions are present. A simple phase model of the three oscillators is developed and it suggests that realistic phase dynamics occur between three model oscillators with coupling close to a synchronisation transition. The coupling topology suggests that the AP bidirectionally communicates phase information to the NTS and the 4Vep to synchronise the three structures. A comparison of the model with previous experimental manipulations demonstrates its feasibility to explain DVC circadian phasing. Finally, we show that simulating steadily decaying coupling improves the model's ability to capture experimental phase dynamics. [ABSTRACT FROM AUTHOR]

Rodent studies indicate that impaired glucose utilization or hypoglycemia is associated with the cellular activation of neurons in the medulla (Winslow, 1733) (MY), believed to control feeding behavior and glucose counterregulation. However, such activation has been tracked primarily within hours of the challenge, rather than sooner, and has been poorly mapped within standardized brain atlases. Here, we report that, within 15 min of receiving 2-deoxy-d-glucose (2-DG; 250 mg/kg, i.v.), which can trigger glucoprivic feeding behavior, marked elevations were observed in the numbers of rhombic brain (His, 1893) (RB) neuronal cell profiles immunoreactive for the cellular activation marker(s), phosphorylated p44/42 MAP kinases (phospho-ERK1/2), and that some of these profiles were also catecholaminergic. We mapped their distributions within an open-access rat brain atlas and found that 2-DG-treated rats (compared to their saline-treated controls) displayed greater numbers of phospho-ERK1/2+ neurons in the locus ceruleus (Wenzel and Wenzel, 1812) (LC) and the nucleus of solitary tract (>1840) (NTS). Thus, the 2-DG-activation of certain RB neurons is more rapid than perhaps previously realized, engaging neurons that serve multiple functional systems and which are of varying cellular phenotypes. Mapping these populations within standardized brain atlas maps streamlines their targeting and/or comparable mapping in preclinical rodent models of disease. [ABSTRACT FROM AUTHOR]

Metabolic programming may be induced by reduction or enhancement of litter size, which lead to neonatal over or undernutrition, respectively. Changes in neonatal nutrition can challenge some regulatory processes in adulthood, such as the hypophagic effect of cholecystokinin (CCK). In order to investigate the effects of nutritional programming on the anorexigenic function of CCK in adulthood, pups were raised in small (SL, 3 pups per dam), normal (NL, 10 pups per dam), or large litters (LL, 16 pups per dam), and on postnatal day 60, male rats were treated with vehicle or CCK (10 µg/Kg) for the evaluation of food intake and c-Fos expression in the area postrema (AP), nucleus of solitary tract (NTS), and paraventricular (PVN), arcuate (ARC), ventromedial (VMH), and dorsomedial (DMH) nuclei of the hypothalamus. Overnourished rats showed increased body weight gain that was inversely correlated with neuronal activation of PaPo, VMH, and DMH neurons, whereas undernourished rats had lower body weight gain, inversely correlated with increased neuronal activation of PaPo only. SL rats showed no anorexigenic response and lower neuron activation in the NTS and PVN induced by CCK. LL exhibited preserved hypophagia and neuron activation in the AP, NTS, and PVN in response to CCK. CCK showed no effect in c-Fos immunoreactivity in the ARC, VMH, and DMH in any litter. These results indicate that anorexigenic actions, associated with neuron activation in the NTS and PVN, induced by CCK were impaired by neonatal overnutrition. However, these responses were not disrupted by neonatal undernutrition. Thus, data suggest that an excess or poor supply of nutrients during lactation display divergent effects on programming CCK satiation signaling in male adult rats. • Body weight is inversely correlated to neuron activity in hypothalamic nuclei. • Opposite neonatal nutrition supply has divergent effects on CCK actions in adulthood. • CCK-induced anorexigenic effect is abolished in overnourished rats. • Neonatal undernourished rats have preserved CCK satiation signaling. • SL rats have lower CCK-induced NTS and PVN neuron activation. [ABSTRACT FROM AUTHOR]

Although the multifaceted mechanisms underlying alcohol use disorder (AUD) have been partially defined, the neurobiological complexity of this disorder is yet to be unraveled. One of the systems that have gained attention in recent times is the gut-brain axis. Although numerous peptides participate in this axis, glucagonlike peptide-1 (GLP-1) plays a central role. GLP-1 is a crucial anorexigenic peptide, with potent abilities to reduce food intake and body weight. The physiological complexity of GLP-1 entails glucose homeostasis, gastrointestinal motility, and the release of insulin and glucagon. As reviewed in this study, acute or repeated treatment with GLP-1 receptor (GLP-1R) agonists decreases alcohol consumption in rodents. Moreover, the abilities of alcohol to promote hyperlocomotion, dopamine release in the nucleus accumbens, and reward in the conditioned place preference paradigm are all suppressed by GLP-1R ligands. Moreover, activation of GLP-1R suppresses the motivation to consume alcohol, alcoholseeking behaviors, and relapse drinking in male rodents. Similarly, abstinence symptoms experienced during alcohol withdrawal are attenuated by activation of the GLP-1 pathway. On a similar note, the activation of GLP-1 receptors within areas of the brain that are processing reward modulates these alcohol-related responses. Another area that is crucial for this ability is the nucleus of the solitary tract, which is where GLP-1 is produced and from which GLP-1-containing neurons project to areas of reward. These findings may have clinical relevance as AUD is associated with polymorphisms in GLP-1-related genes. Although a GLP-1R agonist does not alter alcohol intake in AUD patients, it reduces this consumption in a sub-population of obese AUD individuals. Given the uncertainty of this outcome, additional clinical studies of obese AUD patients should explore the effects of the GLP-1R agonists on alcohol intake and body weight. Furthermore, GLP-1 receptors modulate the behavioral and neurochemical responses to addictive drugs. Taken together, these preclinical and clinical findings imply that the GLP-1 pathway plays a role in the complex mechanisms regulating alcohol and drug consumption patterns, unveiling a novel aspect of addiction medicine. [ABSTRACT FROM AUTHOR]

Ethanol consumption influences cardiovascular functions. In humans, acute consumption of ethanol causes dose-dependent tachycardia. Our previous study showed that ethanol-induced tachycardia might involve decreased nitric oxide (NO) signaling in the brain's medulla. NMDA receptors, another important target of ethanol, are one of the upstream signals of nitric oxide. Reports showed the modulation of NMDA receptor function by estrogen or estrogen receptors. The present study aims to examine the hypothesis that depletion of estrogen by ovariectomy (OVX) might modulate ethanol-induced tachycardia by regulating NMDA receptor function and NO signaling in the cardiovascular regulatory nucleus of the brain. Ethanol (3.2 g/kg, 40% v/v, 10 mL/kg) or saline (10 mL/kg) was administered by oral gavage in sham or OVX female Sprague-Dawley (SD) rats. The blood pressure (BP) and heart rate (HR) were measured using the tail-cuff method. The levels of phosphoserine 896 of the GluN1 subunit (pGluN1-serine 896) and NMDA GluN1 subunits (GluN1) were determined by immunohistochemistry. The expressions of nitric oxide synthase (NOS) and estrogen receptors in the tissue were measured by Western blotting. Nitric oxide contents were measured as total nitrate-nitrite by colorimetric assay kit. In a 2-h observation, there was no significant change in BP between the saline and ethanol groups. However, compared with saline, ethanol caused an increase in HR (tachycardia) in sham control or OVX rats. Interestingly, ethanol produced more significant tachycardia in the OVX group than in the sham control group. Nitric oxide levels were lower in the area of the rostral ventrolateral medulla (RVLM) 60 min following ethanol administration in OVX compared with sham control, without significant changes in the expression of NOS and estrogen receptors (ERα and ERβ). In addition, a decrease in the immunoreactivity of pGluN1-serine 896, without significant changes in GluN1, was found in neurons of RVLM 40 min following ethanol administration in OVX compared with sham control. Our results suggest that depletion of estradiol (E2) by OVX might exacerbate the tachycardia following ethanol administration, the underlying mechanism of which might be associated with decreased NMDA receptor function and NO level in the RVLM. [ABSTRACT FROM AUTHOR]

The article focuses on pharmacotherapy for the management of obesity. Topics include discussing the etiology of obesity and hormonal control of hunger; and the importance of medications that suppress hunger or increase satiety, early in weight management, for maintenance with medications for weight management, including GLP-1 agonists, phentermine, orlistat, and naltrexone/bupropion.

