Dorsal Motor Nucleus Research Articles

Whole-brain activation signatures of weight-lowering drugs

ObjectiveThe development of effective anti-obesity therapeutics relies heavily on the ability to target specific brain homeostatic and hedonic mechanisms controlling body weight. To obtain further insight into neurocircuits recruited by anti-obesity drug treatment, the present study aimed to determine whole-brain activation signatures of six different weight-lowering drug classes. MethodsChow-fed C57BL/6J mice (n = 8 per group) received acute treatment with lorcaserin (7 mg/kg; i.p.), rimonabant (10 mg/kg; i.p.), bromocriptine (10 mg/kg; i.p.), sibutramine (10 mg/kg; p.o.), semaglutide (0.04 mg/kg; s.c.) or setmelanotide (4 mg/kg; s.c.). Brains were sampled two hours post-dosing and whole-brain neuronal activation patterns were analysed at single-cell resolution using c-Fos immunohistochemistry and automated quantitative three-dimensional (3D) imaging. ResultsThe whole-brain analysis comprised 308 atlas-defined mouse brain areas. To enable fast and efficient data mining, a web-based 3D imaging data viewer was developed. All weight-lowering drugs demonstrated brain-wide responses with notable similarities in c-Fos expression signatures. Overlapping c-Fos responses were detected in discrete homeostatic and non-homeostatic feeding centres located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures as well as the dopaminergic system. ConclusionsWhole-brain c-Fos expression signatures of various weight-lowering drug classes point to a discrete set of brain regions and neurocircuits which could represent key neuroanatomical targets for future anti-obesity therapeutics.

Human coronaviruses in idiopathic Parkinson's disease: Implications of SARS-CoV-2's modulation of the host's transcriptome.

ObjectiveA recent study on the effects of SARS-CoV-2 infection on the host's transcriptome indicated the perturbation of several pathways associated with neurodegeneration, including but not limited to Parkinson's and Huntington's diseases. The purpose of this study was to determine overlapping pathways between iPD vs. Controls and those associated with SARS-CoV-2 infection.MethodsGene set enrichment analyses (GSEA) were performed on gene expression data from tissues donated by idiopathic Parkinson's disease patients (iPD). These included dorsal motor nucleus of the vagus (DMNV), substantia nigra (SN), whole blood (WB) and peripheral blood mononuclear cell samples (PBMC). Enriched pathways detected by GSEA results were subsequently compared to (a) those retrieved by two independently constructed SARS-CoV-2 – host interactomes, as well as (b) previously published pathway data. For all analyses, a false discovery rate (FDR) <0.05 was considered statistically significant.ResultsAnalysis of iPD data revealed multiple immune response and viral parasitism -related pathways (FDR < 0.05). Head-to-head comparisons as well as confirmatory analyses revealed several pathways and gene ontology (GO) terms overlapping between iPD tissues and SARS-CoV-2 induced transcriptomic changes: “Parkinson's Disease” and “Huntington's Disease” (overlapping in DMNV, ION, SN, and WB; FDR < 0.05), “NAFLD” (overlapping in DMNV, SN, PBMC and WB; FDR < 0.05), mRNA surveillance and proteostasis pathways (All datasets; FDR < 0.5), among others.ConclusionThe overlap noted in this comparative transcriptomic study outlines the potential contribution of human coronaviruses in the pathogenesis of iPD. Furthermore, given SARS-CoV-2's neuroinvasive potential, closer scrutiny is warranted towards its contribution in the long-term development of neurodegenerative disease.

Poly (ADP-ribose) polymerase 1 and Parkinson's disease: A study in post-mortem human brain

Poly (ADP-ribose) polymerase 1 (PARP1) is crucial in both maintenance of genome integrity and cell death. PARP1 activation has been very recently linked to Parkinson's disease (PD) and its role in inducing the pathologic accumulation of α-Synuclein demonstrated in a PD mouse model. The objective of this study was to investigate the presence and localization of PARP1 in PD brain. PARP1 localization was assessed by immunostaining and confocal microscopy in post-mortem human brains obtained from PD patients (Braak stage VI) compared to controls. PARP1 positive nuclei in substantia nigra, mainly in dopaminergic neurons but also in astrocytes and oligodendrocytes, were decreased in PD. The same alteration was observed in several areas that are affected in PD pathology, namely the dorsal motor nucleus of vagus, frontal and cingulate cortex, whereas no changes in PARP1 staining were detectable in the inferior olivary nucleus that is unaffected in PD. In addition, PARP1 co-localizes with α-Synuclein that is accumulated in the cytoplasm and in Lewy bodies of PD tissue sections. Our data reveal previously unknown changes of PARP1 localization in the brain of PD patients, in both neurons and glia, supporting its widespread involvement in this pathology and its potential use as a therapeutic target.

