Microcircuit synchronization and heavy tailed synaptic weight distribution in preBötzinger Complex contribute to generation of breathing rhythm

The preBötzinger Complex, the mammalian inspiratory rhythm generator, encodes inspiratory time as motor pattern. Spike synchronization throughout this sparsely connected network generates inspiratory bursts albeit with variable latencies after preinspiratory activity onset in each breathing cycle. Using preBötC rhythmogenic microcircuit minimal models, we examined the variability in probability and latency to burst, mimicking experiments. Among various physiologically plausible graphs of 1000 point neurons with experimentally determined neuronal and synaptic parameters, directed Erdős-Rényi graphs best captured the experimentally observed dynamics. Mechanistically, preBötC (de)synchronization and oscillatory dynamics are regulated by the efferent connectivity of spiking neurons that gates the amplification of modest preinspiratory activity through input convergence. Furthermore, to replicate experiments, a lognormal distribution of synaptic weights was necessary to augment the efficacy of convergent coincident inputs. These mechanisms enable exceptionally robust yet flexible preBötC attractor dynamics that, we postulate, represent universal temporal-processing and decision-making computational motifs throughout the brain.

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Monosynaptic projections to excitatory and inhibitory preBötzinger Complex neurons

10.1101/694711 ◽

2019 ◽

Cited By ~ 3

Author(s):

Cindy F. Yang ◽

Euiseok J. Kim ◽

Edward M. Callaway ◽

Jack L. Feldman

Keyword(s):

Red Nucleus ◽

Pattern Generator ◽

Solitary Tract ◽

Physiological Control ◽

Bötzinger Complex ◽

Key Driver ◽

Parabrachial Nuclei ◽

Prebotzinger Complex ◽

The Brain ◽

Prebötzinger Complex

AbstractThe key driver of breathing rhythm is the preBötzinger Complex (preBötC) whose activity is modulated by various categorical inputs, e.g., volitional, physiological, emotional. While the preBötC is highly interconnected with other regions of the breathing central pattern generator (bCPG) in the brainstem, there is no data about the direct projections to either excitatory and inhibitory preBötC subpopulations from other elements of the bCPG or from suprapontine regions. Using modified rabies tracing, we identified neurons throughout the brain that send monosynaptic projections to identified excitatory and inhibitory preBötC neurons. Within the brainstem, neurons from sites in the bCPG, including the contralateral preBötC, Bötzinger Complex (BötC), the nucleus of the solitary tract (NTS), parafacial region (pFL/pFV or RTN/pFRG), and parabrachial nuclei, send direct projections to both excitatory and inhibitory preBötC neurons. Suprapontine inputs to the excitatory and inhibitory preBötC neurons include the superior colliculus, red nucleus, amygdala, hypothalamus, and cortex; these projections represent potential direct pathways for volitional, emotional, and physiological control of breathing.

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II. Excitatory amino acid receptors in the brain-gut axis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.280.6.g1055 ◽

2001 ◽

Vol 280 (6) ◽

pp. G1055-G1060 ◽

Cited By ~ 54

Author(s):

Pamela J. Hornby

Keyword(s):

Metabotropic Glutamate Receptors ◽

Excitatory Amino Acid ◽

Motor Pattern ◽

Pattern Generation ◽

Gut Contents ◽

Dorsal Vagal Complex ◽

Gastric Accommodation ◽

Metabotropic Glutamate ◽

Therapeutic Benefits ◽

The Brain

In the last decade, there has been a dramatic increase in academic and pharmaceutical interest in central integration of vago-vagal reflexes controlling the gastrointestinal tract. Associated with this, there have been substantial efforts to determine the receptor-mediated events in the dorsal vagal complex that underlie the physiological responses to distension or variations in the composition of the gut contents. Strong evidence supports the idea that glutamate is a transmitter in afferent vagal fibers conveying information from the gut to the brain, and the implications of this are discussed in this themes article. Furthermore, both ionotropic and metabotropic glutamate receptors mediate pre- and postsynaptic control of glutamate transmission related to several reflexes, including swallowing motor pattern generation, gastric accommodation, and emesis. The emphasis of this themes article is on the potential therapeutic benefits afforded by modulation of these receptors at the site of the dorsal vagal complex.

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ATP sensitivity of preBötzinger complex neurones in neonatal ratin vitro: mechanism underlying a P2 receptor-mediated increase in inspiratory frequency

The Journal of Physiology ◽

10.1113/jphysiol.2007.143024 ◽

2008 ◽

Vol 586 (5) ◽

pp. 1429-1446 ◽

Cited By ~ 30

Author(s):

A. R. Lorier ◽

J. Lipski ◽

G. D. Housley ◽

J. J. Greer ◽

G. D. Funk

Keyword(s):

P2 Receptor ◽

Prebotzinger Complex ◽

Prebötzinger Complex

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Neural mechanisms underlying respiratory regulation within the preBötzinger complex of the rabbit

Respiratory Physiology & Neurobiology ◽

10.1016/j.resp.2021.103736 ◽

2021 ◽

pp. 103736

Author(s):

Elenia Cinelli ◽

Donatella Mutolo ◽

Tito Pantaleo ◽

Fulvia Bongianni

Keyword(s):

Neural Mechanisms ◽

Respiratory Regulation ◽

Prebotzinger Complex ◽

Prebötzinger Complex

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Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons

Nature Neuroscience ◽

10.1038/nn0901-927 ◽

2001 ◽

Vol 4 (9) ◽

pp. 927-930 ◽

Cited By ~ 344

Author(s):

Paul A. Gray ◽

Wiktor A. Janczewski ◽

Nicholas Mellen ◽

Donald R. McCrimmon ◽

Jack L. Feldman

Keyword(s):

Neurokinin 1 Receptor ◽

Normal Breathing ◽

Neurokinin 1 ◽

Prebotzinger Complex ◽

Prebötzinger Complex

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cAMP‐dependent modulation of I h underlies the P2Y 1 receptor‐mediated excitation of the preBötzinger Complex inspiratory network in vitro

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.551.8 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Yong Zhang ◽

Vivian Biancardi ◽

Ana Miranda Tapia ◽

Toka Abu Jaib ◽

Alexander Gourine ◽

...