On 10 September 1938, Godlowski was appointed associate professor at the Faculty of Medicine of Stefan Batory University by the President of Poland [[3]]. Godlowski was already a promising researcher in his early years, and his work received praise, as evidenced from correspondence with Otto Marburg and the Dutch neurologist Louis Jacob Joseph Muskens. Godlowski was survived by his widow Zofia, a laryngologist who never remarried, and their 5-year-old son Kazimierz, who became a renowned archeologist and served as a professor at Jagiellonian University [[1], [3]]. [Extracted from the article]

The article focuses on the remarkable weight loss effectiveness of incretin-mimetic drugs, highlighting their ability to suppress appetite through gut-brain signaling and inhibit adaptive responses to weight loss. Topics discussed include the physiological mechanisms of these drugs, potential concerns regarding long-term safety, and the possibility of targeting specific neurocircuits for more precise obesity treatment.

Our previous studies have shown that electroacupuncture (EA) at the Jianshi-Neiguan acupoints (P5-6, overlying the median nerve) attenuates sympathoexcitatory responses through its influence on neuronal activity in the rostral ventrolateral medulla (rVLM). The nucleus tractus solitarii (NTS) receives input from somatic nerve stimulation. Connections between the NTS and the rVLM during EA stimulation have not been investigated and thus were the focus of the present study. Seven to ten days after unilateral microinjection of a rhodamine-conjugated microsphere retrograde tracer (100 nl) into the rVLM, rats were subjected to EA or sham-EA without electrical stimulation. EA was performed for 30 min at the P5-6 acupoints bilaterally. Perikarya containing the microsphere tracer were found in the NTS of both groups. Compared to controls (needle placement without electrical stimulation, n = 7), c-Fos immunoreactivity and neurons double-labeled with c-Fos, an immediate early gene, and the tracer were significantly increased in the NTS of EA-treated rats (all P

Our previous studies have shown that electroacupuncture (EA) at the Jianshi-Neiguan acupoints (P5-6, overlying the median nerve) attenuates sympathoexcitatory responses through its influence on neuronal activity in the rostral ventrolateral medulla (rVLM). The nucleus tractus solitarii (NTS) receives input from somatic nerve stimulation. Connections between the NTS and the rVLM during EA stimulation have not been investigated and thus were the focus of the present study. Seven to ten days after unilateral microinjection of a rhodamine-conjugated microsphere retrograde tracer (100 nl) into the rVLM, rats were subjected to EA or sham-EA without electrical stimulation. EA was performed for 30 min at the P5-6 acupoints bilaterally. Perikarya containing the microsphere tracer were found in the NTS of both groups. Compared to controls (needle placement without electrical stimulation, n = 7), c-Fos immunoreactivity and neurons double-labeled with c-Fos, an immediate early gene, and the tracer were significantly increased in the NTS of EA-treated rats (all P

This article discusses the implications of µ-opioid receptor expression in the brainstem for respiratory control. The rise in opioid use has led to a significant increase in fatal opioid overdoses, which has become a public health crisis. Opioid-induced respiratory depression (OIRD) is a global issue that requires coordinated efforts in public health policy, medical education, and patient safety initiatives. The article explores the expression of µ-opioid receptors in specific brainstem areas involved in respiratory control and related behaviors. Understanding the neural control of breathing and the impact of opioids at various levels is crucial for developing interventions and improving patient outcomes. [Extracted from the article]

Introduction: Chronic hypertension is accompanied by either blood-brain barrier (BBB) leakage and autonomic dysfunction. There is no consensus on the mechanism determining increased BBB permeability within autonomic areas. While some reports suggested tight junction’s breakdown, others indicated the involvement of transcytosis rather than paracellular transport changes. Interestingly, exercise training was able to restore both BBB permeability and autonomic control of the circulation. We sought now to clarify the mechanism(s) governing hypertension- and exercise-induced BBB permeability. Methods: Spontaneously hypertensive rats (SHR) and normotensive controls submitted to 4-week aerobic training (T) or sedentary protocol (S) were chronically cannulated for baseline hemodynamic and autonomic recordings and evaluation of BBB permeability. Brains were harvested for measurement of BBB function (FITC-10 kDa leakage), ultrastructural analysis of BBB constituents (transmission electron microscopy) and caveolin-1 expression (immunofluorescence). Results: In SHR-S the increased pressure, augmented sympathetic vasomotor activity, higher sympathetic and lower parasympathetic modulation of the heart and the reduced baroreflex sensitivity were accompanied by robust FITC-10kDa leakage, large increase in transcytotic vesicles number/capillary, but no change in tight junctions’ density within the paraventricular nucleus of the hypothalamus, the nucleus of the solitary tract and the rostral ventrolateral medulla. SHR-T exhibited restored BBB permeability and normalized vesicles counting/capillary simultaneously with a normal autonomic modulation of heart and vessels, resting bradycardia and partial pressure reduction. Caveolin-1 expression ratified the counting of transcellular, not other cytoplasmatic vesicles. Additionally, T caused in both groups significant increases in tight junctions’ extension/ capillary border. Discussion: Data indicate that transcytosis, not the paracellular transport, is the primary mechanism underlying both hypertension- and exercise-induced BBB permeability changes within autonomic areas. The reduced BBB permeability contributes to normalize the autonomic control of the circulation, which suppresses pressure variability and reduces the occurrence of end-organ damage in the trained SHR. Data also disclose that hypertension does not change but exercise training strengthens the resistance of the paracellular pathway in both strains. [ABSTRACT FROM AUTHOR]

As a traditional medical therapy, stimulation at the Lianquan (CV23) acupoint, located at the depression superior to the hyoid bone, has been shown to be beneficial in dysphagia. However, little is known about the neurological mechanism by which this peripheral stimulation approach treats for dysphagia. Here, we first identified a cluster of excitatory neurons in layer 5 (L5) of the primary motor cortex (M1) that can regulate swallowing function in male mice by modulating mylohyoid activity. Moreover, we found that focal ischemia in the M1 mimicked the post-stroke dysphagia (PSD) pathology, as indicated by impaired water consumption and electromyographic responses in the mylohyoid. This dysfunction could be rescued by electroacupuncture (EA) stimulation at the CV23 acupoint (EA-CV23) in a manner dependent on the excitatory neurons in the contralateral M1 L5. Furthermore, neuronal activation in both the parabrachial nuclei (PBN) and nucleus tractus solitarii (NTS), which was modulated by the M1, was required for the ability of EA-CV23 treatment to improve swallowing function in male PSD model mice. Together, these results uncover the importance of the M1-PBN-NTS neural circuit in driving the protective effect of EA-CV23 against swallowing dysfunction and thus reveal a potential strategy for dysphagia intervention. Difficulty swallowing after stroke and the neural circuitry underlying this is not fully understood. Here the authors demonstrate, using a mouse model, a potential neural circuit mechanism for effects of electroacupuncture on swallowing behaviour in post-stroke dysphagia. [ABSTRACT FROM AUTHOR]