Voltage-Gated Sodium Channels Mediating Conduction in Vagal Motor Fibers Innervating the Esophageal Striated Muscle

The vagal motor fibers innervating the esophageal striated muscle are essential for esophageal motility including swallowing and vomiting. However, it is unknown which subtypes of voltage-gated sodium channels (NaV1s) regulate action potential conduction in these efferent nerve fibers. The information on the NaV1s subtypes is necessary for understanding their potential side effects on upper gut, as novel inhibitors of NaV1s are developed for treatment of pain. We used isolated superfused (35 °C) vagally-innervated mouse esophagus striated muscle preparation (mucosa removed) to measure isometric contractions of circular striated muscle evoked by electrical stimulation of the vagus nerve. NaV1 inhibitors were applied to the de-sheathed segment of the vagus nerve. Tetrodotoxin (TTX) applied to the vagus nerve completely abolished electrically evoked contractions. The selective NaV1.7 inhibitor PF-05089771 alone partially inhibited contractions and caused a >3-fold rightward shift in the TTX concentration-inhibition curve. The NaV1.1, NaV1.2 and NaV1.3 group inhibitor ICA-121431 failed to inhibit contractions, or to alter TTX concentration-inhibition curves in the absence or in the presence of PF-05089771. RT-PCR indicated lack of NaV1.4 expression in nucleus ambiguus and dorsal motor nucleus of the vagus nerve, which contain motor and preganglionic neurons projecting to the esophagus. We conclude that the action potential conduction in the vagal motor fibers to the esophageal striated muscle in the mouse is mediated by TTX-sensitive voltage gated sodium channels including NaV1.7 and most probably NaV1.6. The role of NaV1.6 is supported by ruling out other TTX-sensitive NaV1s (NaV1.1-1.4) in the NaV1.7-independent conduction.

Improvement in colonic inflammatory injury in rats via activating dorsal cholinergic neurons of vagus with electroacupuncture at sensitized acupoints

To observe the effect of electroacupuncture (EA) at sensitized acupoints on choline acetyltransferase positive (ChAT+) neurons in dorsal motor nucleus (DMV) of brainstem vagus in the colitis model rats and explore the mechanism of the improvement in colonic inflammatory injury in the rats. A total of 79 male SD rats were randomized into five groups, i.e. a normal group (20 rats), a normal plus sensitized acupoint group (5 rats), a model group (34 rats), an EA-1 group (15 rats) and an EA-2 group (5 rats). In the model group and the EA groups, 5% dextran sulfate sodium (DSS) was adopted for 6-day free drinking to establish colitis model rats. By injecting Evans blue (EB) into the caudal vein in the model rats, the sensitized acupoints were determined. Afterwards, in the normal plus sensitized acupoint group, the EA-1 group and the EA-2 group, EA was exerted at the sensitized acupoints, with disperse-dense wave, 2 Hz/ 15 Hz in frequency and 2 mA in intensity, for 30 min of intervention each day. The intervention lasted for 6 days in the EA-1 group and for 1 day in both the normal plus sensitized acupoint group and the EA-2 group. On day 0, 7 and 13 of experiment, successively, the score of disease activity index (DAI), the score of colonic histological damage, as well as the changes in the mechanical paw withdrawal threshold and thermal paw withdrawal latency were evaluated in the normal group, the model group and the EA-1 group. On day 7 of experiment, using immunofluorescence staining, the activation of different lamina neurons of spinal dorsal horn and ChAT+ neurons in DMV was observed in the normal group, the normal plus sensitized acupoint group, the model group and the EA-2 group separately. The EB extravasating areas were distributed in the segments from T12 to S1 on the body surface of colitis model rats, mainly focusing at L2 and L5. Therefore, "Shangjuxu" (ST 37) was taken as the sensitized acupoint. Compared with the normal group on day 7 and 13 of experiment, the mechanical paw withdrawal threshold were reduced (P<0.001), DAI scores and the scores of colonic histological damage were increased (P<0.001) in the model group. Compared with the normal group on day 7 of experiment, thermal paw withdrawal latency in the model group was reduced (P<0.001). Compared with the model group on day 13 of experiment, the mechanical paw withdrawal threshold was increased (P<0.001), DAI score and the score of colonic histological damage were reduced (P<0.01, P<0.05) in the EA-1 group. Compared with the normal group, the activated numbers of the neurons in superficial laminae (Ⅰand Ⅱ) at spinal dorsal horn of L4 to L6 and ChAT+ neurons in DMV were increased in the normal plus sensitized acupoint group and the model group (P<0.05, P<0.01). Compared with the normal plus sensitized acupoint group and the model group, the activated numbers of the neurons in superficial laminae at spinal dorsal horn of L4 to L6 and ChAT+ neurons in DMV were increased in the EA-2 group (P<0.001). The segmental dominance (acupoints) from T12 to S1 on the body surface of colitis rats is sensitized. EA at sensitized acupoints effectively relieves colonic inflammatory injury, which is probably by activating superficial lamina neurons of spinal dorsal horn and ChAT+ neurons of DMV.

