Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding.
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ABSTRACT:
SUBMITTER: Cheng W
PROVIDER: S-EPMC7104375 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Medial nucleus tractus solitarius (mNTS) neurons express leptin receptors (LepRs), and intra-mNTS delivery of leptin reduces food intake and body weight. Here, the contribution of endogenous LepR signaling in mNTS neurons to energy balance control was examined. Knockdown of LepR in mNTS and area postrema (AP) neurons of rats (LepRKD) via adeno-associated virus short hairpin RNA-interference (AAV-shRNAi) resulted in significant hyperphagia for chow, high-fat, and sucrose diets, yielding increased body weight and adiposity. The chronic hyperphagia of mNTS/AP LepRKD rats is likely mediated by a reduction in leptin potentiation of gastrointestinal satiation signaling, as LepRKD rats showed decreased sensitivity to the intake-reducing effects of cholecystokinin. LepRKD rats showed increased basal AMP-kinase activity in mNTS/AP micropunches, and pharmacological data suggest that this increase provides a likely mechanism for their chronic hyperphagia. Overall these findings demonstrate that LepRs in mNTS and AP neurons are required for normal energy balance control.
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Project description:Leptin receptor-expressing (LepRb-expressing) neurons of the nucleus tractus solitarius (NTS; LepRbNTS neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and that produce the food intake-suppressing PPG cleavage product glucagon-like peptide-1 [GLP1]) represent a subpopulation of mouse LepRbNTS cells. Using Leprcre, Ppgcre, and Ppgfl mouse lines, along with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we examined roles for Ppg in GLP1NTS and LepRbNTS cells for the control of food intake and energy balance. We found that the cre-dependent ablation of NTS Ppgfl early in development or in adult mice failed to alter energy balance, suggesting the importance of pathways independent of NTS GLP1 for the long-term control of food intake. Consistently, while activating GLP1NTS cells decreased food intake, LepRbNTS cells elicited larger and more durable effects. Furthermore, while the ablation of NTS Ppgfl blunted the ability of GLP1NTS neurons to suppress food intake during activation, it did not impact the suppression of food intake by LepRbNTS cells. While Ppg/GLP1-mediated neurotransmission plays a central role in the modest appetite-suppressing effects of GLP1NTS cells, additional pathways engaged by LepRbNTS cells dominate for the suppression of food intake.
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Project description:The nucleus tractus solitarius (NTS) integrates visceral sensory signals with information from the forebrain to control homeostatic functions, including food intake. Melanocortin 3/4 receptor (MC3/4R) ligands administered directly to the caudal brainstem powerfully modulate meal size but not frequency, suggesting the enhancement of visceral satiety signals. Using whole-cell recordings from rat brainstem slices, we examined the effects of melanocortin ligands, alpha-melanocyte-stimulating hormone (alphaMSH) and melanotan II (MTII), on EPSC in NTS neurons. Thirty-two percent of NTS neurons responded to perfusion with MTII or alphaMSH with either an increase (24%) or a decrease (8%) in the frequency, but not amplitude, of spontaneous EPSCs; the effects of MTII were abolished by pretreatment with SHU9119. After surgical vagal deafferentation, only four of 34 (9%) NTS neurons responded to MTII with an increase in EPSC frequency. When EPSCs were evoked by electrical stimulation of the tractus solitarius in Krebs' solution with 2.4 mm Ca(2+)(e), alphaMSH and MTII increased the amplitude in six of the 28 neurons tested, decreased amplitude in 14 with no effect in the remaining eight neurons. In four of six neurons unresponsive to MTII, decreasing Ca(2+)(e) levels to 1.5 mM uncovered an excitatory effect of MTII on EPSC amplitude. Reverse transcription-PCR analysis revealed the presence of MC4R, but not MC3R, in nodose ganglia. These results show that MC4R signaling leads mainly to presynaptic modulation of glutamatergic synaptic transmission and suggest that melanocortinergic-induced decrease of food intake may occur via enhancement of vagal afferent satiation signals from the gastrointestinal tract.
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Project description:Baroreceptor afferents project to the cardiovascular region of the nucleus tractus solitarius (cvNTS), and their cvNTS target neurons may play a role in governing the sensitivity and operating range of the arterial baroreceptor reflex (baroreflexes). Recent studies have shown differential gene and protein expression in the cvNTS in response to changed arterial pressure. However, the extent of these responses is unknown. Therefore, we collected differential global gene expression data in a time series following acute hypertension in awake, freely moving rats. To acquire statistically significant results and place them in functional context, we overcame several quality control requirements and developed novel analytical approaches. The physiologically new findings from the study are that acute hypertension causes very extensive, time-varying gene regulatory changes, many involving neuronal function-specific genes and systems of genes. We use standard genomic analysis methods to manage the large data sets and to develop results such as heat maps to examine patterns and clusters in the gene regulation. We used the Gene Ontology categories to provide functional context. To place our findings in the context of the relevant literature, we developed two graphical representations of the networks implicated, linking receptors and channels to signaling pathways. The results point to the multivariate complexity of the response and implicate a group of receptors as candidates for mediating nucleus tractus solitarius baroreflex function in hypertension by identifying concurrent upregulation of receptor genes. We were able to make transcription factor binding predictions and record dysregulation of heart rate correlated with the transcriptional response.
