Spinal pattern generation

Recent research in the field of spinal pattern generation has concentrated on three main areas: the effects of various transmitters on spinal rhythmic patterns in reduced preparations (neonatal rats, chick embryos, tadpole embryos, lampreys); the changes in membrane properties of different elements of the generating circuits; and the interactions between central generating mechanisms and afferent inputs. The important message is that new properties of neural membranes, as well as new reflex responses, have been identified that could not have been predicted in the absence of such rhythmic activity.     

Synaptic mechanisms in invertebrate pattern generation

Although individual neurons can be intrinsically oscillatory and can be network pacemakers, motor patterns are often generated in a more distributed manner. Synaptic connections with other neurons are important because they either modify the rhythm of the pacemaker cell or are essential for pattern generation in the first place. Computational studies of half-center oscillators have made much progress in describing how neurons make transitions between active and inactive phases in these simple networks. In addition to characterizing phase transitions, recent studies have described the synaptic mechanisms that are important for the initiation and maintenance of activity in half-center oscillators.     

Sensitivity of basic oscillatory mechanisms for pattern generation and detection

 Intrinsic oscillators are the basic building blocks of central pattern generators, which model the neural circuits underlying pattern generation. Coupled intrinsic oscillators have been shown to synchronize their oscillatory frequencies and to maintain a characteristic pattern of phase relationships. Recently, oscillatory neurons have also been identified in sensory systems that are involved in decoding phase information. It has been hypothesized that the neural oscillators are part of neural circuits that implement phase-locked loops (PLLs), which are well-known electrical circuits for temporal decoding. Thus, there is evidence that intrinsic neural oscillators participate in both temporal pattern generation and temporal pattern decoding. The present paper investigates the dynamics underlying forced oscillators and forced PLLs, using a single framework, and compares both their stability and sensitivity characteristics. In particular, a method for assessing whether an oscillatory neuron is forced directly or indirectly, as part of a PLL, is developed and applied to published data. Received: 17 July 2000 / Accepted in revised form: 14 March 2001     

The contribution of sensory inputs to the pattern generation of breathing

Current concepts of the basic neural control system and its modulation by afferent inputs are reviewed. It is emphasized that, in analogy with locomotion, the central pattern generator (CPG) for automatic metabolic respiration does not depend on any afferent feedback from receptors sensitive to the movements of the "pump," or the streams of pumped air, for its production of a rhythmic motor output provides the CPG receives some "drive" inputs above threshold and adequate bias. The operation for a variety of reflexes and feedback loops is of fundamental importance, however, for adapting the breathing pattern to the varying requirements for gas exchange to the many behavioural, nonmetabolic demands on the breathing apparatus which are competing with its primary metabolic control functions. The presentation is focussed also on available evidence that the respiratory CPG exerts powerful modulations on the transmission in these reflex pathways controlling the pattern of breathing and adjusting it to the various metabolic and behavioural demands. Mechanisms for "gating," "phasic gain changes," and "phase-dependent reflex reversal" are exemplified.     

State-dependent sensory gating in olfactory cortex

Sensory systems show behavioral state-dependent gating of information flow that largely depends on the thalamus. Here we examined whether the state-dependent gating occurs in the central olfactory pathway that lacks a thalamic relay. In urethane-anesthetized rats, neocortical EEG showed a periodical alternation between two states: a slow-wave state (SWS) characterized by large and slow waves and a fast-wave state (FWS) characterized by faster waves. Single-unit recordings from olfactory cortex neurons showed robust spike responses to adequate odorants during FWS, whereas they showed only weak responses during SWS. The state-dependent change in odorant-evoked responses was observed in a majority of olfactory cortex neurons, but in only a small percentage of olfactory bulb neurons. These findings demonstrate a powerful state-dependent gating of odor information in the olfactory cortex that works in synchrony with the gating of other sensory systems. They suggest a state-dependent switchover of signal processing modes in the olfactory cortex.     

Central nervous mechanisms in the generation of the pattern of breathing

The role of the B?tzinger complex (B?tC) and the pre-B?tzinger complex (pre-B?tC) in the genesis of the breathing pattern was investigated in anesthetized, vagotomized, paralysed and artificially ventilated rabbits making use of bilateral microinjections of kainic acid (KA) and excitatory amino acid (EAA) receptor antagonists. KA microinjections into either the B?tC or the pre-B?tC transiently eliminated respiratory rhythmicity in the presence of tonic phrenic activity (tonic apnea). Rhythmic activity resumed as low-amplitude, high-frequency irregular oscillations, superimposed on tonic inspiratory activity and displayed a progressive, although incomplete recovery. Microinjections of kynurenic acid (KYN) and D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) into the B?tC caused a pattern of breathing characterized by low-amplitude, high-frequency irregular oscillations and subsequently tonic apnea. Responses to KYN and D-AP5 in the pre-B?tC were similar, although less pronounced than those elicited by these drugs in the B?tC and never characterized by tonic apnea. Microinjections of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) into the B?tC and the pre-B?tC induced much less intense responses mainly consisting of increases in respiratory frequency. The results show that the investigated medullary regions play a prominent role in the genesis of the normal pattern of breathing through the endogenous activation of EAA receptors.     

