GABAergic effects on respiratory neuronal discharge during opossum development

1993 ◽  
Vol 264 (2) ◽  
pp. R331-R336
Author(s):  
J. P. Farber
Keyword(s):  
Gabaa Receptors ◽  
Breathing Pattern ◽  
Age Groups ◽  
Neuronal Firing ◽  
Respiratory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Firing Rates ◽  
Medullary Respiratory Neurons ◽  
Expiratory Neurons ◽  
Gabaa Antagonist

Changes in breathing pattern between immature and adult animals could be due in part to changing postsynaptic sensitivity to particular neurotransmitters by respiratory neurons and/or to the fate of these neurotransmitters after release. To probe for such effects, gamma-aminobutyric acid (GABA) and the GABAA antagonist, bicuculline, were pressure injected by micropipette in very small volumes (approximately 25 pl) near identified medullary respiratory neurons in Inactin-anesthetized adult and suckling opossums. At a concentration of 10 mM, GABA induced suppression of respiratory neurons firing in animals from about 3 wk of age (the youngest animals tested) onward, with the largest responses occurring in adults. For those age groups tested with 0.5 and 50 mM GABA, shorter and longer responses, respectively, were observed. Bicuculline increased the discharge of respiratory units at all ages tested, but responses normalized to initial firing rates did not systematically differ between sucklings down to 4 wk of age and adults. Bicuculline also influenced the onset and cessation of firing in both inspiratory and expiratory neurons. Discharge of respiratory neurons in immature suckling opossums is characterized by few spikes and low firing rates with each breath. However, recovery of neuronal firing from an exogenous load of GABA and release of neuronal firing after antagonism of GABAA receptors does not show a developmental pattern that would implicate GABA as the crucial mediator of these effects.

Functional associations among simultaneously monitored lateral medullary respiratory neurons in the cat. II. Evidence for inhibitory actions of expiratory neurons

1987 ◽  
Vol 57 (4) ◽  
pp. 1101-1117 ◽  
Author(s):  
B. G. Lindsey ◽  
L. S. Segers ◽  
R. Shannon
Keyword(s):  
Discharge Rate ◽  
Respiratory Neurons ◽  
Short Time Scale ◽  
Axonal Projections ◽  
Medullary Respiratory Neurons ◽  
Antidromic Stimulation ◽  
Expiratory Neurons ◽  
Short Time ◽  
And Control ◽  
The Brain

Arrays of extracellular electrodes were used to monitor simultaneously several (2-8) respiratory neurons in the lateral medulla of anesthetized, paralyzed, bilaterally vagotomized, artificially ventilated cats. Efferent phrenic nerve activity was also recorded. The average discharge rate as a function of time in the respiratory cycle was determined for each neuron. Most cells were tested for spinal or vagal axonal projections using antidromic stimulation methods. Cross-correlational methods were used to analyze spike trains of 480 cell pairs. Each pair included at least one neuron most active during the expiratory phase. All simultaneously recorded neurons were located in the same side of the brain stem. Twenty-six percent (33/129) of the expiratory (E) neuron pairs exhibited short time scale correlations indicative of paucisynaptic interactions or shared inputs, whereas 8% (27/351) of the pairs consisting of an E neuron and an inspiratory (I) cell were similarly correlated. Evidence for several inhibitory actions of E neurons was found: 1) inhibition of I neurons by E neurons with both decrementing (DEC) and augmenting (AUG) firing patterns; 2) inhibition of E-DEC and E-AUG neurons by E-DEC cells; 3) inhibition of E-DEC and E-AUG neurons by E-AUG neurons; and 4) inhibition of E-DEC neurons by tonic I-E phase-spanning cells. Because several cells were recorded simultaneously, direct evidence for concurrent parallel and serial inhibitory processes was also obtained. The results suggest and support several hypotheses for mechanisms that may help to generate and control the pattern and coordination of respiratory motoneuron activities.