Dosimetric evaluation of dorsal vagal complex and vestibular apparatus in head-and-neck cancer patients treated with intensity-modulated radiotherapy

Purpose: The purpose of this study was to dosimetrically evaluate the dose received by dorsal vagal complex (DVC) and vestibular apparatus in patients with head-and-neck cancer treated with intensity-modulated radiotherapy (IMRT). Materials and Methods: Twenty histopathologically confirmed head-and-neck cancer patients, preferably oropharynx and nasopharynx that were treated with IMRT from a period of 2018–2020, were retrospectively analyzed in this study. DVC and vestibular apparatus were contoured, and the doses received by them were noted. Results: The average minimum dose to the entire DVC and vestibular apparatus was 25.134 Gy (range, 8.77–37.49 Gy) and 12.812 Gy (range, 1.07–28.57 Gy); the average maximum point dose to the DVC and vestibular apparatus was 35.896 Gy (range, 24.29–45.53 Gy) and 33.266 Gy (range, 3.19–60.72 Gy); and the average mean dose to the entire DVC and vestibular apparatus volume was 30.151 Gy (range, 16.48–40.83 Gy) and 21.484 Gy (range, 2.99–39.42 Gy), respectively; the average volume of DVC and vestibular apparatus was 0.52 cm3 (range, 0.3–0.8 cm3) and 0.36 (range, 0.2–0.6 cm3), respectively. Conclusions: Considering the DVC and vestibular apparatus as an organ for conformal avoidance, there can be a possibility in the reduction of nausea and vomiting while treating patients of head-and-neck cancer with radiation.

Potential Crosstalk Between Parkinson's Disease and Energy Metabolism.

Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (α-Syn) in the substantia nigra (SN) and the degeneration of nigrostriatal dopaminergic (DAergic) neurons. Some studies have reported that the pathology of PD originates from the gastrointestinal (GI) tract, which also serves as an energy portal, and develops upward along the neural pathway to the central nervous system (CNS), including the dorsal motor nucleus of vagus (DMV), SN, and hypothalamus, which are also involved in energy metabolism control. Therefore, we discuss the alterations of nuclei that regulate energy metabolism in the development of PD. In addition, due to their anti-inflammatory, antiapoptotic and antioxidative roles, metabolism-related peptides are involved in the progression of PD. Furthermore, abnormal glucose and lipid metabolism are common in PD patients and exacerbate the pathological changes in PD. Therefore, in this review, we attempt to explain the correlation between PD and energy metabolism, which may provide possible strategies for PD treatment.

The Medullary Targets of Neurally Conveyed Sensory Information from the Rat Hepatic Portal and Superior Mesenteric Veins.

Vagal and spinal sensory endings in the wall of the hepatic portal and superior mesenteric veins (PMV) provide the brain with chemosensory information important for energy balance and other functions. To determine their medullary neuronal targets, we injected the transsynaptic anterograde viral tracer HSV-1 H129-772 (H129) into the PMV wall or left nodose ganglion (LNG) of male rats, followed by immunohistochemistry (IHC) and high-resolution imaging. We also determined the chemical phenotype of H129-infected neurons, and potential vagal and spinal axon terminal appositions in the dorsal motor nucleus of the vagus (DMX) and the nucleus of the solitary tract (NTS). PMV wall injections generated H129-infected neurons in both nodose ganglia and in thoracic dorsal root ganglia (DRGs). In the medulla, cholinergic preganglionic parasympathetic neurons in the DMX were virtually the only targets of chemosensory information from the PMV wall. H129-infected terminal appositions were identified on H129-infected somata and dendrites in the DMX, and on H129-infected DMX dendrites that extend into the NTS. Sensory transmission via vagal and possibly spinal routes from the PMV wall therefore reaches DMX neurons via axo-somatic appositions in the DMX and axo-dendritic appositions in the NTS. However, the dearth of H129-infected NTS neurons indicates that sensory information from the PMV wall terminates on DMX neurons without engaging NTS neurons. These previously underappreciated direct sensory routes into the DMX enable a vago-vagal and possibly spino-vagal reflexes that can directly influence visceral function.

The neurosphere assay: an effective in vitro technique to study neural stem cells.

The neurosphere assay: an effective in vitro technique to study neural stem cells.

MET Receptor Tyrosine Kinase Regulates Lifespan Ultrasonic Vocal Communication and Vagal Motor Neuron Development

The vagal motor nucleus ambiguus (nAmb) innervates the intrinsic muscles of the larynx, providing direct motor control over vocal production in humans and rodents. Here, we demonstrate in mice that embryonic deletion of the MET receptor tyrosine kinase (MET) in the developing brainstem results in severe deficits in ultrasonic vocalization in early postnatal life. Abnormal vocalization patterns persisted into adulthood in more than 70% of mice, with others recovering the ability to vocalize, reflecting some heterogeneity in circuit restitution. Deletion of MET in the developing brainstem also resulted in a loss of one-third of motor neurons in the nAmb, demonstrating that early developmental signaling through MET is required for proper formation of the nAmb. Together, the data establish MET as a required molecular component for normal development of a subset of neurons in the nAmb involved in lifespan ultrasonic vocalization.

Electroacupuncture ameliorates intestinal inflammation by activating α7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus.

Inflammatory cytokines produced by muscularis macrophages largely contribute to the pathological signs of postoperative ileus (POI). Electroacupuncture (EA) can suppress inflammation, mainly or partly via activation of vagal efferent. The goal of this study was to investigate the mechanisms by which EA stimulation at an hindlimb region ameliorates inflammation in POI.Methods: Intestinal motility and inflammation were examined after 24 h after intestinal manipulation (IM)-induced POI in mice. Local immune response in the intestinal muscularis, expression of macrophages, α7 nicotinic acetylcholine receptor (α7nAChR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined by flow cytometry, Western Blot, qPCR and immunofluorescence. The effects of α7nAChR antagonists (methyllycaconitine and α-bungarotoxin) and JAK2/STAT3 inhibitors (AG490 and WP1066) were also administered in a subset of mice prior to EA. In the parasympathetic pathways, intestinal motility and inflammation were determined after cervical vagotomy and sub-diaphragmatic vagotomy. The expression of gamma absorptiometry aminobutyric acid (GABAA) receptor in dorsal motor nucleus of vagal (DMV) cholinergic neurons was assessed by immunofluorescence and the response to DMV microinjection of bicuculine (antagonist of GABAA receptor) or muscimol (agonist of GABAA receptor) were assessed.Results: EA suppressed intestinal inflammation and promoted gastrointestinal motility. Mechanistically, EA activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in macrophages which reduced the production of inflammatory cytokines. Furthermore, we also demonstrated that hindlimb region stimulation drove vagal efferent output by inhibiting the expression of GABAA receptor in DMV to ameliorate inflammation.Conclusions: The present study revealed that EA of hindlimb regions inhibited the expression of GABAA receptor in DMV neurons, whose excited vagal nerve, in turn suppressed IM-induced inflammation via activation of α7nAChR-mediated JAK2/STAT3 signaling pathway.

Neuroarchitectonics of the medulla oblongata of cattle

The article presents data from the study of neuroarchitectonics of the medulla oblongata of cattle. The main attention was paid to the peculiarities of neuronal morphology, determination of their type and prevalence of a certain population of cells in the tissue. The study was performed on 23 brain samples taken from animals aged 2–11 years. To reveal the architectonics of neurons, methods of fabric impregnation with silver were used according to Golgi, Ramon-Kahal and Bolshovsky. The main criteria for determining the type of cells were such features as: cell body size, its shape, number and distribution of processes, their thickness, tortuosity and branching. According to the results, we can identify four main populations of neurons, which are represented by such morphofunctional cell types as: reticular, large polygonal (motor), small round (sensory) and spindle-shaped. The largest population consists of reticular neurons, the second most common are sensory, then motor and the least represented spindle-shaped. It was found that the population of sensory-type neurons includes such structures as the Gracilis and Cutaneus nucleus, the complex of olive inferior nuclei and the nucleus of the solitary tract. Motor are represented respectively in the dorsal, ventral and lateral motor nuclei, the hipoglossy nucleus, the ventral nucleus of the vagus nerve and the ventral subunit of the dorsal nucleus of the vagus nerve. Spindle-shaped neurons are represented only in the dorsal subunit of the dorsal nucleus of the vagus nerve, and reticular form the largest population represented by the reticular formation and the lateral nucleus. A certain pattern of distribution of cell types in the tissue is traced. Thus, the most archaic and architectural – reticular neurons form the center of cell mass, while specialized forms of cells – motor and sensory distributed on the periphery. In a separate type, spindle-shaped neurons of the dorsal nucleus of the vagus nerve are isolated, as cells of the transition link from reticular to motor.

Behavioral Deficits and Brain α-Synuclein and Phosphorylated Serine-129 α-Synuclein in Male and Female Mice Overexpressing Human α-Synuclein.

Alpha-synuclein (α-syn) is involved in pathology of Parkinson's disease, and 90% of α-syn in Lewy bodies is phosphorylated at serine 129 (pS129 α-syn). To assess behavior impairments and brain levels of α-syn and pS129 α-syn in mice overexpressing human α-syn under Thy1 promoter (Thy1-α-syn) and wild type (wt) littermates. Motor and non-motor behaviors were monitored, brain human α-syn levels measured by ELISA, and α-syn and pS129 α-syn mapped by immunohistochemistry. Male and female wt littermates did not show differences in the behavioral tests. Male Thy1-α-syn mice displayed more severe impairments than female counterparts in cotton nesting, pole tests, adhesive removal, finding buried food, and marble burying. Concentrations of human α-syn in the olfactory regions, cortex, nigrostriatal system, and dorsal medulla were significantly increased in Thy1-α-syn mice, higher in males than females. Immunoreactivity of α-syn was not simply increased in Thy1-α-syn mice but had altered localization in somas and fibers in a few brain areas. Abundant pS129 α-syn existed in many brain areas of Thy1-α-syn mice, while there was none or only a small amount in a few brain regions of wt mice. The substantia nigra, olfactory regions, amygdala, lateral parabrachial nucleus, and dorsal vagal complex displayed different distribution patterns between wt and transgenic mice, but not between sexes. The severer abnormal behaviors in male than female Thy1-α-syn mice may be related to higher brain levels of human α-syn, in the absence of sex differences in the altered brain immunoreactivity patterns of α-syn and pS129 α-syn.

Peripheral and central regulation of insulin by the intestine and microbiome.

Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.

Optogenetic stimulation of the liver-projecting melanocortinergic pathway promotes hepatic glucose production

The central melanocortin system plays a fundamental role in the control of feeding and body weight. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) also regulate overall glucose homeostasis via insulin-dependent and -independent pathways. Here, we report that a subset of ARC POMC neurons innervate the liver via preganglionic parasympathetic acetylcholine (ACh) neurons in the dorsal motor nucleus of the vagus (DMV). Optogenetic stimulation of this liver-projecting melanocortinergic pathway elevates blood glucose levels that is associated with increased expression of hepatic gluconeogenic enzymes in female and male mice. Pharmacological blockade and knockdown of the melanocortin-4 receptor gene in the DMV abolish this stimulation-induced effect. Activation of melanocortin-4 receptors inhibits DMV cholinergic neurons and optogenetic inhibition of liver-projecting parasympathetic cholinergic fibers increases blood glucose levels. This elevated blood glucose is not due to altered pancreatic hormone release. Interestingly, insulin-induced hypoglycemia increases ARC POMC neuron activity. Hence, this liver-projecting melanocortinergic circuit that we identified may play a critical role in the counterregulatory response to hypoglycemia.

The Subnuclear Distribution of 5-HT1A Receptors in the Human Nucleus of the Solitary Tract and Selected Structures of the Caudal Medulla

The distribution of 5-HT1A receptors in the subnuclei of the human caudal nucleus of solitary tract and adjacent structures in the dorsal vagal complex was studied using [3H]8-OH-DPAT, a highly selective 5-HT1A receptor agonist. The highest binding of the labeled ligand was found in the dorsal motor nucleus of the vagus, followed by the medial, intermediate, and subpostremal subnuclei of the nucleus of solitary tract. Previous animal studies suggest an important role for these structures in the regulation of visceral function, particularly for the gastrointestinal and cardiovascular systems. The results of this study suggest the possibility of an analogous role for 5-HT1A receptors in the regulation of these autonomic pathways in humans as well.

Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain

ObjectivesThe dorsal vagal complex (DVC) senses insulin and controls glucose homeostasis, feeding behaviour and body weight. Three-days of high-fat diet (HFD) in rats are sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in the DVC. We investigated the effects that altered Drp1 activity in the DVC has on feeding behaviour. Additionally, we aimed to uncover the molecular events and the neuronal cell populations associated with DVC insulin sensing and resistance. MethodsEight-week-old male Sprague Dawley rats received DVC stereotactic surgery for brain infusion to facilitate the localised administration of insulin or viruses to express mutated forms of Drp1 or to knockdown inducible nitric oxide synthase (iNOS) in the NTS of the DVC. High-Fat diet feeding was used to cause insulin resistance and obesity. ResultsWe showed that Drp1 activation in the DVC increases weight gain in rats and Drp1 inhibition in HFD-fed rats reduced food intake, weight gain and adipose tissue. Rats expressing active Drp1 in the DVC had higher levels of iNOS and knockdown of DVC iNOS in HFD-fed rats led to a reduction of food intake, weight gain and adipose tissue. Finally, inhibiting mitochondrial fission in DVC astrocytes was sufficient to protect rats from HFD-dependent insulin resistance, hyperphagia, weight gain and fat deposition. ConclusionWe uncovered new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.

Musings on the wanderer: What's new in our understanding of vago-vagal reflexes? VI. Central vagal circuits that control glucose metabolism.

Neurons in the brain stem dorsal vagal complex (DVC) take part in a continuous bidirectional crosstalk, in which they receive and respond to a vast array of signaling molecules, including glucose. Importantly, chronic dysregulation of blood glucose concentration, a hallmark of high prevalence pathologies, such as diabetes and metabolic syndrome, can induce neuroplasticity in DVC neural networks, which is hypothesized to either contribute to or compensate for the glycemic or insulinemic dysregulation observed in these conditions. Here, we revisit the topic of vagal reflexes to review recent research on the importance of DVC function in regulating systemic glucose homeostasis and the neuroplastic changes in this brain region that are associated with systemic glucose alterations. We also discuss the critical connection between these nuclei and the gut and the role of central vagal circuits in the favorable outcomes associated with bariatric surgical procedures for metabolic disorders.

Dual synaptic inhibitions of brainstem neurons by GABA and glycine with impact on Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disease caused mostly by mutations in the MECP2 gene. People with RTT show breathing dysfunction attributable to the high rate of sudden death. Previous studies have shown that insufficient GABA synaptic inhibition contributes to the breathing abnormalities in mouse models of RTT, while it remains elusive how the glycine system is affected. We found that optogenetic stimulation of GAD-expressing neurons in mice produced GABAergic and glycinergic postsynaptic inhibitions of neurons in the hypoglossal nucleus (XII) and the dorsal motor nucleus of vagus (DMNV). By sequential applications of bicuculline and strychnine, such inhibition appeared approximately 44% GABAA ergic and 52% glycinergic in XII neurons, and approximately 49% GABAA ergic and 46% glycinergic in DMNV neurons. Miniature inhibitory postsynaptic potentials (mIPSCs) in these neurons were approximately 47% GABAA ergic and 49% glycinergic in XII neurons, and approximately 48% versus 50% in DMNV neurons, respectively. Consistent with the data, our single-cell polymerase chain reaction studies indicated that transcripts of GABAA receptor γ2 subunit (GABAA Rγ2) and glycine receptor β subunit (GlyRβ) were simultaneously expressed in these cells. In MeCP2R168X mice, proportions of GABAA ergic and glycinergic mIPSCs became approximately 28% versus 69% in XII neurons, and approximately 31% versus 66% in DMNV cells. In comparison with control mice, the GABAA ergic and glycinergic mIPSCs decreased significantly in the XII and DMNV neurons from the MeCP2R168X mice, so did the transcripts of GABAA Rγ2 and GlyRβ. These results suggest that XII and DMNV neurons adopt dual GABAA ergic and glycinergic synaptic inhibitions, and with Mecp2 disruption these neurons rely more on glycinergic synaptic inhibition.

Identification of a brainstem locus that inhibits tumor necrosis factor

In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiac-superior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity.