Dynamics Analysis of Firing Patterns in Pre-Botzinger Complex Neurons Model.
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ABSTRACT:
SUBMITTER: Yuan Q
PROVIDER: S-EPMC8239244 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Identification of two markers of neurons in the pre-Bötzinger complex (pre-BötC), the neurokinin 1 receptor (NK1R) and somatostatin (Sst) peptide, has been of great utility in understanding the essential role of the pre-BötC in breathing. Recently, the transcription factor dbx1 was identified as a critical, but transient, determinant of glutamatergic pre-BötC neurons. Here, to identify additional markers, we constructed and screened a single-cell subtractive cDNA library from pre-BötC inspiratory neurons. We identified the glycoprotein reelin as a potentially useful marker, because it is expressed in distinct populations of pre-BötC and inspiratory bulbospinal ventral respiratory group (ibsVRG) neurons. Reelin ibsVRG neurons were larger (27.1 ± 3.8 μm in diameter) and located more caudally (>12.8 mm caudal to Bregma) than reelin pre-BötC neurons (15.5 ± 2.4 μm in diameter, <12.8 mm rostral to Bregma). Pre-BötC reelin neurons coexpress NK1R and Sst. Reelin neurons were also found in the parahypoglossal and dorsal parafacial regions, pontine respiratory group, and ventromedial medulla. Reelin-deficient (Reeler) mice exhibited impaired respones to hypoxia compared with littermate controls. We suggest that reelin is a useful molecular marker for pre-BötC neurons in adult rodents and may play a functional role in pre-BötC microcircuits.
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Project description:The response of a neuronal population over a space of inputs depends on the intrinsic properties of its constituent neurons. Two main modes of single neuron dynamics-integration and resonance-have been distinguished. While resonator cell types exist in a variety of brain areas, few models incorporate this feature and fewer have investigated its effects. To understand better how a resonator's frequency preference emerges from its intrinsic dynamics and contributes to its local area's population firing rate dynamics, we analyze the dynamic gain of an analytically solvable two-degree of freedom neuron model. In the Fokker-Planck approach, the dynamic gain is intractable. The alternative Gauss-Rice approach lifts the resetting of the voltage after a spike. This allows us to derive a complete expression for the dynamic gain of a resonator neuron model in terms of a cascade of filters on the input. We find six distinct response types and use them to fully characterize the routes to resonance across all values of the relevant timescales. We find that resonance arises primarily due to slow adaptation with an intrinsic frequency acting to sharpen and adjust the location of the resonant peak. We determine the parameter regions for the existence of an intrinsic frequency and for subthreshold and spiking resonance, finding all possible intersections of the three. The expressions and analysis presented here provide an account of how intrinsic neuron dynamics shape dynamic population response properties and can facilitate the construction of an exact theory of correlations and stability of population activity in networks containing populations of resonator neurons.
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Project description:To understand the neural origins of rhythmic behavior one must characterize the central pattern generator circuit and quantify the population size needed to sustain functionality. Breathing-related interneurons of the brainstem pre-Bötzinger complex (preBötC) that putatively comprise the core respiratory rhythm generator in mammals are derived from Dbx1-expressing precursors. Here, we show that selective photonic destruction of Dbx1 preBötC neurons in neonatal mouse slices impairs respiratory rhythm but surprisingly also the magnitude of motor output; respiratory hypoglossal nerve discharge decreased and its frequency steadily diminished until rhythm stopped irreversibly after 85±20 (mean ± SEM) cellular ablations, which corresponds to ?15% of the estimated population. These results demonstrate that a single canonical interneuron class generates respiratory rhythm and contributes in a premotor capacity, whereas these functions are normally attributed to discrete populations. We also establish quantitative cellular parameters that govern network viability, which may have ramifications for respiratory pathology in disease states.
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Project description:RationaleIn adult rats, bilateral ablation of pre-Bötzinger complex (preBötC) neurokinin 1-expressing (NK1R) neurons leads to a progressive and irreversible disruption in breathing pattern, initially during sleep, eventually resulting in an ataxic breathing pattern during wakefulness.ObjectivesHere we determine whether ablation of fewer preBötC NK1R neurons leads to a persistent pattern of disordered breathing during sleep but not during wakefulness.MethodsAdult male Sprague-Dawley rats (n = 12) were instrumented to record diaphragmatic, abdominal, and neck EMG, and EEG. Fourteen days later, a second surgery was performed to stereotaxically microinject into the preBötC on one side the toxin saporin conjugated to substance P (SP-SAP), which selectively ablates NK1R neurons.Measurements and main resultsPostinjection, rats were monitored within a plethysmograph until they were killed (Days 21-51). At Days 6-9 post-unilateral SP-SAP injection, respiratory pattern during sleep, particularly REM sleep, became increasingly disordered, characterized by an increase in frequency of central sleep apnea and hypopneas (36.8 +/- 7.4 episodes/h of REM vs. 6 +/- 2.0 episodes/h in preinjection controls; P < 0.05), whereas breathing during resting wakefulness remained stable. Unlike bilateral SP-SAP-injected rats, an ataxic breathing pattern did not develop during wakefulness. Rats that were monitored up to 51 days post-SP-SAP injection continued to have sleep-disordered breathing; breathing during wakefulness remained relatively stable. Histologic analysis of the ventrolateral medulla confirmed that NK1R neurons within the preBötC on the injected but not on the contralateral side of the medulla were ablated.ConclusionsGradual loss of preBötC NK1R neurons may be an underlying factor of sleep-disordered breathing, in particular of central sleep apnea.