Differing activities of medullary respiratory neurons in eupnea and gasping

1991 ◽  
Vol 70 (3) ◽  
pp. 1265-1270 ◽  
Author(s):  
D. Zhou ◽  
M. J. Wasicko ◽  
J. M. Hu ◽  
W. M. St John
Keyword(s):  
Carbon Monoxide ◽  
Brain Stem ◽  
Phrenic Nerve ◽  
Peak Discharge ◽  
Discharge Frequency ◽  
Respiratory Neurons ◽  
Ventilatory Pattern ◽  
Medullary Respiratory Neurons ◽  
Inspiratory Neurons ◽  
Expiratory Neurons

Our purpose was to compare further eupneic ventilatory activity with that of gasping. Decerebrate, paralyzed, and ventilated cats were used; the vagi were sectioned within the thorax caudal to the laryngeal branches. Activities of the phrenic nerve and medullary respiratory neurons were recorded. Antidromic invasion was used to define bulbospinal, laryngeal, or not antidromically activated units. The ventilatory pattern was reversibly altered to gasping by exposure to 1% carbon monoxide in air. In eupnea, activities of inspiratory neurons commenced at various times during inspiration, and for most the discharge frequency gradually increased. In gasping, the peak discharge frequency of inspiratory neurons was unaltered. However, all commenced activities at the start of the phrenic burst and reached peak discharge almost immediately. The discharge frequencies of all groups of expiratory neurons fell in gasping, with many neurons ceasing activity entirely. These data are consistent with the hypothesis that brain stem mechanisms controlling eupnea and gasping differ fundamentally.

Effects on breathing of medullary bicuculline microinjections in immature opossums

1995 ◽  
Vol 269 (6) ◽  
pp. R1295-R1300
Author(s):  
J. P. Farber
Keyword(s):  
Breathing Pattern ◽  
Receptor Activation ◽  
Didelphis Virginiana ◽  
Peak Amplitude ◽  
Ventrolateral Medulla ◽  
Blue Dye ◽  
Gamma Aminobutyric Acid ◽  
Glass Micropipette ◽  
Gabaa Antagonist

The role of medullary gamma-aminobutyric acid A (GABAA)-receptor activation in the expression of breathing was studied in suckling opossums (Didelphis virginiana) from 4 to 8 wk of age. Animals were anesthetized with a thiobarbiturate, and the ventral medulla was exposed so that drugs could be microinjected into the medulla with a two-barrel glass micropipette. The GABAA antagonist bicuculline at approximately 1-3 pmol total dose was injected in volumes < 1 nl; injections of saline with pontamine sky blue dye were used as controls and to mark location. Breathing pattern was assessed using diaphragm electromyography (EMG). Effective sites for bicuculline microinjection were obtained in the ventrolateral medulla, with both lateral reticular and inferior olive nuclei present as rostrocaudal markers. Responses among 18 tested animals included increased duration of breaths (Ttot) and duration of inspiration (Ti). Peak amplitude of the diaphragm EMG and peak amplitude of the diaphragm/Ti were not consistently affected. Transient apnea, lasting at least 8 s, occurred in five of the animals. Control solutions did not elicit respiratory responses. These results suggest that neural circuitry in the medulla, using the neurotransmitter GABA, can have an early role in the modulation of breathing pattern.

Respiratory muscle control during vomiting

1990 ◽  
Vol 68 (2) ◽  
pp. 237-241 ◽  
Author(s):  
Alan D. Miller
Keyword(s):  
Response Pattern ◽  
Respiratory Muscles ◽  
Respiratory Neurons ◽  
Abdominal Muscles ◽  
Inspiratory Muscles ◽  
Medullary Respiratory Neurons ◽  
Gastric Contents ◽  
Expiratory Neurons ◽  
Expiratory Muscles ◽  
Thoracic And Abdominal