Exposure to acute intermittent hypoxia (AIH) induces prolonged increases (long term facilitation, LTF) in phrenic and sympathetic nerve activity (PhrNA, SNA) under basal conditions, and enhanced respiratory and sympathetic responses to hypoxia. The mechanisms and neurocircuitry involved are not fully defined. We tested the hypothesis that the nucleus tractus solitarii (nTS) is vital to augmentation of hypoxic responses and the initiation and maintenance of elevated phrenic (p) and splanchnic sympathetic (s) LTF following AIH. nTS neuronal activity was inhibited by nanoinjection of the GABAA receptor agonist muscimol before AIH exposure or after development of AIH-induced LTF. AIH but not sustained hypoxia induced pLTF and sLTF with maintained respiratory modulation of SSNA. nTS muscimol before AIH increased baseline SSNA with minor effects on PhrNA. nTS inhibition also markedly blunted hypoxic PhrNA and SSNA responses, and prevented altered sympathorespiratory coupling during hypoxia. Inhibiting nTS neuronal activity before AIH exposure also prevented the development of pLTF during AIH and the elevated SSNA after muscimol did not increase further during or following AIH exposure. Furthermore, nTS neuronal inhibition after the development of AIHinduced LTF substantially reversed but did not eliminate the facilitation of PhrNA. Together these findings demonstrate that mechanisms within the nTS are critical for initiation of pLTF during AIH. Moreover, ongoing nTS neuronal activity is required for full expression of sustained elevations in PhrNA following exposure to AIH although other regions likely also are important. Together, the data indicate that AIH-induced alterations within the nTS contribute to both the development and maintenance of pLTF. [ABSTRACT FROM AUTHOR]

Recent findings from our laboratory demonstrated that the rostral nucleus of the solitary tract (rNST) retains some responsiveness to sugars in double-knock-out mice lacking either the T1R11T1R3 (KO113) or T1R21T1R3 (KO213) taste receptor heterodimers. Here, we extended these findings in the parabrachial nucleus (PBN) of male and female KO113 mice using warm stimuli to optimize sugar responses and employing additional concentrations and pharmacological agents to probe mechanisms. PBN T1R-independent sugar responses, including those to concentrated glucose, were more evident than in rNST. Similar to the NST, there were no "sugar-best" neurons in KO113 mice. Nevertheless, 1000 mM glucose activated nearly 55% of PBN neurons, with responses usually occurring in neurons that also displayed acid and amiloride-insensitive NaCl responses. In wild-type (WT) mice, concentrated sugars activated the same electrolyte-sensitive neurons but also "sugarbest" cells. Regardless of genotype, phlorizin, an inhibitor of the sodium-glucose co-transporter (SGLT), a component of a hypothesized alternate glucose-sensing mechanism, did not diminish responses to 1000 mM glucose. The efficacy of concentrated sugars for driving neurons broadly responsive to electrolytes implied an origin from Type III taste bud cells. To test this, we used the carbonic anhydrase (CA) inhibitor dorzolamide (DRZ), previously shown to inhibit amiloride-insensitive sodium responses arising from Type III taste bud cells. Dorzolamide had no effect on sugar-elicited responses in WT sugar-best PBN neurons but strongly suppressed them in WT and KO113 electrolyte-generalist neurons. These findings suggest a novel T1R-independent mechanism for hyperosmotic sugars, involving a CA-dependent mechanism in Type III taste bud cells. [ABSTRACT FROM AUTHOR]

Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as "brain fog" and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling. We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control—factors affected by long COVID. Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID. [ABSTRACT FROM AUTHOR]

The article presents a study which explores the experience-dependent plasticity of gustatory insular cortex circuits and taste preferences. It mentions that results of the study establish a fundamental link between gustatory experience, sweet preference, inhibitory plasticity, and cortical circuit function and highlight the importance of early life nutrition in setting taste preferences.

The monoaminergic neurotransmitter 5-hydroxytryptamine (5-HT) is known to be involved in several physiological, behavioural and neuroendocrine functions in vertebrates. In this study, we investigated the distribution of 5-HT neuronal system in the central nervous system (CNS) of Sphaerotheca breviceps tadpoles at metamorphic climax stage. In the telencephalon, there was no 5-HT-immunoreactive (5-HT-ir) perikarya, but conspicuous fibres were observed in the olfactory bulb, pallium, subpallium and amygdala complexes. The preoptic area showed dense 5-HT-ir somata and cerebrospinal fluid contacting fibres, whereas a few varicose 5-HT-ir fibres were noticed in the suprachiasmatic nucleus. 5-HT-ir cells and fibres were found in the ventral, lateral dorsal subdivisions of the hypothalamus and in the nucleus tuberculi posterioris, but only 5-HT-ir fibres were localised in the periventricular area and pituitary gland. Numerous 5-HT-ir cells and/or fibres were detected in the thalamus, entopeduncular area and mesencephalic subdivisions. In the rhombencephalon, although 5-HT-ir cells and fibres were noticed in the subdivisions of the raphe nucleus and reticular formation, a moderate plexus of fibres was observed in the cerebellum, parabrachial nucleus and solitary tract. Distinct 5-HT-ir fibres, but no perikarya, were observed in the rostral spinal cord. Overall, extensively labelled 5-HT-ir cells and fibres in the CNS of the metamorphic tadpole suggest possible roles for the involvement of 5-HT in various somatosensory, behavioural and neuroendocrine functions during final stages of development. [ABSTRACT FROM AUTHOR]

The autonomic nervous system (ANS) is a diffuse network that regulates physiological systems to maintain body homeostasis by integrating inputs from the internal and external environment, including the sympathetic, parasympathetic, and enteric nervous systems (ENS). Recent evidence suggests that ANS is one of the key neural pathways for acupuncture signal transduction, which has attracted worldwide attention in the acupuncture field. Here, we reviewed the basic and clinical research published in PubMed over the past 20 years on the effects of acupuncture on ANS regulation and homeostasis maintenance. It was found that acupuncture effectively alleviates ANS dysfunction-associated symptoms in its indications, such as migraine, depression, insomnia, functional dyspepsia, functional constipation. Acupuncture stimulation on some specific acupoints activates sensory nerve fibers, the spinal cord, and the brain. Using information integration and efferents from a complex network of autonomic nuclei of the brain, such as the insular cortex (IC), prefrontal cortex, anterior cingulate cortex (ACC), amygdala (AMG), hypothalamus, periaqueductal gray (PAG), nucleus tractus solitarius (NTS), ventrolateral medulla (VLM), nucleus ambiguus (AMB), acupuncture alleviates visceral dysfunction, inflammation via efferent autonomic nerves, and relieves pain and pain affect. The modulating pattern of sympathetic and parasympathetic nerves is associated with acupuncture stimulation on specific acupoints, intervention parameters, and disease models, and the relationships among them require further exploration. In conclusion, ANS is one of the therapeutic targets for acupuncture and mediates acupuncture's actions, which restores homeostasis. A systemic study is needed to determine the rules and mechanisms underlying the effects of acupoint stimulation on corresponding organs mediated by specific central nervous networks and the efferent ANS. [ABSTRACT FROM AUTHOR]

Background: Taste impairments are often accompanied by olfactory impairments in the early stage of Parkinson's disease (PD). The development of animal models is required to elucidate the mechanisms underlying taste impairments in PD. Objective: This study was conducted to clarify whether the intranasal administration of rotenone causes taste impairments prior to motor deficits in mice. Methods: Rotenone was administrated to the right nose of mice once a day for 1 or 4 week(s). In the 1-week group, taste, olfactory, and motor function was assessed before and after a 1-week recovery period following the rotenone administration. Motor function was also continuously examined in the 4-weeks group from 0 to 5 weeks. After a behavioral test, the number of catecholamine neurons (CA-Nos) was counted in the regions responsible for taste, olfactory, and motor function. Results: taste and olfactory impairments were simultaneously observed without locomotor impairments in the 1-week group. The CA-Nos was significantly reduced in the olfactory bulb and nucleus of the solitary tract. In the 4-week group, locomotor impairments were observed from the third week, and a significant reduction in the CA-Nos was observed in the substantia nigra (SN) and ventral tegmental area (VTA) at the fifth week along with the weight loss. Conclusion: The intranasal administration of rotenone caused chemosensory and motor impairments in an administration time-period dependent manner. Since chemosensory impairments were expressed prior to the locomotor impairments followed by SN/VTA CA neurons loss, this rotenone administration model may contribute to the clarification of the prodromal symptoms of PD. [ABSTRACT FROM AUTHOR]