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Project description:Genome stability requires complete DNA duplication exactly once before division. In eukaryotes, cyclin-dependent kinase (CDK) plays a dual role in this regulation by inhibiting helicase loading factors and activating origin firing. CDK drives initiation by phosphorylation of two substrates, Sld2 and Sld3, forming the transient and limiting intermediate called the pre-initiation complex (pre-IC). The importance and mechanism of dissociation of the pre-IC from origins is not understood. Here we show in the budding yeast Saccharomyces cerevisiae that CDK phosphorylations of Sld3 and Sld2 are specifically and rapidly turned-over during interphase by the PP2A and PP4 phosphatases. Inhibition of dephosphorylation of Sld3/Sld2 causes dramatic defects in replication initiation genome-wide, retention of the pre-IC at origins and cell death. These studies not only provide a mechanism to ensure that Sld3/Sld2 are dephosphorylated before helicase loading factors but also establish a novel positive role for phosphatases in eukaryotic origin firing.
2021-11-01 | GSE186490 | GEO
Project description:Inspiratory breathing movements depend on pre-Bötzinger complex (preBötC) interneurons that express calcium (Ca2+)-activated nonselective cationic current (ICAN) to generate robust neural bursts. Hypothesized to be rhythmogenic, reducing ICAN is predicted to slow down or stop breathing; its contributions to motor pattern would be reflected in the magnitude of movements (output). We tested the role(s) of ICAN using reverse genetic techniques to diminish its putative ion channels Trpm4 or Trpc3 in preBötC neurons in vivo. Adult mice transduced with Trpm4-targeted short hairpin RNA (shRNA) progressively decreased the tidal volume of breaths yet surprisingly increased breathing frequency, often followed by gasping and fatal respiratory failure. Mice transduced with Trpc3-targeted shRNA survived with no changes in breathing. Patch-clamp and field recordings from the preBötC in mouse slices also showed an increase in the frequency and a decrease in the magnitude of preBötC neural bursts in the presence of Trpm4 antagonist 9-phenanthrol, whereas the Trpc3 antagonist pyrazole-3 (pyr-3) showed inconsistent effects on magnitude and no effect on frequency. These data suggest that Trpm4 mediates ICAN, whose influence on frequency contradicts a direct role in rhythm generation. We conclude that Trpm4-mediated ICAN is indispensable for motor output but not the rhythmogenic core mechanism of the breathing central pattern generator.
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Project description:The subthalamic nucleus (STN) is an effective therapeutic target for deep brain stimulation (DBS) for Parkinson's disease (PD), and histamine levels are elevated in the basal ganglia in PD patients. However, the effect of endogenous histaminergic modulation on STN neuronal activities and the neuronal mechanism underlying STN-DBS are unknown. Here, we report that STN neuronal firing patterns are more crucial than firing rates for motor control. Histamine excited STN neurons, but paradoxically ameliorated parkinsonian motor deficits, which we attributed to regularizing firing patterns of STN neurons via the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) channel coupled to the H2 receptor. Intriguingly, DBS increased histamine release in the STN and regularized STN neuronal firing patterns under parkinsonian conditions. HCN2 contributed to the DBS-induced regularization of neuronal firing patterns, suppression of excessive ? oscillations, and alleviation of motor deficits in PD. The results reveal an indispensable role for regularizing STN neuronal firing patterns in amelioration of parkinsonian motor dysfunction and a functional compensation for histamine in parkinsonian basal ganglia circuitry. The findings provide insights into mechanisms of STN-DBS as well as potential therapeutic targets and STN-DBS strategies for PD.