The changes in thoracic and abdominal pressures that generate vomiting are produced by coordinated action of the major respiratory muscles. During vomiting, the diaphragm and external intercostal (inspiratory) muscles co-contract with abdominal (expiratory) muscles in a series of bursts of activity that culminates in expulsion. Internal intercostal (expiratory) muscles contract out of phase with these muscles during retching and are inactive during expulsion. The periesophageal portion of the diaphragm relaxes during expulsion, presumably facilitating rostral movement of gastric contents. Recent studies have begun to examine to what extent medullary respiratory neurons are involved in the control of these muscles during vomiting. Bulbospinal expiratory neurons in the ventral respiratory group caudal to the obex discharge at the appropriate time during (fictive) vomiting to activate either abdominal or internal intercostal motoneurons. The pathways that drive phrenic and external intercostal motoneurons during vomiting have yet to be identified. Most bulbospinal inspiratory neurons in the dorsal and ventral respiratory groups do not have the appropriate response pattern to initiate activation of these motoneurons during (fictive) vomiting. Relaxation of the periesophageal diaphragm during vomiting could be brought about, at least in part, by reduced firing of bulbospinal inspiratory neurons.Key words: brain stem, bulbospinal respiratory neurons, vomiting center critique, diaphragm, abdominal muscles.

Maximum discharge rates of respiratory neurons during opossum development

1993 ◽  
Vol 75 (5) ◽  
pp. 2040-2044 ◽  
Author(s):  
J. P. Farber
Keyword(s):  
Action Potentials ◽  
Firing Frequency ◽  
Neuronal Firing ◽  
Didelphis Virginiana ◽  
Respiratory Neurons ◽  
Postnatal Life ◽  
Low Frequencies ◽  
Medullary Respiratory Neurons ◽  
Discharge Rates ◽  
Before And After

The observed low frequencies of action potentials observed in medullary respiratory neurons of immature opossums (Didelphis virginiana) could occur because these cells are incapable of achieving higher sustained firing rates. Nonsustainability of firing might also help explain why the inspired breath is brief (approximately 0.1 s) in the youngest opossums and rises very slowly during postnatal life. Firing frequencies of medullary respiratory neurons were examined in spontaneously breathing thiobarbiturate-anesthetized opossums before and after stimulation by the glutamate agonists, N-methyl-D-aspartate (NMDA; 20 mM) or kainic acid (KA; 0.5 mM). Drugs were applied using progressively larger pressure injections through a micropipette; animals were tested from the 5th postnatal wk to adulthood. With a sufficient injection volume, stimulation of cell firing would be followed by apparent suppression of action potentials. A maximum "sustained" firing frequency was obtained from the last injection where discharge remained elevated for at least 0.5 s. Inspiratory and expiratory neurons tested with either drug showed the lowest rates of firing in opossums at 5–9 wk of age compared with 10- to 14-wk-old animals and/or adults. Despite higher rates of discharge in 10- to 14-wk-old animals and/or adults, maximum sustained neuronal firing in the youngest animals was at a higher frequency than during spontaneous breathing and, at least in the cell population tested, does not represent a limitation that might affect breathing pattern.

scholarly journals A deep convolutional visual encoding model of neuronal responses in the LGN

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Eslam Mounier ◽  
Bassem Abdullah ◽  
Hani Mahdi ◽  
Seif Eldawlatly
Keyword(s):  
Firing Rate ◽  
Visual Information ◽  
Visual Stimulation ◽  
Neuronal Population ◽  
Neuronal Firing ◽  
Electrode Arrays ◽  
Deep Convolutional Neural Networks ◽  
Firing Rates ◽  
Spatiotemporal Representation