The review analyzes data on the connections and functions of the structures of the central nervous system that form the central autonomic network (CAN), namely the prefrontal cortex, the extended amygdala, the hypothalamus, the central gray matter, the nucleus of the solitary tract, and the ventrolateral region of the medulla oblongata. We consider main properties of the CAN, such as morphological and neurochemical complexity, the presence of several outputs, and state-dependence. It is concluded that the main, but not the only function of the CAN is to maintain homeostasis in the current and predicted behavioral context. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH), an animal model of sleep apnea, has been shown to alter the activity of second-order chemoreceptor neurons in the caudal nucleus of the solitary tract (cNTS). Although numerous studies have focused on excitatory plasticity, few studies have explored CIH-induced plasticity impacting inhibitory inputs to NTS neurons, and the roles of GABAergic and glycinergic inputs on heightened cNTS excitability following CIH are unknown. In addition, changes in astrocyte function may play a role in cNTS plasticity responses to CIH. This study tested the effects of a 7-day CIH protocol on miniature inhibitory postsynaptic currents (mIPSCs) in cNTS neurons receiving chemoreceptor afferents. Normoxia-treated rats primarily displayed GABA mIPSCs, whereas CIH-treated rats exhibited a shift toward combined GABA/glycine-mediated mIPSCs. CIH increased glycinergic mIPSC amplitude and area. This shift was not observed in dorsal motor nucleus of the vagus neurons or cNTS cells from females. Immunohistochemistry showed that strengthened glycinergic mIPSCs were associated with increased glycine receptor protein and were dependent on receptor trafficking in CIH-treated rats. In addition, CIH altered astrocyte morphology in the cNTS, and inactivation of astrocytes following CIH reduced glycine receptor-mediated mIPSC frequency and overall mIPSC amplitude. In cNTS, CIH produced changes in glycine signaling that appear to reflect increased trafficking of glycine receptors to the cell membrane. Increased glycine signaling in cNTS associated with CIH also appears to be dependent on astrocytes. Additional studies will be needed to determine how CIH influences glycine receptor expression and astrocyte function in cNTS. [ABSTRACT FROM AUTHOR]

[Display omitted] • Chronic heterotypic stress impaired gastric emptying in male rats but not in females. • Greater sympathetic outflow was found in control females than male counterparts • Sexual dimorphism was seen in hindbrain catecholaminergic but not in cholinergic cells It has been reported that the clinical symptoms of functional dyspepsia (FD) exacerbate upon stress while the gender-related factors have been incompletely understood. This study aims to investigate the role of sex in chronic heterotypic stress (CHS)-induced autonomic and gastric motor dysfunction. For CHS, the rats were exposed to the combination of different stressors for 7 consecutive days. Subsequently, electrocardiography was recorded in anesthetized rats to evaluate heart rate variability (HRV) for the determination of autonomic outflow and sympathovagal balance. Solid gastric emptying (GE) was measured in control and CHS-loaded male and female rats. The immunoreactivities of catecholaminergic cell marker tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), corticotropin releasing factor (CRF), and estrogen receptor (ER-α/β) were evaluated in medullary and pontine brainstem sections by immunohistochemistry. Compared with the controls, CHS significantly delayed GE in males but not in females. There was no significant sex-related difference in parasympathetic indicator HF under either control or CHS conditions. Sympathetic indicator LF was significantly higher in control females compared to the males. The higher sympathetic output in females was found to be attenuated upon CHS; in contrast, the elevated sympathetic output was detected in CHS-loaded males. No sex- or stress-related effect was observed on ChAT immunoreactivity in the dorsal motor nucleus of N.vagus (DMV). In males, greater number of TH-ir cells was observed in the caudal locus coeruleus (LC), while they were more densely detected in the rostral LC of females. Regardless of sex, CHS elevated immunoreactivity of TH throughout the LC. Under basal conditions, greater number of TH-ir cells was detected in the rostral ventrolateral medulla (RVLM) of females. In contrast, CHS remarkably increased the number of TH-ir cells in the RVLM of males which was found to be decreased in females. There was no sex-related alteration in TH immunoreactivity in the nucleus tractus solitarius (NTS) of control rats, while CHS affected both sexes in a similar manner. Compared with females, CRF immunoreactivity was prominently observed in control males, while both of which were stimulated by CHS. ER-α/β was found to be co-expressed with TH in the NTS and LC which exhibit no alteration related to either sex or stress status. These results indicate a sexual dimorphism in the catecholaminergic and the CRF system in brainstem which might be involved in the CHS-induced autonomic and visceral dysfunction occurred in males. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) involves the degeneration of dopaminergic neurons in the substantia nigra (SNpc) and manifests with both classic and non-classic motor symptoms, including respiratory failure. Our study aims to investigate the involvement of the commissural and intermediate nucleus of the solitary tract (cNTS and iNTS) in the attenuated respiratory response to hypoxia in PD. Using a PD rat model induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of male Wistar rats, we explored potential alterations in the population of Phox2b neurons or hypoxia-activated neurons in the NTS projecting to the retrotrapezoid nucleus (RTN). Additionally, we explored neuronal connectivity between SNpc and cNTS. Projections pathways were assessed using unilateral injection of the retrograde tracer Fluorogold (FG) in the cNTS and RTN. Neuronal activation was evaluated by analyzing fos expression in rats exposed to hypoxia. In the PD model, the ventilatory response, measured through whole-body plethysmography, was impaired at both baseline and in response to hypoxia. A reduction in Phox2b-expressing neurons or hypoxia-activated neurons projecting to the RTN was observed. Additionally, we identified an indirect pathway linking the SNpc and cNTS, which passes through the periaqueductal gray (PAG). In conclusion, our findings suggest impairment in the SNpc-PAG-cNTS pathway in the PD model, explaining the loss of Phox2b-expressing neurons or hypoxia-activated neurons in the cNTS and subsequent respiratory impairment during hypoxic stimulation. We propose that the reduced population of Phox2b-expressing neurons in the NTS may include the same neurons activated by hypoxia and projecting to the RTN. [Display omitted] • The dopaminergic neurons of the SNpc do not have a direct connection to the cNTS. • SNpc and cNTS communication may be indirect via PAG neurons and impaired in PD model. • There is impaired ventilatory response to hypoxia in PD model. • Impaired hypoxia response may result from cNTS neuron degeneration. • cNTS neurons impaired in PD model likely express Phox2b and project to the RTN. [ABSTRACT FROM AUTHOR]

• Perceived increase in vascular stretch decreases salt intake after water deprivation. • NTS AT1R+ neurons and afferents may integrate sensory and endocrine input. • NTS AT1R+neurons and afferents regulate salt intake in water-deprived mice. 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. [ABSTRACT FROM AUTHOR]

[Display omitted] Food deprivation is used in many experimental models and is becoming increasingly prevalent in human diets. The impact of food deprivation on specific brain regions, including the nucleus of the tractus solitarius (NTS), a region that is involved in hunger and satiety sensing, remains to be determined. The NTS is a heterogeneous nucleus that includes corticotropin releasing factor receptor 1 (CRF1) neurons. CRF1 is implicated in both stress and appetite regulation, but the effects of food deprivation on CRF1 NTS neurons are unclear. We used immunofluorescence to examine the effects of 24-hour food deprivation on NTS activity in male and female Sprague-Dawley (SD) rats and CRF1-cre rats using cFos, an immediate early gene and neuronal marker of activation. NTS activity was increased in food deprived male but not female SD rats. In food deprived CRF1-cre rats, males had an increased proportion of active CRF1 + neurons with no change in females. In CRF1-cre rats, increased global NTS activity was observed in food deprived and refed males. Activation of CRF1 + neurons was also increased after deprivation but was reduced by refeeding. In females, food deprivation decreased global NTS activity that was then increased by refeeding, while CRF1 activity was unchanged. Collectively, these data suggest the NTS is differentially activated after food deprivation in a sex-specific manner, whereby males are more sensitive than females. These results provide insight into the role of brainstem stress circuitry in changes associated with conditions including intermittent fasting and eating disorders like anorexia. [ABSTRACT FROM AUTHOR]

Stimulation of vagal afferent endings with intravenous phenylbiguanide (PBG) causes both bradycardia and vasodepression, simulating neurally mediated syncope. Activation of µ-opioid receptors in the nucleus tractus solitarius (NTS) increases blood pressure. Electroacupuncture (EA) stimulation of somatosensory nerves underneath acupoints P5-6, ST36-37, LI6-7 or G37-39 selectively but differentially modulates sympathoexcitatory responses. We therefore hypothesized that EA-stimulation at P5-6 or ST36-37, but not LI6-7 or G37-39 acupoints, inhibits the bradycardia and vasodepression through a µ-opioid receptor mechanism in the NTS. We observed that stimulation at acupoints P5-6 and ST36-37 overlying the deep somatosensory nerves and LI6-7 and G37-39 overlying cutaneous nerves differentially evoked NTS neural activity in anesthetized and ventilated animals. Thirty-min of EA-stimulation at P5-6 or ST36-37 reduced the depressor and bradycardia responses to PBG while EA at LI6-7 or G37-39 did not. Congruent with the hemodynamic responses, EA at P5-6 and ST36-37, but not at LI6-7 and G37-39, reduced vagally evoked activity of cardiovascular NTS cells. Finally, opioid receptor blockade in the NTS with naloxone or a specific μ-receptor antagonist reversed P5-6 EA-inhibition of the depressor, bradycardia and vagally evoked NTS activity. These data suggest that point specific EA stimulation inhibits PBG-induced vasodepression and bradycardia responses through a μ-opioid mechanism in the NTS.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output. We hypothesized that deficiency in Mecp2 gene reduces GABAergic neurotransmission in the NTS. Using whole-cell patch-clamp recordings in NTS slices, we measured spontaneous inhibitory postsynaptic currents (sIPSCs), miniature IPSCs (mIPSCs), NTS-evoked IPSCs (eIPSCs), and GABAA receptor (GABAA-R) agonist-induced responses. Compared to those from wild-type mice, NTS neurons from Mecp2-null mice had significantly (p

Dear Editor, Baclofen is a g-aminobutyric acid agonist (GABA) commonly used in clinical practice to manage spasticity of both spinal and cerebral origin; it is administered by oral or intrathecal. This report provides additional support for possible adverse cerebral effects in ITB therapy, due also to a moderate dose change in the long-term continuous ITB administration. As a rule, an intrathecal baclofen (ITB) pump allows a patient to receive lower doses of baclofen at a constant rate with fewer side effects than the oral route. [Extracted from the article]

Chemotherapeutic agent-induced nausea and vomiting are the severe adverse effects that are induced by their stimulations on the peripheral and/or central emetic nerve pathways. Even though ginger has been widely used as an herbal medicine to treat emesis, mechanisms underlying its neuronal actions are still less clear. The present study aimed to determine the chemotherapeutic agent vincristine-induced effect on gastroesophageal vagal afferent nerve endings and the potential inhibitory role of ginger constituent 6-shogaol on such response. Two-photon neuron imaging studies were performed in ex vivo gastroesophageal-vagal preparations from Pirt-GCaMP6 transgenic mice. Vincristine was applied to the gastroesophageal vagal afferent nerve endings, and the evoked calcium influxes in their intact nodose ganglion neuron somas were recorded. The responsive nodose neuron population was first characterized, and the inhibitory effects of 5-HT3 antagonist palonosetron, TRPA1 antagonist HC-030031, and ginger constituent 6-shogaol were then determined. Vincristine application at gastroesophageal vagal afferent nerve endings elicited intensive calcium influxes in a sub-population of vagal ganglion neurons. These neurons were characterized by their positive responses to P2X2/3 receptor agonist α,β-methylene ATP and TRPA1 agonist cinnamaldehyde, suggesting their nociceptive placodal nodose C-fiber neuron lineages. Pretreatment with TRPA1 selective blocker HC-030031 inhibited vincristine-induced calcium influxes in gastroesophageal nodose C-fiber neurons, indicating that TRPA1 played a functional role in mediating vincristine-induced activation response. Such inhibitory effect was comparable to that from 5-HT3 receptor antagonist palonosetron. Alternatively, pretreatment with ginger constituent 6-shogaol significantly attenuated vincristine-induced activation response. The present study provides new evidence that chemotherapeutic agent vincristine directly activates vagal nodose nociceptive C-fiber neurons at their peripheral nerve endings in the upper gastrointestinal tract. This activation response requires both TRPA1 and 5-HT3 receptors and can be attenuated by ginger constituent 6-shogaol. [ABSTRACT FROM AUTHOR]

Lateral medullary syndrome (LMS) is an ischemic stroke of the medulla oblongata that involves the territory of the posterior inferior cerebellar artery. LMS is often missed as the cause of autonomic dysregulation in patients with recent brain stem stroke. Due to the location of the nucleus tractus solitarius (NTS), the dorsal vagal nucleus, and the nucleus ambiguous in the lateral medulla oblongata, patients with LMS occasionally have autonomic dysregulation–associated clinical manifestations. We report a case of LMS-associated autonomic dysregulation. The case presented by recurrent syncope, requiring permanent pacemaker placement. This case shows the importance of recognizing LMS as a potential cause of life-threatening arrhythmias, heart block, and symptomatic bradycardia. Extended cardiac monitoring should be considered for patients with medullary strokes. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy balance. In the brain, Glucagon-like peptide 1 (GLP-1), encoded by the proglucagon 'Gcg' gene, produced in a distinct population of neurons in the nucleus tractus solitarius (NTS), has been shown to regulate feeding behavior leading to the suppression of appetite. However, neuronal networks that mediate endogenous GLP-1 action in the CNS on feeding and energy balance are not well understood. Results: We analyzed the distribution of GLP-1R-expressing neurons and axonal projections of NTS GLP-1-producing neurons in the mouse brain. GLP-1R neurons were found to be broadly distributed in the brain and specific forebrain regions, particularly the hypothalamus, including the arcuate nucleus of the hypothalamus (ARC), a brain region known to regulate energy homeostasis and feeding behavior, that receives dense NTSGcg neuronal projections. The impact of GLP-1 signaling in the ARC GLP-1R-expressing neurons and the impact of activation of ARC GLP-1R on food intake was examined. Application of GLP-1R specific agonist Exendin-4 (Exn-4) enhanced a proportion of the ARC GLP-1R-expressing neurons and pro-opiomelanocortin (POMC) neuronal action potential firing rates. Chemogenetic activation of the ARC GLP-1R neurons by using Cre-dependent hM3Dq AAV in the GLP-1R-ires-Cre mice, established that acute activation of the ARC GLP-1R neurons significantly suppressed food intake but did not have a strong impact on glucose homeostasis. Conclusions: These results highlight the importance of central GLP-1 signaling in the ARC that express GLP-1R that upon activation, regulate feeding behavior. [ABSTRACT FROM AUTHOR]

The study presents a novel approach of programing pain inhibition in chronic pain patients based on the hypothesis that pain perception is modulated by dysfunctional dorsal medial nucleus tractus solitarii (dmNTS) reflex arcs that produce diminished baroreflex sensitivity (BRS) resulting from a conditioned response. This study tested whether administration of noxious and non-noxious electrical stimuli synchronized with the cardiac cycle resets BRS, reestablishing pain inhibition. A total of 30 pain-free normotensives controls (NC) and 32 normotensives fibromyalgia (FM) patients received two, ≈8 min-epochs of cardiac-gated, peripheral electrical stimuli. Non-painful and painful electrical stimuli were synchronized to the cardiac cycle as the neuromodulation experimental protocol (EP) with two control conditions (CC1, CC2). BRS, heart-rate-variability (HRV), pain threshold and tolerance, and clinical pain intensity were assessed. Reduced BRS in FM at baseline increased by 41% during two, ≈8 min-epochs of stimulation. Thresholds in FM increased significantly during the experimental protocol (all Ps < 0.001) as did HRV. FM levels of clinical pain significantly decreased by 35.52% during the experimental protocol but not during control stimulations (p < 0.001). Baroreceptor training may reduce FM pain by BRS-mediated effects on intrinsic pain regulatory systems and autonomic responses. [ABSTRACT FROM AUTHOR]

Background: Functional dyspepsia (FD) is a disorder of gut–brain interaction, and its putative pathophysiology involves dysregulation of gastric motility and central processing of gastric afference. The vagus nerve modulates gastric peristalsis and carries afferent sensory information to brainstem nuclei, specifically the nucleus tractus solitarii (NTS). Here, we combine MRI assessment of gastric kinematics with measures of NTS functional connectivity to the brain in patients with FD and healthy controls (HC), in order to elucidate how gut–brain axis communication is associated with FD pathophysiology. Methods: Functional dyspepsia and HC subjects experienced serial gastric MRI and brain fMRI following ingestion of a food‐based contrast meal. Gastric function indices estimated from 4D cine MRI data were compared between FD and HC groups using repeated measure ANOVA models, controlling for ingested volume. Brain connectivity of the NTS was contrasted between groups and associated with gastric function indices. Key Results: Propagation velocity of antral peristalsis was significantly lower in FD compared to HC. The brain network defined by NTS connectivity loaded most strongly onto the Default Mode Network, and more strongly onto the Frontoparietal Network in FD. FD also demonstrated higher NTS connectivity to insula, anterior cingulate and prefrontal cortices, and pre‐supplementary motor area. NTS connectivity was linked to propagation velocity in HC, but not FD, whereas peristalsis frequency was linked with NTS connectivity in patients with FD. Conclusions & Inferences: Our multi‐modal MRI approach revealed lower peristaltic propagation velocity linked to altered brainstem‐cortical functional connectivity in patients suffering from FD suggesting specific plasticity in gut–brain communication. [ABSTRACT FROM AUTHOR]

Glyght is a new photochromic compound described as an effective modulator of glycine receptors at heterologous expression, in brain slices and in zebrafish larvae. Glyght also caused weak inhibition of GABAA-mediated currents in a cell line expressing α1/β2/γ2 GABAA receptors. However, the effects of Glyght on GABAergic transmission in the brain have not been analysed, which does not allow a sufficiently comprehensive assessment of the effects of the compound on the nervous system. Therefore, in this study using whole-cell patch-clamp recording, we analysed the Glyght (100 µM) action on evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in mice hippocampal slices. Two populations of cells were found: the first responded by reducing the GABAergic eIPSCs' amplitude, whereas the second showed no sensitivity to the compound. Glyght did not affect the ionic currents' amplitude induced by GABA application, suggesting the absence of action on postsynaptic GABA receptors. Additionally, Glyght had no impact on the paired-pulse modulation of GABAergic eIPSCs, indicating that Glyght does not modulate the neurotransmitter release mechanisms. In the presence of strychnine, an antagonist of glycine receptors, the Glyght effect on GABAergic synaptic transmission was absent. Our results suggest that Glyght can modulate GABAergic synaptic transmission via action on extrasynaptic glycine receptors. [ABSTRACT FROM AUTHOR]

Neuroimmune interactions pathways are the current interests of neuroimmunophysiology. As it shown, n. vagus is a part of neuroimmune communications, so determination of activation patterns of n. vagus is the relevant task. The aim of the study is to determine the amount of с-Fos-positive neurons in nuclei tractus solitarius (NTS) and dorsal motor nuclei (DMX) in rat medulla oblongata after subdiaphragmatic vagotomy and various antigens administration. Immunohistochemistry and morphometry were performed for determination of с-Fos-positive neurons amount in different zones of NTS and DMN. In the cells of DMX were not abserved any с-Fos-positive neurons in control and after subdiaphragmatic vagotomy. LPS administration (500 µg/kg) induced the increasing of с-Fos-positive neurons amount in NTS, particularly in medial NTS. Subdiaphragmatic vagotomy leads to increasing of с-Fos-positive neurons amount in NTS after LPS or SEB (500 µg/kg) administration. LPS injection after subdiaphragmatic vagotomy induced an activation of neurons of the lateral, medial and central NTS, while SEB administration induced only medial NTS activation. Therefore, the pattern of NTS response to the introduction of certain antigens are shown. Subdiaphragmatic vagotomy leads to activation of NTS after the introduction of LPS and SEB. [ABSTRACT FROM AUTHOR]

The most common medicinal claims for cannabis are relief from chronic pain, stimulation of appetite, and as an antiemetic. However, the mechanisms by which cannabis reduces pain and prevents nausea and vomiting are not fully understood. Among more than 450 constituents in cannabis, the most abundant cannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids either directly or indirectly modulate ion channel function. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel responsible for mediating several modalities of pain, and it is expressed in both the peripheral and the central pain pathways. Activation of TRPV1 in sensory neurons mediates nociception in the ascending pain pathway, while activation of TRPV1 in the central descending pain pathway, which involves the rostral ventral medulla (RVM) and the periaqueductal gray (PAG), mediates antinociception. TRPV1 channels are thought to be implicated in neuropathic/spontaneous pain perception in the setting of impaired descending antinociceptive control. Activation of TRPV1 also can cause the release of calcitonin gene-related peptide (CGRP) and other neuropeptides/neurotransmitters from the peripheral and central nerve terminals, including the vagal nerve terminal innervating the gut that forms central synapses at the nucleus tractus solitarius (NTS). One of the adverse effects of chronic cannabis use is the paradoxical cannabis-induced hyperemesis syndrome (HES), which is becoming more common, perhaps due to the wider availability of cannabis-containing products and the chronic use of products containing higher levels of cannabinoids. Although, the mechanism of HES is unknown, the effective treatment options include hot-water hydrotherapy and the topical application of capsaicin, both activate TRPV1 channels and may involve the vagal-NTS and area postrema (AP) nausea and vomiting pathway. In this review, we will delineate the activation of TRPV1 by cannabinoids and their role in the antinociceptive/nociceptive and antiemetic/emetic effects involving the peripheral, spinal, and supraspinal structures. [ABSTRACT FROM AUTHOR]

The article discusses the research on the relationship between neuronal activity and interneuronal transfer of α-synuclein, a Parkinson-associated protein, and the mechanisms underlying this relationship. The results show that rescue experiments provide the first evidence of a causal link between these pathological effects of neuronal stimulation and indicate a mechanistic role of oxidant stress in hyperactivity-induced transfer of α-synuclein spreading.