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Project description:Introduction:Identifying the potential firing patterns following different brain regions under normal and abnormal conditions increases our understanding of events at the level of neural interactions in the brain. Furthermore, it is important to be capable of modeling the potential neural activities to build precise artificial neural networks. The Izhikevich model is one of the simplest biologically-plausible models, i.e. capable of capturing most recognized firing patterns of neurons. This property makes the model efficient in simulating the large-scale networks of neurons. Improving the Izhikevich model for adapting with the neuronal activity of rat brain with great accuracy would make the model effective for future neural network implementations. Methods:Data sampling from two brain regions, the HIP and BLA, was performed by the extracellular recordings of male Wistar rats, and spike sorting was conducted by Plexon offline sorter. Further analyses were performed through NeuroExplorer and MATLAB. To optimize the Izhikevich model parameters, a genetic algorithm was used. In this algorithm, optimization tools, like crossover and mutation, provide the basis for generating model parameters populations. The process of comparison in each iteration leads to the survival of better populations until achieving the optimum solution. Results:In the present study, the possible firing patterns of the real single neurons of the HIP and BLA were identified. Additionally, an improved Izhikevich model was achieved. Accordingly, the real neuronal spiking pattern of these regions' neurons and the corresponding cases of the Izhikevich neuron spiking pattern were adjusted with great accuracy. Conclusion:This study was conducted to elevate our knowledge of neural interactions in different structures of the brain and accelerate the quality of future large-scale neural networks simulations, as well as reducing the modeling complexity. This aim was achievable by performing the improved Izhikevich model, and inserting only the plausible firing patterns and eliminating unrealistic ones.
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Project description:KEY POINTS:Neurons in the hypothalamus of the brain which secrete the peptide kisspeptin are important regulators of reproduction, and normal reproductive development. Electrical activity, in the form of action potentials, or spikes, leads to secretion of peptides and neurotransmitters, influencing the activity of downstream neurons; in kisspeptin neurons, this activity is highly irregular, but the mechanism of this is not known. In this study, we show that irregularity depends on the presence of a particular type of potassium ion channel in the membrane, which opens transiently in response to electrical excitation. The results contribute to understanding how kisspeptin neurons generate and time their membrane potential spikes, and how reliable this process is. Improved understanding of the activity of kisspeptin neurons, and how it shapes their secretion of peptides, is expected to lead to better treatment for reproductive dysfunction and disorders of reproductive development. ABSTRACT:Kisspeptin neurons in the hypothalamus are critically involved in reproductive function, via their effect on GnRH neuron activity and consequent gonadotropin release. Kisspeptin neurons show an intrinsic irregularity of firing, but the mechanism of this remains unclear. To address this, we carried out targeted whole-cell patch-clamp recordings of kisspeptin neurons in the arcuate nucleus (Kiss1Arc ), in brain slices isolated from adult male Kiss-Cre:tdTomato mice. Cells fired irregularly in response to constant current stimuli, with a wide range of spike time variability, and prominent subthreshold voltage fluctuations. In voltage clamp, both a persistent sodium (NaP) current and a fast transient (A-type) potassium current were apparent, activating at potentials just below the threshold for spiking. These currents have also previously been described in irregular-spiking cortical interneurons, in which the A-type current, mediated by Kv4 channels, interacts with NaP current to generate complex dynamics of the membrane potential, and irregular firing. In Kiss1Arc neurons, A-type current was blocked by phrixotoxin, a specific blocker of Kv4.2/4.3 channels, and consistent expression of Kv4.2 transcripts was detected by single-cell RT-PCR. In addition, firing irregularity was correlated to the density of A-type current in the membrane. Using conductance injection, we demonstrated that adding Kv4-like potassium conductance (gKv4 ) to a cell produces a striking increase in firing irregularity, and excitability is reduced, while subtracting gKv4 has the opposite effects. Thus, we propose that Kv4 interacting dynamically with NaP is a key determinant of the irregular firing behaviour of Kiss1Arc neurons, shaping their physiological function in gonadotropin release.
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Project description:Inspiratory active pre-Bötzinger complex (preBötC) networks produce the neural rhythm that initiates and controls breathing movements. We previously identified the preBötC in the newborn rat brainstem and established anatomically defined transverse slices in which the preBötC remains active when exposed at one surface. This follow-up study uses a neonatal mouse model in which the preBötC as well as a genetically defined class of respiratory interneurons can be identified and selectively targeted for physiological recordings. The population of glutamatergic interneurons whose precursors express the transcription factor Dbx1 putatively comprises the core respiratory rhythmogenic circuit. Here, we used intersectional mouse genetics to identify the brainstem distribution of Dbx1-derived neurons in the context of observable respiratory marker structures. This reference brainstem atlas enabled online histology for generating calibrated sandwich slices to identify the preBötC location, which was heretofore unspecified for perinatal mice. Sensitivity to opioids ensured that slice rhythms originated from preBötC neurons and not parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN) cells because opioids depress preBötC, but not pFRG/RTN rhythms. We found that the preBötC is centered ~0.4 mm caudal to the facial motor nucleus in this Cre/lox reporter mouse during postnatal days 0-4. Our findings provide the essential basis for future optically guided electrophysiological and fluorescence imaging-based studies, as well as the application of other Cre-dependent tools to record or manipulate respiratory rhythmogenic neurons. These resources will ultimately help elucidate the mechanisms that promote respiratory-related oscillations of preBötC Dbx1-derived neurons and thus breathing.
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