Keyword(s):

Prebotzinger Complex ◽

Prebötzinger Complex

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Mechanisms Underlying Regulation of Respiratory Pattern by Nicotine in PreBötzinger Complex

Journal of Neurophysiology ◽

10.1152/jn.2001.85.6.2461 ◽

2001 ◽

Vol 85 (6) ◽

pp. 2461-2467 ◽

Cited By ~ 56

Author(s):

Xuesi M. Shao ◽

Jack L. Feldman

Keyword(s):

Respiratory Frequency ◽

Neonatal Rat ◽

Respiratory Pattern ◽

Dependent Manner ◽

Baseline Noise ◽

Arterial Blood ◽

Inspiratory Neurons ◽

Excitatory Neurotransmission ◽

Prebotzinger Complex ◽

Prebötzinger Complex

Cholinergic neurotransmission plays a role in regulation of respiratory pattern. Nicotine from cigarette smoke affects respiration and is a risk factor for sudden infant death syndrome (SIDS) and sleep-disordered breathing. The cellular and synaptic mechanisms underlying this regulation are not understood. Using a medullary slice preparation from neonatal rat that contains the preBötzinger Complex (preBötC), the hypothesized site for respiratory rhythm generation, and generates respiratory-related rhythm in vitro, we examined the effects of nicotine on excitatory neurotransmission affecting inspiratory neurons in preBötC and on the respiratory-related motor activity from hypoglossal nerve (XIIn). Microinjection of nicotine into preBötC increased respiratory frequency and decreased the amplitude of inspiratory bursts, whereas when injected into XII nucleus induced a tonic activity and an increase in amplitude but not in frequency of inspiratory bursts from XIIn. Bath application of nicotine (0.2–0.5 μM, approximately the arterial blood nicotine concentration immediately after smoking a cigarette) increased respiratory frequency up to 280% of control in a concentration-dependent manner. Nicotine decreased the amplitude to 82% and increased the duration to 124% of XIIn inspiratory bursts. In voltage-clamped preBötC inspiratory neurons (including neurons with pacemaker properties), nicotine induced a tonic inward current of −19.4 ± 13.4 pA associated with an increase in baseline noise. Spontaneous excitatory postsynaptic currents (sEPSCs) present during the expiratory period increased in frequency to 176% and in amplitude to 117% of control values; the phasic inspiratory drive inward currents decreased in amplitude to 66% and in duration to 89% of control values. The effects of nicotine were blocked by mecamylamine (Meca). The inspiratory drive current and sEPSCs were completely eliminated by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the presence or absence of nicotine. In the presence of tetrodotoxin (TTX), low concentrations of nicotine did not induce any tonic current or any increase in baseline noise, nor affect the input resistance in inspiratory neurons. In this study, we demonstrated that nicotine increased respiratory frequency and regulated respiratory pattern by modulating the excitatory neurotransmission in preBötC. Activation of nicotinic acetylcholine receptors (nAChRs) enhanced the tonic excitatory synaptic input to inspiratory neurons including pacemaker neurons and at the same time, inhibited the phasic excitatory coupling between these neurons. These mechanisms may account for the cholinergic regulation of respiratory frequency and pattern.

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Flexible categorization in perceptual decision making

10.1101/2020.05.23.110460 ◽

2020 ◽

Cited By ~ 2

Author(s):

Genís Prat-Ortega ◽

Klaus Wimmer ◽

Alex Roxin ◽

Jaime de la Rocha

Keyword(s):

Decision Making ◽

Large Body ◽

Network Models ◽

Perceptual Decision Making ◽

Drift Diffusion ◽

Perceptual Decision ◽

Attractor Dynamics ◽

Attractor Model ◽

Winner Take All ◽

The Brain

AbstractPerceptual decisions require the brain to make categorical choices based on accumulated sensory evidence. The underlying computations have been studied using either phenomenological drift diffusion models or neurobiological network models exhibiting winner-take-all attractor dynamics. Although both classes of models can account for a large body of experimental data, it remains unclear to what extent their dynamics are qualitatively equivalent. Here we show that, unlike the drift diffusion model, the attractor model can operate in different integration regimes: an increase in the stimulus fluctuations or the stimulus duration promotes transitions between decision-states leading to a crossover between weighting mostly early evidence (primacy regime) to weighting late evidence (recency regime). Between these two limiting cases, we found a novel regime, which we name flexible categorization, in which fluctuations are strong enough to reverse initial categorizations, but only if they are incorrect. This asymmetry in the reversing probability results in a non-monotonic psychometric curve, a novel and distinctive feature of the attractor model. Finally, we show psychophysical evidence for the crossover between integration regimes predicted by the attractor model and for the relevance of this new regime. Our findings point to correcting transitions as an important yet overlooked feature of perceptual decision making.

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