AbstractThe Lateral Geniculate Nucleus (LGN) represents one of the major processing sites along the visual pathway. Despite its crucial role in processing visual information and its utility as one target for recently developed visual prostheses, it is much less studied compared to the retina and the visual cortex. In this paper, we introduce a deep learning encoder to predict LGN neuronal firing in response to different visual stimulation patterns. The encoder comprises a deep Convolutional Neural Network (CNN) that incorporates visual stimulus spatiotemporal representation in addition to LGN neuronal firing history to predict the response of LGN neurons. Extracellular activity was recorded in vivo using multi-electrode arrays from single units in the LGN in 12 anesthetized rats with a total neuronal population of 150 units. Neural activity was recorded in response to single-pixel, checkerboard and geometrical shapes visual stimulation patterns. Extracted firing rates and the corresponding stimulation patterns were used to train the model. The performance of the model was assessed using different testing data sets and different firing rate windows. An overall mean correlation coefficient between the actual and the predicted firing rates of 0.57 and 0.7 was achieved for the 10 ms and the 50 ms firing rate windows, respectively. Results demonstrate that the model is robust to variability in the spatiotemporal properties of the recorded neurons outperforming other examined models including the state-of-the-art Generalized Linear Model (GLM). The results indicate the potential of deep convolutional neural networks as viable models of LGN firing.

scholarly journals The Dual Role of the GABAA Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats

2021 ◽  
Vol 22 (13) ◽  
pp. 6772
Author(s):  
Michele Malaguarnera ◽  
Tiziano Balzano ◽  
Mari Carmen Castro ◽  
Marta Llansola ◽  
Vicente Felipo
Keyword(s):  
Gabaa Receptors ◽  
Motor Impairment ◽  
Minimal Hepatic Encephalopathy ◽  
Peripheral Inflammation ◽  
Membrane Expression ◽  
Gabaergic Neurotransmission ◽  
Gaba Transporters ◽  
Suitable Target ◽  
Gabaa Antagonist

Cognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonemia induces neuroinflammation remain unknown. We hypothesized that GABAA receptors can modulate cerebellar neuroinflammation. The GABAA antagonist bicuculline was administrated daily (i.p.) for four weeks in control and hyperammonemic rats. Its effects on peripheral inflammation and on neuroinflammation as well as glutamate and GABA neurotransmission in the cerebellum were assessed. In hyperammonemic rats, bicuculline decreases IL-6 and TNFα and increases IL-10 in the plasma, reduces astrocyte activation, induces the microglia M2 phenotype, and reduces IL-1β and TNFα in the cerebellum. However, in control rats, bicuculline increases IL-6 and decreases IL-10 plasma levels and induces microglial activation. Bicuculline restores the membrane expression of some glutamate and GABA transporters restoring the extracellular levels of GABA in hyperammonemic rats. Blocking GABAA receptors improves peripheral inflammation and cerebellar neuroinflammation, restoring neurotransmission in hyperammonemic rats, whereas it induces inflammation and neuroinflammation in controls. This suggests a complex interaction between GABAergic and immune systems. The modulation of GABAA receptors could be a suitable target for improving neuroinflammation in MHE.

scholarly journals An association study in the Taiwan Biobank elicits the GABAA receptor genes GABRB3, GABRA5, and GABRG3 as candidate loci for sleep duration in the Taiwanese population

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sheue-Jane Hou ◽  
Shih-Jen Tsai ◽  
Po-Hsiu Kuo ◽  
Wan-Yu Lin ◽  
Yu-Li Liu ◽  
...  
Keyword(s):  
Sleep Quality ◽  
Association Study ◽  
Gabaa Receptor ◽  
Sleep Duration ◽  
Gabaa Receptors ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Bonferroni Correction ◽  
Taiwanese Population ◽  
Sleep Timing

Abstract Background Gamma-aminobutyric acid type A (GABAA) receptors mainly mediate the effects of gamma-aminobutyric acid, which is the primary inhibitory neurotransmitter in the central nervous system. Abundant evidence suggests that GABAA receptors play a key role in sleep-regulating processes. No genetic association study has explored the relationships between GABAA receptor genes and sleep duration, sleep quality, and sleep timing in humans. Methods We determined the association between single-nucleotide polymorphisms (SNPs) in the GABAA receptor genes GABRA1, GABRA2, GABRB3, GABRA5, and GABRG3 and sleep duration, sleep quality, and sleep timing in the Taiwan Biobank with a sample of 10,127 Taiwanese subjects. There were 10,142 subjects in the original study cohort. We excluded 15 subjects with a medication history of sedative-hypnotics. Results Our data revealed an association of the GABRB3-GABRA5-GABRG3 gene cluster with sleep duration, which has not been previously identified: rs79333046 (beta = − 0.07; P = 1.21 × 10–3) in GABRB3, rs189790076 (beta = 0.92; P = 1.04 × 10–3) in GABRA5, and rs147619342 (beta = − 0.72; P = 3.97 × 10–3) in GABRG3. The association between rs189790076 in GABRA5 and sleep duration remained significant after Bonferroni correction. A variant (rs12438141) in GABRB3 was also found to act as a potential expression quantitative trait locus. Additionally, we discovered interactions between variants in the GABRB3-GABRA5-GABRG3 gene cluster and lifestyle factors, such as tea and coffee consumption, smoking, and physical activity, that influenced sleep duration, although some interactions became nonsignificant after Bonferroni correction. We also found interactions among GABRB3, GABRA5, and GABRG3 that affected sleep duration. Furthermore, we identified an association of rs7165524 (beta = − 0.06; P = 2.20 × 10–3) in GABRA5 with sleep quality and an association of rs79465949 (beta = − 0.12; P = 3.95 × 10–3) in GABRB3 with sleep timing, although these associations became nonsignificant after Bonferroni correction. However, we detected no evidence of an association of individual SNPs in GABRA1 and GABRA2. Conclusions Our results indicate that rs189790076 in GABRA5 and gene–gene interactions among GABRB3, GABRA5, and GABRG3 may contribute to sleep duration in the Taiwanese population.

Classic Benzodiazepines Modulate the Open–Close Equilibrium in α1β2γ2Lγ-Aminobutyric Acid Type A Receptors

2005 ◽  
Vol 102 (4) ◽  
pp. 783-792 ◽  
Author(s):  
Dirk Rüsch ◽  
Stuart A. Forman
Keyword(s):  
Gabaa Receptors ◽  
Sulfonic Acid ◽  
Site Occupancy ◽  
Type A ◽  
Aminobutyric Acid ◽  
Clinical Effects ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Acid Type ◽  
Benzodiazepine Site

Background Classic benzodiazepine agonists induce their clinical effects by binding to a site on gamma-aminobutyric acid type A (GABAA) receptors and enhancing receptor activity. There are conflicting data regarding whether the benzodiazepine site is allosterically coupled to gamma-aminobutyric acid binding versus the channel open-close (gating) equilibrium. The authors tested the hypothesis that benzodiazepine site ligands modulate alpha1beta2gamma2L GABAA receptor gating both in the absence of orthosteric agonists and when the orthosteric sites are occupied. Methods GABAA receptors were recombinantly expressed in Xenopus oocytes and studied using two-microelectrode voltage clamp electrophysiology. To test gating effects in the absence of orthosteric agonist, the authors used spontaneously active GABAA receptors containing a leucine-to-threonine mutation at residue 264 on the alpha1 subunit. To examine effects on gating when orthosteric sites were fully occupied, they activated wild-type receptors with high concentrations of a partial agonist, piperidine-4-sulfonic acid. Results In the absence of orthosteric agonists, the channel activity of alpha1L264Tbeta2gamma2L receptors was increased by diazepam and midazolam and reduced by the inverse benzodiazepine agonist FG7142. Flumazenil displayed very weak agonism and blocked midazolam from further activating mutant channels. In wild-type receptors activated with saturating concentrations of piperidine-4-sulfonic acid, midazolam increased maximal efficacy. Conclusions Independent of orthosteric site occupancy, classic benzodiazepines modulate the gating equilibrium in alpha1beta2gamma2L GABAA receptors and are therefore allosteric coagonists. A Monod-Wyman-Changeux coagonist gating model quantitatively predicts these effects, suggesting that benzodiazepines minimally alter orthosteric ligand binding.

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