Mechanisms of Left-Right Coordination in Mammalian Locomotor Pattern Generation Circuits: A Mathematical Modeling View

The locomotor gait in limbed animals is defined by the left-right leg coordination and locomotor speed. Coordination between left and right neural activities in the spinal cord controlling left and right legs is provided by commissural interneurons (CINs). Several CIN types have been genetically identified, including the excitatory V3 and excitatory and inhibitory V0 types. Recent studies demonstrated that genetic elimination of all V0 CINs caused switching from a normal left-right alternating activity to a left-right synchronized “hopping” pattern. Furthermore, ablation of only the inhibitory V0 CINs (V0D subtype) resulted in a lack of left-right alternation at low locomotor frequencies and retaining this alternation at high frequencies, whereas selective ablation of the excitatory V0 neurons (V0V subtype) maintained the left–right alternation at low frequencies and switched to a hopping pattern at high frequencies. To analyze these findings, we developed a simplified mathematical model of neural circuits consisting of four pacemaker neurons representing left and right, flexor and extensor rhythm-generating centers interacting via commissural pathways representing V3, V0D, and V0V CINs. The locomotor frequency was controlled by a parameter defining the excitation of neurons and commissural pathways mimicking the effects of N-methyl-D-aspartate on locomotor frequency in isolated rodent spinal cord preparations. The model demonstrated a typical left-right alternating pattern under control conditions, switching to a hopping activity at any frequency after removing both V0 connections, a synchronized pattern at low frequencies with alternation at high frequencies after removing only V0D connections, and an alternating pattern at low frequencies with hopping at high frequencies after removing only V0V connections. We used bifurcation theory and fast-slow decomposition methods to analyze network behavior in the above regimes and transitions between them. The model reproduced, and suggested explanation for, a series of experimental phenomena and generated predictions available for experimental testing

Activity-Dependent Changes in Extracellular Ca2+ and K+ Reveal Pacemakers in the Spinal Locomotor-Related Network

SummaryChanges in the extracellular ionic concentrations occur as a natural consequence of firing activity in large populations of neurons. The extent to which these changes alter the properties of individual neurons and the operation of neuronal networks remains unknown. Here, we show that the locomotor-like activity in the isolated neonatal rodent spinal cord reduces the extracellular calcium ([Ca2+]o) to 0.9 mM and increases the extracellular potassium ([K+]o) to 6 mM. Such changes in [Ca2+]o and [K+]o trigger pacemaker activities in interneurons considered to be part of the locomotor network. Experimental data and a modeling study show that the emergence of pacemaker properties critically involves a [Ca2+]o-dependent activation of the persistent sodium current (INaP). These results support a concept for locomotor rhythm generation in which INaP-dependent pacemaker properties in spinal interneurons are switched on and tuned by activity-dependent changes in [Ca2+]o and [K+]o

Chemoreception and neuroplasticity in respiratory circuits

The respiratory central pattern generator must respond to chemosensory cues to maintain oxygen (O2) and carbon dioxide (CO2) homeostasis in the blood and tissues. To do this, sensorial cells located in the periphery and central nervous system monitor the arterial partial pressure of O2 and CO2 and initiate respiratory and autonomic reflex adjustments in conditions of hypoxia and hypercapnia. In conditions of chronic intermittent hypoxia (CIH), repeated peripheral chemoreceptor input mediated by the nucleus of the solitary tract induces plastic changes in respiratory circuits that alter baseline respiratory and sympathetic motor outputs and result in chemoreflex sensitization, active expiration, and arterial hypertension. Herein, we explored the hypothesis that the CIH-induced neuroplasticity primarily consists of increased excitability of pre-inspiratory/inspiratory neurons in the pre-Bötzinger complex. To evaluate this hypothesis and elucidate neural mechanisms for the emergence of active expiration and sympathetic overactivity in CIH-treated animals, we extended a previously developed computational model of the brainstem respiratory-sympathetic network to reproduce experimental data on peripheral and central chemoreflexes post-CIH. The model incorporated neuronal connections between the 2nd-order NTS neurons and peripheral chemoreceptors afferents, the respiratory pattern generator, and sympathetic neurons in the rostral ventrolateral medulla in order to capture key features of sympathetic and respiratory responses to peripheral chemoreflex stimulation. Our model identifies the potential neuronal groups recruited during peripheral chemoreflex stimulation that may be required for the development of inspiratory, expiratory and sympathetic reflex responses. Moreover, our model predicts that pre-inspiratory neurons in the pre-Bötzinger complex experience plasticity of channel expression due to excessive excitation during peripheral chemoreflex. Simulations also show that, due to positive interactions between pre-inspiratory neurons in the pre-Bötzinger complex and expiratory neurons in the retrotrapezoid nucleus, increased excitability of the former may lead to the emergence of the active expiratory pattern at normal CO2 levels found after CIH exposure. We conclude that neuronal type specific neuroplasticity in the pre-Bötzinger complex induced by repetitive episodes of peripheral chemoreceptor activation by hypoxia may contribute to the development of sympathetic over-activity and hypertension

An integrated neuromechanical model of the mouse to study neural control of locomotion

The 11th International Symposium on Adaptive Motion of Animals and Machines. Kobe University, Japan. 2023-06-06/09. Adaptive Motion of Animals and Machines Organizing Committee.Poster Session P7

Comparative investigation of control mechanisms for turning during quadrupedal robot locomotion

The 11th International Symposium on Adaptive Motion of Animals and Machines. Kobe University, Japan. 2023-06-06/09. Adaptive Motion of Animals and Machines Organizing Committee.Poster Session P

The Functional Role of Striatal Cholinergic Interneurons in Reinforcement Learning From Computational Perspective

In this study, we explore the functional role of striatal cholinergic interneurons, hereinafter referred to as tonically active neurons (TANs), via computational modeling; specifically, we investigate the mechanistic relationship between TAN activity and dopamine variations and how changes in this relationship affect reinforcement learning in the striatum. TANs pause their tonic firing activity after excitatory stimuli from thalamic and cortical neurons in response to a sensory event or reward information. During the pause striatal dopamine concentration excursions are observed. However, functional interactions between the TAN pause and striatal dopamine release are poorly understood. Here we propose a TAN activity-dopamine relationship model and demonstrate that the TAN pause is likely a time window to gate phasic dopamine release and dopamine variations reciprocally modulate the TAN pause duration. Furthermore, this model is integrated into our previously published model of reward-based motor adaptation to demonstrate how phasic dopamine release is gated by the TAN pause to deliver reward information for reinforcement learning in a timely manner. We also show how TAN-dopamine interactions are affected by striatal dopamine deficiency to produce poor performance of motor adaptation

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong