The respiratory rhythm and motor pattern are hypothesized to be generated by a brain stem respiratory network with a rhythmogenic core consisting of neural populations interacting within and between the pre-Bötzinger (pre-BötC) and Bötzinger (BötC) complexes and controlled by drives from other brain stem compartments. Our previous large-scale computational model reproduced the behavior of this network under many different conditions but did not consider neural oscillations that were proposed to emerge within the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) and drive preinspiratory (or late-expiratory, late-E) discharges in the abdominal motor output. Here we extend the analysis of our previously published data and consider new data on the generation of abdominal late-E activity as the basis for extending our computational model. The extended model incorporates an additional late-E population in RTN/pFRG, representing a source of late-E oscillatory activity. In the proposed model, under normal metabolic conditions, this RTN/pFRG oscillator is inhibited by BötC/pre-BötC circuits, and the late-E oscillations can be released by either hypercapnia-evoked activation of RTN/pFRG or by hypoxia-dependent suppression of RTN/pFRG inhibition by BötC/pre-BötC. The proposed interactions between BötC/pre-BötC and RTN/pFRG allow the model to reproduce several experimentally observed behaviors, including quantal acceleration of abdominal late-E oscillations with progressive hypercapnia and quantal slowing of phrenic activity with progressive suppression of pre-BötC excitability, as well as to predict a release of late-E oscillations by disinhibition of RTN/pFRG under normal conditions. The extended model proposes mechanistic explanations for the emergence of RTN/pFRG oscillations and their interaction with the brain stem respiratory network.

Molkov YI, Zoccal DB, Moraes DJ, Paton JF, Machado BH, Rybak IA. Intermittent hypoxia-induced sensitization of central chemoreceptors contributes to sympathetic nerve activity during late expiration in rats. J Neurophysiol 105: 3080 -3091, 2011. First published April 6, 2011 doi:10.1152/jn.00070.2011.-Hypertension elicited by chronic intermittent hypoxia (CIH) is associated with elevated activity of the thoracic sympathetic nerve (tSN) that exhibits an enhanced respiratory modulation reflecting a strengthened interaction between respiratory and sympathetic networks within the brain stem. Expiration is a passive process except for special metabolic conditions such as hypercapnia, when it becomes active through phasic excitation of abdominal motor nerves (AbN) in late expiration. An increase in CO 2 evokes late-expiratory (late-E) discharges phase-locked to phrenic bursts with the frequency increasing quantally as hypercapnia increases. In rats exposed to CIH, the late-E discharges synchronized in AbN and tSN emerge in normocapnia. To elucidate the possible neural mechanisms underlying these phenomena, we extended our computational model of the brain stem respiratory network by incorporating a population of presympathetic neurons in the rostral ventrolateral medulla that received inputs from the pons, medullary respiratory compartments, and retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). Our simulations proposed that CIH conditioning increases the CO 2 sensitivity of RTN/pFRG neurons, causing a reduction in both the CO 2 threshold for emerging the late-E activity in AbN and tSN and the hypocapnic threshold for apnea. Using the in situ rat preparation, we have confirmed that CIHconditioned rats under normal conditions exhibit synchronized late-E discharges in AbN and tSN similar to those observed in control rats during hypercapnia. Moreover, the hypocapnic threshold for apnea was significantly lowered in CIH-conditioned rats relative to that in control rats. We conclude that CIH may sensitize central chemoreception and that this significantly contributes to the neural impetus for generation of sympathetic activity and hypertension.

Visual Abstract

It is widely accepted that the basal ganglia (BG) play a key role in action selection and reinforcement learning. However, despite considerable number of studies, the BG architecture and function are not completely understood. Action selection and reinforcement learning are facilitated by the activity of dopaminergic neurons, which encode reward prediction errors when reward outcomes are higher or lower than expected. The BG are thought to select proper motor responses by gating appropriate actions, and suppressing inappropriate ones. The direct striato-nigral (GO) and the indirect striato-pallidal (NOGO) pathways have been suggested to provide the functions of BG in the two-pathway concept. Previous models confirmed the idea that these two pathways can mediate the behavioral choice, but only for a relatively small number of potential behaviors. Recent studies have provided new evidence of BG involvement in motor adaptation tasks, in which adaptation occurs in a non-error-based manner. In such tasks, there is a continuum of possible actions, each represented by a complex neuronal activity pattern. We extended the classical concept of the two-pathway BG by creating a model of BG interacting with a movement execution system, which allows for an arbitrary number of possible actions. The model includes sensory and premotor cortices, BG, a spinal cord network, and a virtual mechanical arm performing 2D reaching movements. The arm is composed of 2 joints (shoulder and elbow) controlled by 6 muscles (4 mono-articular and 2 bi-articular). The spinal cord network contains motoneurons, controlling the muscles, and sensory interneurons that receive afferent feedback and mediate basic reflexes. Given a specific goal-oriented motor task, the BG network through reinforcement learning constructs a behavior from an arbitrary number of basic actions represented by cortical activity patterns. Our study confirms that, with slight modifications, the classical two-pathway BG concept is consistent with results of previous studies, including non-error based motor adaptation experiments, pharmacological manipulations with BG nuclei, and functional deficits observed in BG-related motor disorders.

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants.

