New Insights into the Spinal Recurrent Inhibitory Pathway Normally and After Motoneuron Regeneration

Despite more than seven decades of intensive research, uncertainty is the hallmark of spinal recurrent inhibition. The simplest possible structure that is formed between the a-motoneuron and its inhibitory interneurons has been the subject of long lasting scientific debate. To date, there is no consensus on the functional significance of this circuit. Even the simplest assumption of a negative feedback loop does not hold true. The current work used the technique of in vivo intracellular recording from the adult rat a-motoneurons to study the normal function and the plasticity after nerve injury and regeneration of this simple, yet intricate spinal circuit. The long lasting notion that inhibition must adversely affect neuronal firing rates has been challenged and the counter-intuitive finding that recurrent inhibition can increase firing rate under certain circumstances is reported for the first time. In addition, recurrent inhibition was found to strongly affect action potential spike timing and was found to prolong the duration of repetitive firing of a-motoneurons. Furthermore, the circuit behavior at different frequencies has been examined and novel findings are reported. The circuit adaptation to peripheral nerve injury and successful regeneration was studied. Results showed that peripheral nerve regeneration failed to restore the structure and function of this central circuit. In conclusion, the current thesis calls for a reevaluation of the concept that recurrent inhibition must suppress a-motoneuron firing and suggests that inhibition in general plays more of a role in modulating firing behavior. Finally, another example of permanent central nervous system dysfunction despite successful peripheral recovery is reported and perhaps adds to the permanent functional deficits that remain in victims of peripheral nerve injury

Molecular, functional and modeling study of cystic fibrosis transmembrane conductance regulator (CFTR) modulation of chloride homeostasis in the rat lumbar spinal cord during postnatal development

In the mature central nervous system (CNS) GABA and glycine are the major inhibitory neurotransmitters. They act via shunting incoming excitatory currents and via moving the membrane potential away from the action potential threshold. However, during development, the action of GABA or glycine can be depolarizing and become even excitatory. This phenomenon plays a significant role in the maturation of the CNS, including neuronal migration and growth, synapse formation and plasticity of GABA synapses (Ben-Ari, 2002). Since synaptic inhibition operate mainly through Cl- fluxes, developmental regulation of this anion is crucial for the establishment of GABA/glycine inhibition

Excitatory postsynaptic potentials in rat neocortical neurons in vitro. III. Effects of a quinoxalinedione non-NMDA receptor antagonist

1. Intracellular microelectrodes were used to obtain recordings from neurons in layer II/III of rat frontal cortex. A bipolar electrode positioned in layer IV of the neocortex was used to evoke postsynaptic potentials. Graded series of stimulation were employed to selectively activate different classes of postsynaptic responses. The sensitivity of postsynaptic potentials and iontophoretically applied neurotransmitters to the non-N-methyl-D-asparate (NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) was examined. 2. As reported previously, low-intensity electrical stimulation of cortical layer IV evoked short-latency early excitatory postsynaptic potentials (eEPSPs) in layer II/III neurons. CNQX reversibly antagonized eEPSPs in a dose-dependent manner. Stimulation at intensities just subthreshold for activation of inhibitory postsynaptic potentials (IPSPs) produced long-latency (10 to 40-ms) EPSPs (late EPSPs or 1EPSPs). CNQX was effective in blocking 1EPSPs. 3. With the use of stimulus intensities at or just below threshold for evoking an action potential, complex synaptic potentials consisting of EPSP-IPSP sequences were observed. Both early, Cl(-)-dependent and late, K(+)-dependent IPSPs were reduced by CNQX. This effect was reversible on washing. This disinhibition could lead to enhanced excitability in the presence of CNQX. 4. Iontophoretic application of quisqualate produced a membrane depolarization with superimposed action potentials, whereas NMDA depolarized the membrane potential and evoked bursts of action potentials. At concentrations up to 5 microM, CNQX selectively antagonized quisqualate responses. NMDA responses were reduced by 10 microM CNQX. D-Serine (0.5-2 mM), an agonist at the glycine regulatory site on the NMDA receptor, reversed the CNQX depression of NMDA responses

Perspectives on the modeling of the neuromusculoskeletal system to investigate the influence of neurodegenerative diseases on sensorimotor control

The understanding of the neurophysiological mechanisms underlying movement control can be much furthered using computational models of the neuromusculoskeletal system. Biologically based multi-scale neuromusculoskeletal models have a great potential to provide new theories and explanations related to mechanisms behind muscle force generation at the molecular, cellular, synaptic, and systems levels. Albeit some efforts have been made to investigate how neurodegenerative diseases alter the dynamics of individual elements of the neuromuscular system, such diseases have not been analyzed from a systems viewpoint using multi-scale models. This perspective article synthesizes what has been done in terms of multi-scale neuromuscular development and points to a few directions where such models could be extended so that they can be useful in the future to discover early predictors of neurodegenerative diseases, as well as to propose new quantitative clinical neurophysiology approaches to follow the course of improvements associated with different therapies (drugs or others). Therefore, this article will present how existing biologically based multi-scale models of the neuromusculoskeletal system could be expanded and adapted for clinical applications. It will point to mechanisms operating at different levels that would be relevant to be considered during model development, along with implications for interpreting experimental results from neurological patients342176186CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP409302/2016-3; 312442/2017-3; 303809/2016-72015/21819-32015/14917-9; 2017/11464-

Inertial Load Compensation by a Model Spinal Circuit During Single Joint Movement

Office of Naval Research (N00014-92-J-1309); CONACYT (Mexico) (63462

How Spinal Neural Networks Reduce Discrepancies between Motor Intention and Motor Realization

This paper attempts a rational, step-by-step reconstruction of many aspects of the mammalian neural circuitry known to be involved in the spinal cord's regulation of opposing muscles acting on skeletal segments. Mathematical analyses and local circuit simulations based on neural membrane equations are used to clarify the behavioral function of five fundamental cell types, their complex connectivities, and their physiological actions. These cell types are: α-MNs, γ-MNs, IaINs, IbINs, and Renshaw cells. It is shown that many of the complexities of spinal circuitry are necessary to ensure near invariant realization of motor intentions when descending signals of two basic types independently vary over large ranges of magnitude and rate of change. Because these two types of signal afford independent control, or Factorization, of muscle LEngth and muscle TEnsion, our construction was named the FLETE model (Bullock and Grossberg, 1988b, 1989). The present paper significantly extends the range of experimental data encompassed by this evolving model.National Science Foundation (IRI-87-16960, IRI-90-24877); Instituto Tecnológico y de Estudios Superiores de Monterre

Biophysical modeling to reverse engineer two mammalian neural circuits lower urinar Y tract and hippocampus

Computational neuroscience provides tools to abstract and generalize principles of neuronal function using mathematics and computers. This dissertation reports biophysical modeling approaches to facilitate reverse engineering of two mammalian neural circuits - the lower urinary tract for the development of stimulation techniques, and the rodent hippocampus to understand mechanisms involved in theta rhythms. The LUT in mammals consists of the urinary bladder, external urethral sphincter (EUS) and the urethra. Control of the LUT is achieved via a neural circuit which integrates distinct components. Dysfunctions of the lower urinary tract (LUT) are caused by a variety of factors including spinal cord injury and diabetes. Our model builds on previous models by using biologically realistic spiking neurons to reproduce neural control of the LUT in both normal function and dysfunction cases. The hippocampus has long been implicated in memory storage and retrieval. Also, hippocampal theta oscillations (4-12 Hz) are consistently recorded during memory tasks and spatial navigation. Previous model revealed five distinct theta generators. The present study extends the work by probing deeper into the intrinsic theta mechanisms via characterizing the mechanisms as being resonant, i.e., inherently produce theta, or synchronizing, i.e., promote coordinated activity, or possibly both. The role of the neuromodulatory state is also investigated.Includes bibliographical references (pages 157-164)

From Parallel Sequence Representations to Calligraphic Control: A Conspiracy of Neural Circuits

Calligraphic writing presents a rich set of challenges to the human movement control system. These challenges include: initial learning, and recall from memory, of prescribed stroke sequences; critical timing of stroke onsets and durations; fine control of grip and contact forces; and letter-form invariance under voluntary size scaling, which entails fine control of stroke direction and amplitude during recruitment and derecruitment of musculoskeletal degrees of freedom. Experimental and computational studies in behavioral neuroscience have made rapid progress toward explaining the learning, planning and contTOl exercised in tasks that share features with calligraphic writing and drawing. This article summarizes computational neuroscience models and related neurobiological data that reveal critical operations spanning from parallel sequence representations to fine force control. Part one addresses stroke sequencing. It treats competitive queuing (CQ) models of sequence representation, performance, learning, and recall. Part two addresses letter size scaling and motor equivalence. It treats cursive handwriting models together with models in which sensory-motor tmnsformations are performed by circuits that learn inverse differential kinematic mappings. Part three addresses fine-grained control of timing and transient forces, by treating circuit models that learn to solve inverse dynamics problems.National Institutes of Health (R01 DC02852