scholarly journals Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii

2015 ◽  
Vol 114 (2) ◽  
pp. 999-1007 ◽  
Author(s):  
Carie R. Boychuk ◽  
Peter Gyarmati ◽  
Hong Xu ◽  
Bret N. Smith
Keyword(s):  
Membrane Potential ◽  
Glucose Concentration ◽  
Blood Glucose Concentration ◽  
Glutamate Release ◽  
Glucose Sensing ◽  
Gabaergic Neurons ◽  
Nucleus Tractus Solitarii ◽  
Acid Decarboxylase ◽  
Action Potential Firing ◽  
Gaba Neurons

Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated.

scholarly journals Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

2015 ◽  
Vol 114 (4) ◽  
pp. 2500-2508 ◽  
Author(s):  
L. Sosulina ◽  
C. Strippel ◽  
H. Romo-Parra ◽  
A. L. Walter ◽  
T. Kanyshkova ◽  
...  
Keyword(s):  
Substance P ◽  
Fluorescent Protein ◽  
Input Resistance ◽  
Receptor Activation ◽  
Gabaergic Neurons ◽  
Acid Decarboxylase ◽  
Central Amygdala ◽  
Cellular Mechanisms ◽  
Action Potential Firing

Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at −101.5 ± 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K+ conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar9,Met(O2)11]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKCδ-negative neurons (80%) and in few PKCδ-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKCδ-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala.

scholarly journals 5-Hydroxytryptamine 2C receptors tonically augment synaptic currents in the nucleus tractus solitarii

2012 ◽  
Vol 108 (8) ◽  
pp. 2292-2305 ◽  
Author(s):  
James R. Austgen ◽  
Heather A. Dantzler ◽  
Brenna K. Barger ◽  
David D. Kline
Keyword(s):  
Membrane Potential ◽  
Brain Stem ◽  
Glutamate Release ◽  
Input Resistance ◽  
Receptor Activation ◽  
Nucleus Tractus Solitarii ◽  
Visceral Afferents ◽  
Receptor Blockade ◽  
Cardiorespiratory System ◽  
Epsc Amplitude

The nucleus tractus solitarii (nTS) is the primary termination and integration point for visceral afferents in the brain stem. Afferent glutamate release and its efficacy on postsynaptic activity within this nucleus are modulated by additional neuromodulators and transmitters, including serotonin (5-HT) acting through its receptors. The 5-HT2 receptors in the medulla modulate the cardiorespiratory system and autonomic reflexes, but the distribution of the 5-HT2C receptor and the role of these receptors during synaptic transmission in the nTS remain largely unknown. In the present study, we examined the distribution of 5-HT2C receptors in the nTS and their role in modulating excitatory postsynaptic currents (EPSCs) in monosynaptic nTS neurons in the horizontal brain stem slice. Real-time RT-PCR and immunohistochemistry identified 5-HT2C receptor message and protein in the nTS and suggested postsynaptic localization. In nTS neurons innervated by general visceral afferents, 5-HT2C receptor activation increased solitary tract (TS)-EPSC amplitude and input resistance and depolarized membrane potential. Conversely, 5-HT2C receptor blockade reduced TS-EPSC and miniature EPSC amplitude, as well as input resistance, and hyperpolarized membrane potential. Synaptic parameters in nTS neurons that receive sensory input from carotid body chemoafferents were also attenuated by 5-HT2C receptor blockade. Taken together, these data suggest that 5-HT2C receptors in the nTS are located postsynaptically and augment excitatory neurotransmission.

scholarly journals High glucose increases action potential firing of catecholamine neurons in the nucleus of the solitary tract by increasing spontaneous glutamate inputs

2017 ◽  
Vol 313 (3) ◽  
pp. R229-R239 ◽  
Author(s):  
Brandon L. Roberts ◽  
Mingyan Zhu ◽  
Huan Zhao ◽  
Crystal Dillon ◽  
Suzanne M. Appleyard
Keyword(s):  
Action Potential ◽  
Glucose Concentration ◽  
Glutamate Release ◽  
Cardiovascular Reflexes ◽  
Solitary Tract ◽  
Action Potential Firing ◽  
Nodose Ganglia ◽  
Potential Firing ◽  
Low Glucose ◽  
The Brain

Glucose is a crucial substrate essential for cell survival and function. Changes in glucose levels impact neuronal activity and glucose deprivation increases feeding. Several brain regions have been shown to respond to glucoprivation, including the nucleus of the solitary tract (NTS) in the brain stem. The NTS is the primary site in the brain that receives visceral afferent information from the gastrointestinal tract. The catecholaminergic (CA) subpopulation within the NTS modulates many homeostatic functions including cardiovascular reflexes, respiration, food intake, arousal, and stress. However, it is not known if they respond to changes in glucose. Here we determined whether NTS-CA neurons respond to changes in glucose concentration and the mechanism involved. We found that decreasing glucose concentrations from 5 mM to 2 mM to 1 mM, significantly decreased action potential firing in a cell-attached preparation, whereas increasing it back to 5 mM increased the firing rate. This effect was dependent on glutamate release from afferent terminals and required presynaptic 5-HT3Rs. Decreasing the glucose concentration also decreased both basal and 5-HT3R agonist-induced increase in the frequency of spontaneous glutamate inputs onto NTS-CA neurons. Low glucose also blunted 5-HT-induced inward currents in nodose ganglia neurons, which are the cell bodies of vagal afferents. The effect of low glucose in both nodose ganglia cells and in NTS slices was mimicked by the glucokinase inhibitor glucosamine. This study suggests that NTS-CA neurons are glucosensing through a presynaptic mechanism that is dependent on vagal glutamate release, 5-HT3R activity, and glucokinase.