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin (Gal) and one type of pruriceptors expressing neurotensin (Nts). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from Nts-expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the Gal-containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the Nts-expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch. [ABSTRACT FROM AUTHOR]

This protocol is a practical guide for preparing acute coronal slices from the midbrain of young adult mice for electrophysiology experiments. It describes two different sets of solutions with their respective incubation strategies and two alternative procedures for brain extraction: decapitation under terminal isoflurane anaesthesia and intracardial perfusion with artificial cerebrospinal fluid under terminal isoflurane anaesthesia. Slices can be prepared from wild-type mice as well as from mice that have been genetically modified or transfected with viral constructs to label subsets of cells. The preparation can be used to investigate the electrophysiological properties of midbrain neurons in combination with pharmacology, opto- and chemogenetic manipulations, and calcium imaging; which can be followed by morphological reconstruction, immunohistochemistry, or single-cell transcriptomics. The protocol also provides a detailed list of materials and reagents including the design for a low-cost and easy to assemble 3D printed slice recovery chamber, general advice for troubleshooting common issues leading to suboptimal slice quality, and some suggestions to ensure good maintenance of a patch-clamp rig. [ABSTRACT FROM AUTHOR]

Objective: Central glucagon-like peptide-1 (GLP-1) is a target in treating obesity due to its effect on suppressing appetite, but the possible downstream key genes that GLP-1 regulated have not been studied in depth. This study intends to screen out the downstream feeding regulation genes of central GLP-1 neurons through bioinformatics analysis and verify them by chemical genetics, which may provide insights for future research. Materials and methods: GSE135862 genetic expression profiles were extracted from the Gene Expression Omnibus (GEO) database. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were carried out. STRING database and Cytoscape software were used to map the protein-protein interaction (PPI) network of the differentially expressed genes (DEGs). After bioinformatics analysis, we applied chemogenetic methods to modulate the activities of GLP-1 neurons in the nucleus tractus solitarius (NTS) and observed the alterations of screened differential genes and their protein expressions in the hypothalamus under different excitatory conditions of GLP-1 neurons. Results: A total of 49 DEGs were discovered, including 38 downregulated genes and 11 upregulated genes. The two genes with the highest expression scores were biglycan (Bgn) and mitogen-activated protein kinase activated protein kinase 3 (Mapkapk3). The results of GO analysis showed that there were 10 molecular functions of differential genes. Differential genes were mainly localized in seven regions around the cells, and enriched in 10 biology processes. The results of the KEGG signaling pathway enrichment analysis showed that differential genes played an important role in seven pathways. The top 15 genes selected according to the Cytoscape software included Bgn and Mapkapk3. Chemogenetic activation of GLP-1 in NTS induced a decrease in food intake and body mass, while chemogenetic inhibition induced the opposite effect. The gene and protein expression of GLP-1 were upregulated in NTS when activated by chemogenetics. In addition, the expression of Bgn was upregulated and that of Mapkapk3 was downregulated in the hypothalamus. Conclusion: Our data showed that GLP-1 could modulate the protein expression of Bgn and Mapkapk3. Our findings elucidated the regulatory network in GLP-1 to obesity and might provide a novel diagnostic and therapeutic target for obesity. [ABSTRACT FROM AUTHOR]

Spinal cord neurons integrate sensory and descending information to produce motor output. The expression of transcription factors has been used to dissect out the neuronal components of circuits underlying behaviors. However, most of the canonical populations of interneurons are heterogeneous and require additional criteria to determine functional subpopulations. Neurons expressing the transcription factor Shox2 can be subclassified based on the co-expression of the transcription factor Chx10 and each subpopulation is proposed to have a distinct connectivity and dierent role in locomotion. Adult Shox2 neurons have recently been shown to be diverse based on their firing properties. Here, in order to subclassify adult mouse Shox2 neurons, we performed multiple analyses of data collected from whole-cell patch clamp recordings of visually-identified Shox2 neurons from lumbar spinal slices. A smaller set of Chx10 neurons was included in the analyses for validation. We performed k-means and hierarchical unbiased clustering approaches, considering electrophysiological variables. Unlike the categorizations by firing type, the clusters displayed electrophysiological properties that could dierentiate between clusters of Shox2 neurons. The presence of clusters consisting exclusively of Shox2 neurons in both clustering techniques suggests that it is possible to distinguish Shox2+Chx10-neurons from Shox2+Chx10+ neurons by electrophysiological properties alone. Computational clusters were further validated by immunohistochemistry with accuracy in a small subset of neurons. Thus, unbiased cluster analysis using electrophysiological properties is a tool that can enhance current interneuronal subclassifications and can complement groupings based on transcription factor and molecular expression. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is a peripheral incretin and centrally active peptide produced in the intestine and nucleus tractus solitarii (NTS), respectively. GLP-1 not only regulates metabolism but also improves cognition and is neuroprotective. While intestinal GLP-1-producing cells have been well characterized, less is known about GLP-1-producing neurons in NTS. We hypothesized that obesity-induced type 2 diabetes (T2D) impairs the function of NTS GLP-1-producing neurons and glycemia normalization counteracts this effect. We used immunohistochemistry/quantitative microscopy to investigate the number, potential atrophy, and activation (cFos-expression based) of NTS GLP-1-producing neurons, in non-diabetic versus obese/T2D mice (after 12 months of high-fat diet). NTS neuroinflammation was also assessed. The same parameters were quantified in obese/T2D mice treated from month 9 to 12 with two unrelated anti-hyperglycemic drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride. We show no effect of T2D on the number and volume but increased activation of NTS GLP-1-producing neurons. This effect was partially normalized by both anti-diabetic treatments, concurrent with decreased neuroinflammation. Increased activation of NTS GLP-1-producing neurons could represent an aberrant metabolic demand in T2D/obesity, attenuated by glycemia normalization. Whether this effect represents a pathophysiological process preceding GLP-1 signaling impairment in the CNS, remains to be investigated. [ABSTRACT FROM AUTHOR]

• CeA lesions significantly increased the total exercise time of rats. • Lesions also increased the time at which an increase in arterial pressure appeared. • High-intensity exercise activated both the CeA and PVN. • Simultaneous CeA and PVN stimulation increased muscle vascular resistance. • CeA activation may limit exercise performance via cardiovascular system regulation. To date, the mechanism of central fatigue during high-intensity exercise has remained unclear. Here we elucidate the central mechanisms of cardiovascular regulation during high-intensity exercise with a focus on the hypothesis that amygdala activation acts to limit maximum exercise performance. In the first of three experiments, we probed the involvement of the central nucleus of the amygdala (CeA) in such regulation. Wistar rats were subjected to a maximum exercise test and their total running time and cardiovascular responses were compared before and after bilateral CeA lesions. Next, probing the role of central pathways, we tested whether high-intensity exercise activated neurons in CeA and/or the hypothalamic paraventricular nucleus (PVN) that project to the nucleus tractus solitarius (NTS). Finally, to understand the potential autonomic mechanisms affecting maximum exercise performance, we measured the cardiovascular responses in anesthetized rats to electrical microstimulation of the CeA, PVN, or both. We have found that (1) CeA lesions resulted in an increase in the total exercise time and the time at which an abrupt increase in arterial pressure appeared, indicating an apparent suppression of fatigue. (2) We confirmed that high-intensity exercise activated both the PVN-NTS and CeA-NTS pathways. Moreover, we discovered that (3) while stimulation of the CeA or PVN alone both induced pressor responses, their simultaneous stimulation also increased muscle vascular resistance. These results are evidence that cardiovascular responses during high-intensity exercise are affected by CeA activation, which acts to limit maximum exercise performance, and may implicate autonomic control modulating the PVN-NTS pathway via the CeA. [ABSTRACT FROM AUTHOR]

Abstract: Neuroimaging studies have revealed important pathomechanisms related to disorders of brain-gut interactions, such as irritable bowel syndrome and functional dyspepsia. More detailed investigations aimed at neural processing in the brainstem, including the key relay station of the nucleus of the solitary tract (NTS), have hitherto been hampered by technical shortcomings. To ascertain these processes in more detail, we used multiecho multiband 7T functional magnetic resonance imaging and a novel translational experimental model based on a nutrient-derived intestinal chemonociceptive stimulus. In a randomized cross-over fashion, subjects received duodenal infusion of capsaicin (the pungent principle in red peppers) and placebo (saline). During infusion, functional magnetic resonance imaging data and concomitant symptom ratings were acquired. Of 26 healthy female volunteers included, 18 were included in the final analysis. Significantly increased brain activation over time during capsaicin infusion, as compared with placebo, was observed in brain regions implicated in pain processing, in particular the NTS. Brain activation in the thalamus, cingulate cortex, and insula was more pronounced in subjects who reported abdominal pain (visual analogue scale > 10 mm), as compared with subjects who experienced no pain. On the contrary, activations at the level of the NTS were independent of subjective pain ratings. The current experimental paradigm therefore allowed us to demonstrate activation of the principal relay station for visceral afferents in the brainstem, the NTS, which was engaged irrespective of the conscious pain response. These findings contribute to understanding the fundamental mechanism necessary for developing novel therapies aimed at correcting disturbances in visceral afferent pain processing. [ABSTRACT FROM AUTHOR]

The role of suprachiasmatic nuclei (SCN) in the anterior hypothalamus as a master ~24 h oscillator (clock) and synchronizer of the circadian regulatory system is reviewed extensively. In contrast, the ample evidence that SCN also exert a circadian-independent impact on homeostasis and metabolism is underappreciated. Therefore, herein we focus on the evidence for SCN participation in homeostatic (non-circadian) mechanisms in regulation of arterial blood pressure and hydro-mineral balance, plasma glucose level, food intake, renin, ACTH/corticosterone, GH, thyroid hormones and melatonin secretion. We conclude that, in addition to their major role in circadian control, SCN also selectively participate in homeostatic control. The evidence supports a model where the ventrolateral region of SCN and especially its vasointestinal polypeptide (VIP)-containing neurons convey the homeostatic influences of SCN to the metabolic regulatory pathways. The precise mechanisms of the rhythmic wisdom of the body, i.e., how SCN circadian clock and the daily behavioral and endocrine rhythms harmonize with the homeostatic regulatory systems defending the relative constancy of the internal milieu, remain to be elucidated. The non-circadian SCN contributions in responses to homeostatic challenges certainly deserve careful consideration in future studies. Abbreviations2-DG: 2-deoxy-D-glucose; AV3V: anteroventral third ventricle region; GRF - growth-hormone-releasing factor; MnPO: median preoptic nucleus; NTS: nucleus of the solitary tract; OVLT: organum vasculosum of the lamina terminalis; PRA: plasma renin activity; SCN: suprachiasmatic nuclei; SD: sleep deprivation; VIP: vasoactive intestinal polypeptide. [ABSTRACT FROM AUTHOR]

Background and aim: Local GABAergic signaling in the dorsal vagal complex (DVC) is essential to control gastric function. While the inhibitory GABAA receptor action on motility in the DVC is well-documented, the role of the GABAB receptor on gastric function is less well-established. Microinjection of baclofen, a selective GABAB receptor agonist, in the dorsal motor nucleus of the vagus (DMV) increases gastric tone and motility, while the effect on motility in the nucleus tractus solitarius (NTS) needs to be investigated. Previous in vitro studies showed that GABAB receptors exert a local inhibitory effect in unidentified NTS neurons. Since the NTS and DMV nuclei have differential control of gastric motility, we compared GABAB receptor activation in the NTS to that reported in the DMV. We microinjected baclofen unilaterally in the NTS while monitoring intragastric pressure and compared its action to optogenetic activation of somatostatin (SST) neurons in transgenic sst-Cre::channelrhodopsin-2 (ChR2) mice. We also performed patch-clamp recordings from SST and DMV neurons in brainstem slices from these mice. Methods: In vivo drug injections and optogenetic stimulation were performed in fasted urethane/a-chloralose anesthetized male mice. Gastric tone and motility were monitored by an intragastric balloon inserted in the antrum and inflated with warm water to provide a baseline intragastric pressure (IGP). Coronal brainstem slices were obtained from the sst-Cre::ChR2 mice for interrogation with optogenetics and pharmacology using electrophysiology. Results: The unilateral microinjection of baclofen into the NTS caused a robust increase in gastric tone and motility that was not affected by ipsilateral vagotomy. Optogenetic activation of SST neurons that followed baclofen effectively suppresses the gastric motility in vivo. In brain slices, baclofen suppressed spontaneous and light-activated inhibitory postsynaptic currents in SST and gastrointestinal-projection DMV neurons and produced outward currents. Conclusion: Our results show that GABAB receptors in the NTS strongly increase gastric tone and motility. Optogenetic stimulation in vivo and in vitro suggests that these receptors activated by baclofen suppress the glutamatergic sensory vagal afferents in the NTS and also inhibit the interneurons and the inhibitory neurons that project to the DMV, which, in turn, increase motility via a cholinergic excitatory pathway to the stomach. [ABSTRACT FROM AUTHOR]

Diabetes and obesity are growing problems worldwide and are associated with a range of acute and chronic complications, including acute myocardial infarction (AMI) and stroke. Novel anti-diabetic medications designed to treat T2DM, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), exert beneficial effects on metabolism and the cardiovascular system. However, the underlying mechanisms are poorly understood. GLP-1RAs induce anorexic effects by inhibiting the central regulation of food intake to reduce body weight. Central/peripheral administration of GLP-1RAs inhibits food intake, accompanied by an increase in c-Fos expression in neurons within the paraventricular nucleus (PVN), amygdala, the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPB) and arcuate nucleus (ARC), induced by the activation of GLP-1 receptors in the central nervous system (CNS). Therefore, GLP-1RAs need to pass through the blood-brain barrier to exert their pharmacological effects. In addition, studies revealed that SGLT-2is could reduce the risk of chronic heart failure in people with type 2 diabetes. SGLT-2 is extensively expressed throughout the CNS, and c-Fos expression was also observed within 2 hours of administration of SGLT-2is in mice. Recent clinical studies reported that SGLT-2is improved hypertension and atrial fibrillation by modulating the "overstimulated" renin-angiotensin-aldosterone system (RAAS) and suppressing the sympathetic nervous system (SNS) by directly/indirectly acting on the rostral ventrolateral medulla. Despite extensive research into the central mechanism of GLP-1RAs and SGLT-2is, the penetration of the blood-brain barrier (BBB) remains controversial. This review discusses the interaction between GLP-1RAs and SGLT-2is and the BBB to induce pharmacological effects via the CNS. [ABSTRACT FROM AUTHOR]

Neurons in the brainstem preBötzinger complex (preBötC) generate the rhythm and rudimentary motor pattern for inspiratory breathing movements. We performed whole-cell patch-clamp recordings from inspiratory neurons in the preBötC of neonatal mouse slices that retain breathing-related rhythmicity in vitro. We classified neurons based on their electrophysiological properties and genetic background, and then aspirated their cellular contents for single-cell RNA sequencing (scRNA-seq). This data set provides the raw nucleotide sequences (FASTQ files) and annotated files of nucleotide sequences mapped to the mouse genome (mm10 from Ensembl), which includes the fragment counts, gene lengths, and fragments per kilobase of transcript per million mapped reads (FPKM). These data reflect the transcriptomes of the neurons that generate the rhythm and pattern for inspiratory breathing movements. Measurement(s) nucleotide sequences Technology Type(s) Illumina Sequencing Factor Type(s) genotype: Dbx1-derived vs. non-Dbx1-derived neurons in the mouse preBötzinger complex • electrophysiological properties: Type-1 vs. Type-2 inspiratory preBötzinger complex neurons Sample Characteristic - Organism Mus musculus Sample Characteristic - Environment laboratory environment Sample Characteristic - Location contiguous United States of America [ABSTRACT FROM AUTHOR]