Emergent mechanisms in multiple pattern generation of the lobster pyloric network

By using a hard-wired oscillator network, multiple pattern generation of the lobster pyloric network is simulated. The network model is constructed using a relaxation oscillator representing an oscillatory or quiescent (i.e. steady-state) neuron. Modulatory inputs to the network are hypothesized to cause changes in the dynamical properties of each pyloric neuron: the oscillatory frequency, the postinhibitory rebound property, and the resting membrane potential. Changes in each of these properties are induced by changing appropriate parameters of the oscillator. By changing seven parameters of the network as a whole, modulatory input-dependent patterns are successfully simulated. Received: 13 July 1999 / Accepted in revised form: 17 December 1999     

Connexin-based gap junction hemichannels: gating mechanisms

Connexins (Cxs) form hemichannels and gap junction channels. Each gap junction channel is composed of two hemichannels, also termed connexons, one from each of the coupled cells. Hemichannels are hexamers assembled in the ER, the Golgi, or a post Golgi compartment. They are transported to the cell surface in vesicles and inserted by vesicle fusion, and then dock with a hemichannel in an apposed membrane to form a cell-cell channel. It was thought that hemichannels should remain closed until docking with another hemichannel because of the leak they would provide if their permeability and conductance were like those of their corresponding cell-cell channels. Now it is clear that hemichannels formed by a number of different connexins can open in at least some cells with a finite if low probability, and that their opening can be modulated under various physiological and pathological conditions. Hemichannels open in different kinds of cells in culture with conductance and permeability properties predictable from those of the corresponding gap junction channels. Cx43 hemichannels are preferentially closed in cultured cells under resting conditions, but their open probability can be increased by the application of positive voltages and by changes in protein phosphorylation and/or redox state. In addition, increased activity can result from the recruitment of hemichannels to the plasma membrane as seen in metabolically inhibited astrocytes. Mutations of connexins that increase hemichannel open probability may explain cellular degeneration in several hereditary diseases. Taken together, the data indicate that hemichannels are gated by multiple mechanisms that independently or cooperatively affect their open probability under physiological as well as pathological conditions.     

Spinal cord sensory systems after neonatal capsaicin

Animals with a severe reduction in the number of afferent C-fibres as a consequence of neonatal administration of capsaicin, exhibit a number of neurological and behavioral deficits including increased nociceptive thresholds, altered somato-visceral and viscero-visceral reflexes, depressed cardiovascular and respiratory reflexes and changes in the organisation of spinal cord sensory systems. The reduction in the number of C-fibres produced by neonatal capsaicin does not cause a decrease of similar magnitude in the number of dorsal horn cells driven by the surviving C-fibres. Twenty-two per cent of dorsal horn neurones in capsaicin treated animals respond to electrical stimulation of the surviving afferent C-fibres: a reduction of only 50% from control values. Inhibitory controls on afferent C-fibre evoked responses of dorsal horn neurones are weaker in capsaicin treated rate than in control animals. The cutaneous receptive fields of some dorsal horn neurones can increase in size following stimulation of afferent C-fibres. Tonic descending inhibition on C-fibre evoked responses of dorsal horn neurones is reduced in capsaicin treated rats: fewer neurones show tonic descending inhibition in these animals and those that do are subjected to less powerful inhibitions than similar neurones from control animals. However, some central inhibitory mechanism are unchanged after neonatal capsaicin treatment, specially those that do not involve afferent C-fibres. We suggest that the nervous system develops central inhibition in response to and directed towards the excitations mediated by its afferent drives. Therefore reduced central inhibition in response to a decreased number of afferent C-fibres can compensate for the lost capacity in the signalling of peripheral noxious events.     

Spinal mechanisms of NPY analgesia

We review previously published data, and present some new data, indicating that spinal application of neuropeptide Y (NPY) reduces behavioral and neurophysiological signs of acute and chronic pain. In models of acute pain, early behavioral studies showed that spinal (intrathecal) administration of NPY and Y2 receptor agonists decrease thermal nociception. Subsequent neurophysiological studies indicated that Y2-mediated inhibition of excitatory neurotransmitter release from primary afferent terminals in the substantia gelatinosa may contribute to the antinociceptive actions of NPY. As with acute pain, NPY reduced behavioral signs of inflammatory pain such as mechanical allodynia and thermal hyperalgesia; however, receptor antagonist studies indicate an important contribution of spinal Y1 rather than Y2 receptors. Interestingly, Y1 agonists suppress inhibitory synaptic events in dorsal horn neurons (indeed, well known mu-opioid analgesic drugs produce similar cellular actions). To resolve the behavioral and neurophysiological data, we propose that NPY/Y1 inhibits the spinal release of inhibitory neurotransmitters (GABA and glycine) onto inhibitory neurons, e.g. disinhibition of pain inhibition, resulting in hyporeflexia. The above mechanisms of Y1- and Y2-mediated analgesia may also operate in the setting of peripheral nerve injury, and new data indicate that NPY dose-dependently inhibits behavioral signs of neuropathic pain. Indeed, neurophysiological studies indicate that Y2-mediated inhibition of Ca(2+) channel currents in dorsal root ganglion neurons is actually increased after axotomy. We conclude that spinal delivery of Y1 agonists may be of use in the treatment of chronic inflammatory pain, and that the use of Y1 and Y2 agonists in neuropathic pain warrants further consideration.     

Separable gating mechanisms in a Mammalian pacemaker channel

Despite permeability to both K(+) and Na(+), hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels contain the K(+) channel signature sequence, GYG, within the selectivity filter of the pore. Here, we show that this region is involved in regulating gating in a mouse isoform of the pacemaker channel (mHCN2). A mutation in the GYG sequence of the selectivity filter (G404S) had different effects on the two components of the wild-type current; it eliminated the slowly activating current (I(f)) but, surprisingly, did not affect the instantaneous current (I(inst)). Confocal imaging and immunocytochemistry showed G404S protein on the periphery of the cells, consistent with the presence of channels on the plasma membrane. Experiments with the wild-type channel showed that the rate of I(f) deactivation and I(f) amplitude had a parallel dependence on the ratio of K(+)/Na(+) driving forces. In addition, the amplitude of fully activated I(f), unlike I(inst), was not well predicted by equal and independent flow of K(+) and Na(+). The data are consistent with two separable gating mechanisms associated with pacemaker channels: one (I(f)) that is sensitive to voltage, to a mutation in the selectivity filter, and to driving forces for permeating cations and another (I(inst)) that is insensitive to these influences.     

Spinal and sensory neuromodulation of spinal neuronal networks in humans

The present experiments were designed to gain additionally insight into how the spinal networks process direct spinal stimulation and peripheral sensory inputs to control posture and locomotor movements. We have developed a plantar pressure stimulation system that can deliver naturalistic postural and gait-related patterns of pressure to the soles of the feet to simulate standing and walking, thereby activating and/or modulating the automated spinal circuitry responsible for standing and locomotion. In the present study we compare the patterns of activation among selected motor pools and the kinematic consequences of these activation patterns in response to patterned heel-to-toe mechanical stimulation of the soles of the feet, and/or transcutaneous electrical spinal stimulation, for postural and locomotion regulation. The studies were performed in healthy individuals (n = 12) as well as in subjects (n = 2) with motor complete spinal cord injury. We found that plantar pressure stimulation and/or spinal stimulation can effectively facilitate locomotor output in the subjects placed with their legs in gravity neutral position. We have shown synergistic effects of combining sensory and spinal cord stimulation, suggesting that the two networks are different, but complementary. Also we provide evidence that plantar stimulation could serve as a novel neuro-rehabilitation tool alone or as part of a multi-modal approach to restoring motor function after complete paralysis due to SCI.     

Cortical mechanisms of sensory learning and object recognition

Learning about the world through our senses constrains our ability to recognise our surroundings. Experience shapes perception. What is the neural basis for object recognition and how are learning-induced changes in recognition manifested in neural populations? We consider first the location of neurons that appear to be critical for object recognition, before describing what is known about their function. Two complementary processes of object recognition are considered: discrimination among diagnostic object features and generalization across non-diagnostic features. Neural plasticity appears to underlie the development of discrimination and generalization for a given set of features, though tracking these changes directly over the course of learning has remained an elusive task.     

Transduction mechanisms in airway sensory nerves.

The induction of action potentials in airway sensory nerves relies on events leading to the opening of cation channels in the nerve terminal membrane and subsequent membrane depolarization. If the membrane depolarization is of sufficient rate and amplitude, action potential initiation will occur. The action potentials are then conducted to the central nervous system, leading to the initiation of various sensations and cardiorespiratory reflexes. Triggering events in airway sensory nerves include mechanical perturbation, inflammatory mediators, pH, temperature, and osmolarity acting through a variety of ionotropic and metabotropic receptors. Action potential initiation can be modulated (positively or negatively) through independent mechanisms caused mainly by autacoids and other metabotropic receptor ligands. Finally, gene expression of sensory nerves can be altered in adult mammals. This neuroplasticity can change the function of sensory nerves and likely involve both neurotrophin and use-dependent mechanisms. Here we provide a brief overview of some of the transduction mechanisms underlying these events.