scholarly journals Glucose prevents the fall in ventromedial hypothalamic GABA that is required for full activation of glucose counterregulatory responses during hypoglycemia

2010 ◽  
Vol 298 (5) ◽  
pp. E971-E977 ◽  
Author(s):  
Wanling Zhu ◽  
Daniel Czyzyk ◽  
Sachin A. Paranjape ◽  
Ligang Zhou ◽  
Adam Horblitt ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Glucose Concentration ◽  
Gaba Release ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Gabaergic Neurons ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
The Brain ◽  
Full Activation

Local delivery of glucose into a critical glucose-sensing region within the brain, the ventromedial hypothalamus (VMH), can suppress glucose counterregulatory responses to systemic hypoglycemia. Here, we investigated whether this suppression was accomplished through changes in GABA output in the VMH. Sprague-Dawley rats had catheters and guide cannulas implanted. Eight to ten days later, microdialysis-microinjection probes were inserted into the VMH, and they were dialyzed with varying concentrations of glucose from 0 to 100 mM. Two groups of rats were microdialyzed with 100 mM glucose and microinjected with either the KATP channel opener diazoxide or a GABAA receptor antagonist. These animals were then subjected to a hyperinsulinemic-hypoglycemic glucose clamp. As expected, perfusion of glucose into the VMH suppressed the counterregulatory responses. Extracellular VMH GABA levels positively correlated with the concentration of glucose in the perfusate. In turn, extracellular GABA concentrations in the VMH were inversely related to the degree of counterregulatory hormone release. Of note, microinjection of either diazoxide or the GABAA receptor antagonist reversed the suppressive effects of VMH glucose delivery on counterregulatory responses. Some GABAergic neurons in the VMH respond to changes in local glucose concentration. Glucose in the VMH dose-dependently stimulates GABA release, and this in turn dose-dependently suppresses the glucagon and epinephrine responses to hypoglycemia. These data suggest that during hypoglycemia a decrease in glucose concentration within the VMH may provide an important signal that rapidly inactivates VMH GABAergic neurons, reducing inhibitory GABAergic tone, which in turn enhances the counterregulatory responses to hypoglycemia.

PKC-mediated toxicity of elevated glucose concentration on cardiomyocyte function

2014 ◽  
Vol 307 (4) ◽  
pp. H587-H597 ◽  
Author(s):  
Mark W. Sims ◽  
James Winter ◽  
Sean Brennan ◽  
Robert I. Norman ◽  
G. André Ng ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Concentration ◽  
Contractile Function ◽  
Blood Glucose Concentration ◽  
Specific Inhibitor ◽  
Wistar Rat ◽  
Patch Clamp Recording ◽  
Electrical Stability ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose

While it is well established that mortality risk after myocardial infarction (MI) increases in proportion to blood glucose concentration at the time of admission, it is unclear whether there is a direct, causal relationship. We investigated potential mechanisms by which increased blood glucose may exert cardiotoxicity. Using a Wistar rat or guinea-pig isolated cardiomyocyte model, we investigated the effects on cardiomyocyte function and electrical stability of alterations in extracellular glucose concentration. Contractile function studies using electric field stimulation (EFS), patch-clamp recording, and Ca2+ imaging were used to determine the effects of increased extracellular glucose concentration on cardiomyocyte function. Increasing glucose from 5 to 20 mM caused prolongation of the action potential and increased both basal Ca2+ and variability of the Ca2+ transient amplitude. Elevated extracellular glucose concentration also attenuated the protection afforded by ischemic preconditioning (IPC), as assessed using a simulated ischemia and reperfusion model. Inhibition of PKCα and β, using Gö6976 or specific inhibitor peptides, attenuated the detrimental effects of glucose and restored the cardioprotected phenotype to IPC cells. Increased glucose concentration did not attenuate the cardioprotective role of PKCε, but rather activation of PKCα and β masked its beneficial effect. Elevated extracellular glucose concentration exerts acute cardiotoxicity mediated via PKCα and β. Inhibition of these PKC isoenzymes abolishes the cardiotoxic effects and restores IPC-mediated cardioprotection. These data support a direct link between hyperglycemia and adverse outcome after MI. Cardiac-specific PKCα and β inhibition may be of clinical benefit in this setting.

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