Cutaneous sensory feedback from the paw pads plays an important role in regulating body balance, especially in challenging environments like ladder or slope walking. Here, we investigated the contribution of cutaneous sensory feedback from the paw pads to balance control in cats stepping on a split-belt treadmill. Fore- and hindpaws were anesthetized unilaterally using lidocaine injections. We evaluated body balance in intact and compromised cutaneous feedback conditions during split-belt locomotion with belt speed ratios of 0.5, 1.0, 1.5 and 2.0. Measures of body balance included step width, relative duration of limb support phases, lateral bias of center of mass (CoM) and margins of static and dynamic stability. In the intact condition, static and dynamic balance declined with increasing belt-speed ratio due to a lateral shift of the CoM toward the borders of support on the slower moving belt. Anesthesia of the ipsilateral paws improved locomotor balance with increasing belt speed ratios by reversing the CoM shift, decreasing the relative duration of the two-limb support phase, increasing the duration of four- or three-limb support phases, increasing the hindlimb step width and static stability. We observed no changes in most balance measures in anesthetized conditions during tied-belt locomotion at 0.4 m s−1. CoM lateral displacements closely resembled those of the inverted pendulum and of human walking. We propose that unilaterally compromised cutaneous feedback from the paw pads is compensated by improving lateral balance and by shifting the body toward the anesthetized paws to increase tactile sensation during the stance phase.

Table of contentsA1 Functional advantages of cell-type heterogeneity in neural circuitsTatyana O. SharpeeA2 Mesoscopic modeling of propagating waves in visual cortexAlain DestexheA3 Dynamics and biomarkers of mental disordersMitsuo KawatoF1 Precise recruitment of spiking output at theta frequencies requires dendritic h-channels in multi-compartment models of oriens-lacunosum/moleculare hippocampal interneuronsVladislav Sekulić, Frances K. SkinnerF2 Kernel methods in reconstruction of current sources from extracellular potentials for single cells and the whole brainsDaniel K. Wójcik, Chaitanya Chintaluri, Dorottya Cserpán, Zoltán SomogyváriF3 The synchronized periods depend on intracellular transcriptional repression mechanisms in circadian clocks.Jae Kyoung Kim, Zachary P. Kilpatrick, Matthew R. Bennett, Kresimir JosićO1 Assessing irregularity and coordination of spiking-bursting rhythms in central pattern generatorsIrene Elices, David Arroyo, Rafael Levi, Francisco B. Rodriguez, Pablo VaronaO2 Regulation of top-down processing by cortically-projecting parvalbumin positive neurons in basal forebrainEunjin Hwang, Bowon Kim, Hio-Been Han, Tae Kim, James T. McKenna, Ritchie E. Brown, Robert W. McCarley, Jee Hyun ChoiO3 Modeling auditory stream segregation, build-up and bistabilityJames Rankin, Pamela Osborn Popp, John RinzelO4 Strong competition between tonotopic neural ensembles explains pitch-related dynamics of auditory cortex evoked fieldsAlejandro Tabas, André Rupp, Emili Balaguer-BallesterO5 A simple model of retinal response to multi-electrode stimulationMatias I. Maturana, David B. Grayden, Shaun L. Cloherty, Tatiana Kameneva, Michael R. Ibbotson, Hamish MeffinO6 Noise correlations in V4 area correlate with behavioral performance in visual discrimination taskVeronika Koren, Timm Lochmann, Valentin Dragoi, Klaus ObermayerO7 Input-location dependent gain modulation in cerebellar nucleus neuronsMaria Psarrou, Maria Schilstra, Neil Davey, Benjamin Torben-Nielsen, Volker SteuberO8 Analytic solution of cable energy function for cortical axons and dendritesHuiwen Ju, Jiao Yu, Michael L. Hines, Liang Chen, Yuguo YuO9 C. elegans interactome: interactive visualization of Caenorhabditis elegans worm neuronal networkJimin Kim, Will Leahy, Eli ShlizermanO10 Is the model any good? Objective criteria for computational neuroscience model selectionJustas Birgiolas, Richard C. Gerkin, Sharon M. CrookO11 Cooperation and competition of gamma oscillation mechanismsAtthaphon Viriyopase, Raoul-Martin Memmesheimer, Stan GielenO12 A discrete structure of the brain wavesYuri Dabaghian, Justin DeVito, Luca PerottiO13 Direction-specific silencing of the Drosophila gaze stabilization systemAnmo J. Kim, Lisa M. Fenk, Cheng Lyu, Gaby MaimonO14 What does the fruit fly think about values? A model of olfactory associative learningChang Zhao, Yves Widmer, Simon Sprecher,Walter SennO15 Effects of ionic diffusion on power spectra of local field potentials (LFP)Geir Halnes, Tuomo Mäki-Marttunen, Daniel Keller, Klas H. Pettersen,Ole A. Andreassen...

Rhythmic limb movements during locomotion are controlled by central pattern generator (CPG) circuits located in the spinal cord. It is considered that these circuits are composed of individual rhythm generators (RGs) for each limb interacting with each other through multiple commissural and long propriospinal circuits. The organization and operation of each RG are not fully understood, and different competing theories exist about interactions between its flexor and extensor components, as well as about leftright commissural interactions between the RGs. The central idea of circuit organization proposed in this study is that with an increase of excitatory input to each RG (or an increase in locomotor speed) the rhythmogenic mechanism of the RGs changes from "flexor-driven" rhythmicity to a "classical half-center" mechanism. We test this hypothesis using our experimental data on changes in duration of stance and swing phases in the intact and spinal cats walking on the ground or tied-belt treadmills (symmetric conditions) or split-belt treadmills with different left and right belt speeds (asymmetric conditions). We compare these experimental data with the results of mathematical modeling, in which simulated CPG circuits operate in similar symmetric and asymmetric conditions with matching or differing control drives to the left and right RGs. The obtained results support the proposed concept of state-dependent changes in RG operation and specific commissural interactions between the RGs. The performed simulations and mathematical analysis of model operation under different conditions provide new insights into CPG network organization and limb coordination during locomotion.