| S-EPMC2494808 | biostudies-literature
Project description:Endogenous nitric oxide (NO) has been implicated in the regulation of neuronal activity which mediates cardiovascular reflexes. However, there is controversy concerning the role of NO in the nucleus tractus solitarius (NTS). The present study aims to elucidate the possible physiological role of endogenous NO in modulating the excitatory vagal afferent input to NTS neurons.All the experiments in the rat were conducted under anaesthetic conditions. Ionophoresis method was used for the application of NO donor or nitric oxide synthase (NOS) inhibitor, and single unit recording method was employed to detect the effects of these applications on vagal afferent- or cardio-pulmonary C-fibre reflex-evoked neuronal excitation in NTS.Ionophoresis applications of L-arginine (L-Arg), a substrate of NOS, and sodium nitroprusside (SNP), a NO donor, both attenuated the vagal afferent-evoked discharge by (51.5+/-7.6)% (n = 17) and (68.3+/-7.1)% (n = 9), respectively. In contrast, application of D-Arg at the same current exerted no overall effect on this input. Also, both L-Arg and SNP inhibited spontaneous firing of most of the recorded neurons. In contrast, ionophoresis application of N(G)-nitro-L-arginine methyl ester (L-NAME) enhanced vagal afferent-evoked excitation by (66.3+/-11.4)% (n = 7). In addition, ionophoresis application of L-Arg and SNP significantly attenuated cardio-pulmonary C-fibre reflex-induced excitation in the tested NTS neurons.Activation of local NO pathway in the NTS could suppress vagal afferent-evoked excitation, suggesting that NO is an important neuromodulator of visceral sensory input in the NTS.
| S-EPMC5552507 | biostudies-other
Project description:Previously, many different types of NTS barosensitive neurons were identified. However, the time course of NTS barosensitive neuronal activity (NA) in response to arterial pressure (AP) changes, and the relationship of NA-AP changes, have not yet been fully quantified. In this study, we made extracellular recordings of single NTS neurons firing in response to AP elevation induced by occlusion of the descending aorta in anesthetized rats. Our findings were that: 1) Thirty-five neurons (from 46 neurons) increased firing, whereas others neurons either decreased firing upon AP elevation, or were biphasic: first decreased firing upon AP elevation and then increased firing during AP decrease. 2) Fourteen neurons with excitatory responses were activated and rapidly increased their firing during the early phase of AP increase (early neurons); whereas 21 neurons did not increase firing until the mean arterial pressure changes (ΔMAP) reached near/after the peak (late neurons). 3) The early neurons had a significantly higher firing rate than late neurons during AP elevation at a similar rate. 4) Early neuron NA-ΔMAP relationship could be well fitted and characterized by the sigmoid logistic function with the maximal gain of 29.3. 5) The increase of early NA correlated linearly with the initial heart rate (HR) reduction. 6) The late neurons did not contribute to the initial HR reduction. However, the late NA could be well correlated with HR reduction during the late phase. Altogether, our study demonstrated that the NTS excitatory neurons could be grouped into early and late neurons based on their firing patterns. The early neurons could be characterized by the sigmoid logistic function, and different neurons may differently contribute to HR regulation. Importantly, the grouping and quantitative methods used in this study may provide a useful tool for future assessment of functional changes of early and late neurons in disease models.
| S-EPMC5383029 | biostudies-literature
Project description:Central oxytocin receptor (OT-R) signaling reduces food intake and increases energy expenditure, but the central sites and mechanisms mediating these effects are unresolved. We showed previously that pharmacological activation of OT-R in hindbrain/nucleus tractus solitarius (NTS) amplifies the intake-inhibitory effects of gastrointestinal (GI) satiation signals. Unexplored were the energetic effects of hindbrain OT-R agonism and the physiological relevance of NTS OT-R signaling on food intake and energy expenditure control. Using a virally mediated OT-R knockdown (KD) strategy and a range of behavioral paradigms, this study examined the role of endogenous NTS OT-R signaling on satiation-mediated food intake inhibition and thermogenic control. Results showed that, compared with controls, NTS OT-R KD rats consumed larger meals, were less responsive to the intake-inhibitory effects of a self-ingested preload, and consumed more chow following a 24-hour fast. These data indicate that NTS OT-R signaling is necessary for normal satiation control. Whereas both control and NTS OT-R KD rats increased core temperature following high-fat diet maintenance (relative to chow maintenance), the percent increase in core temperature was greater in control compared with NTS OT-R KD rats during the light cycle. Hindbrain oxytocin agonist delivery increased core temperature in both control and NTS OT-R KD rats and the percent increase relative to vehicle treatment was not significantly different between groups. Together, data reveal a critical role for endogenous NTS OT-R signaling in mediating the intake-inhibitory effects of endogenous GI satiation signals and in diet-induced thermogenesis.
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Project description:The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is approved for the treatment of obesity; however, there is still much to be learned regarding the neuronal sites of action that underlie its suppressive effects on food intake and body weight. Peripherally administered liraglutide in rats acts in part through central GLP-1Rs in both the hypothalamus and the hindbrain. Here, we extend findings supporting a role for hindbrain GLP-1Rs in mediating the anorectic effects of liraglutide in male rats. To dissociate the contribution of GLP-1Rs in the area postrema (AP) and the nucleus tractus solitarius (NTS), we examined the effects of liraglutide in both NTS AAV-shRNA-driven Glp1r knockdown and AP-lesioned animals. Knockdown of NTS GLP-1Rs, but not surgical lesioning of the AP, attenuated the anorectic and body weight-reducing effects of acutely delivered liraglutide. In addition, NTS c-Fos responses were maintained in AP-lesioned animals. Moreover, NTS Glp1r knockdown was sufficient to attenuate the intake- and body weight-reducing effects of chronic daily administered liraglutide over 3 weeks. Development of improved obesity pharmacotherapies requires an understanding of the cellular phenotypes targeted by GLP-1R agonists. Fluorescence in situ hybridization identified Glp1r transcripts in NTS GABAergic neurons, which when inhibited using chemogenetics, attenuated the food intake- and body weight-reducing effects of liraglutide. This work demonstrates the contribution of NTS GLP-1Rs to the anorectic potential of liraglutide and highlights a phenotypically distinct (GABAergic) population of neurons within the NTS that express the GLP-1R and are involved in the mediation of liraglutide signaling.
| S-EPMC7211411 | biostudies-literature
Project description:The nucleus tractus solitarius (NTS) receives subdiaphragmatic visceral sensory information via vagal A- or C-fibers. We have recently shown that, in contrast to cardiovascular NTS medialis neurons, which respond to either purinergic or vanilloid agonists, the majority of esophageal NTS centralis (cNTS) neurons respond to vanilloid agonists, whereas a smaller subset responds to both vanilloid and purinerigic agonists. The present study aimed to further investigate the neurochemical and synaptic characteristics of cNTS neurons using whole cell patch-clamp, single cell RT-PCR and immunohistochemistry. Excitatory postsynaptic currents (EPSCs) were evoked in cNTS by tractus solitarius stimulation, and in 19 of 64 neurons perfusion with the purinergic agonist αβ-methylene ATP (αβMeATP) increased the evoked EPSC amplitude significantly. Furthermore, neurons with αβMeATP-responsive synaptic inputs had different probabilities of release compared with nonresponsive neurons. Single cell RT-PCR revealed that 8 of 13 αβMeATP-responsive neurons expressed metabotropic glutamate receptor 8 (mGluR8) mRNA, which our previous studies have suggested is a marker of glutamatergic neurons, whereas only 3 of 13 expressed glutamic acid dehydroxylase, a marker of GABAergic neurons. A significantly lower proportion of αβMeATP-nonresponsive neurons expressed mGluR8 (2 of 30 neurons), whereas a greater proportion expressed glutamic acid dehydroxylase (12 of 30 neurons). Esophageal distension significantly increased the number of colocalized mGluR8- and c-Fos-immunoreactive neurons in the cNTS from 8.0 ± 4% to 20 ± 2.5%. These data indicate that cNTS comprises distinct neuronal subpopulations that can be distinguished based on their responses to purinergic agonists and that these subpopulations have distinct neurochemical and synaptic characteristics, suggesting that integration of sensory inputs from the esophagus relies on a discrete organization of synapses between vagal afferent fibers and cNTS neurons.
| S-EPMC4297788 | biostudies-literature
Project description:Background and purposeSecond-hand tobacco smoke (SHS) exposure in children increases the risk of asthma and sudden infant death syndrome. Epidemiological and experimental data have suggested SHS can alter neuroplasticity in the CNS, associated with substance P. We hypothesized that exposure to SHS in young primates changed the effect of substance P on the plasticity of neurons in the nucleus tractus solitarius (NTS), where airway sensory information is first processed in the CNS.Experimental approachThirteen-month-old rhesus monkeys were exposed to filtered air (FA, n= 5) or SHS (n= 5) for >6 months from 50 days of their fetal age. Whole-cell patch-clamp recordings were performed on NTS neurons in brainstem slices from these animals to record the intrinsic cell excitability in the absence or presence of the NK(1) receptor antagonist, SR140333 (3 µM).Key resultsNeurons were electrophysiologically classified based on their spiking onset from a hyperpolarized membrane potential into two phenotypes: rapid-onset spiking (RS) and delayed-onset spiking (DS) types. In RS neurons, SR140333 reduced the spiking response, similarly in both FA- and SHS-exposed animals. In DS neurons, SR140333 almost abolished the spiking response in FA-exposed animals, but had no effect in SHS-exposed animals.Conclusions and implicationsThe contribution of NK(1) receptors to cell excitability depended on firing phenotype of primate NTS neurons and was disrupted by SHS exposure, specifically in DS neurons. Our findings reveal a novel NK(1) receptor function in the primate brainstem and support the hypothesis that chronic exposure to SHS in children causes tachykinin-related neuroplastic changes in the CNS.
| S-EPMC3111680 | biostudies-literature