Evidence from long-term decentralization in vitro
By Muriel Thoby-Brisson and John Simmers
The authors suggested that a persistent functional recovery from elimination of some of the central nervous inputs on which network operation normally depends.
Central modulatory inputs exert a long-term influence on the CPG in addition to their short-term permissive action on rethymogenesis.
Sunday, May 17, 2009
Injury induced dendritic plasticity in the mature central nervous system
by Matylda Macias
Sometimes this relatively stable situation can be made more plastic even in mature CNS.
One of the stimuli, which can induce it, is damage, which leads to destruction of existing connections.
Several studies have shown that cortical injury by itself enhances the plastic potential of cortical dendrites in peri-infarct and in contralateral, unaffected homotopic areas (Kolb and Gibb 1991, Jones and Schallert 1992).
Post injury dendritic arborization is entirely dependent on maintenance of the ipsilateral (unaffected) forelimb activity.
Dendritic arborization necessary for the recovery.
Recovery is activity-dependent.
Sometimes this relatively stable situation can be made more plastic even in mature CNS.
One of the stimuli, which can induce it, is damage, which leads to destruction of existing connections.
Several studies have shown that cortical injury by itself enhances the plastic potential of cortical dendrites in peri-infarct and in contralateral, unaffected homotopic areas (Kolb and Gibb 1991, Jones and Schallert 1992).
Post injury dendritic arborization is entirely dependent on maintenance of the ipsilateral (unaffected) forelimb activity.
Dendritic arborization necessary for the recovery.
Recovery is activity-dependent.
Thursday, May 7, 2009
Mechanisms for recovery of motor function following cortical damage
by Randolph J. Nudo
- Intact tissue undergoes structural and functional changes that could play a substantial role in neurological recovery after focal injury to the cerebral cortex.
- Waves of growth promotion and inhibition modulate the self-repair processes of the brain.
- Entire cortical networks participate in the recovery process.
Early demonstrasions of post-injury plasticity
- Behavioral experience is a potent modulator of post-injury cortical plasticity.
New insights into the cellular and molecular mechanisms underlying local reorganization
- Neurite outgrowth in the peri-infarct region (increased GAP-43 immunoreactivity).
- Synaptogenesis (elevated synaptophysin staining).
- Axonal sprouting (traact-tracting methods).
- Surviving neurons becme hyperexcitable with upregulation of NMDA receptors and downregulation of GABAA receptors.
- Growth-promoting gene expression.
- Exploiting this new understanding of cellular and molecular events following injury might provide new treatment approaches for recovery after CNS injury.
Plastic events remotes from the cortical injury
- The excitability of areas remote from the site of infarct is altered for significant periods of time after injury by upregulation of NMDA receptors and downregulation of GABAA receptors.
- Alteration of intercortical wiring patterns among different cortical fields.
- Dendritic arborization and synaptogenesis (2 weeks ~ 1 month) in contralateral side.
- role of neural stem cells is still unclear.
Re-emmergence of the mass action principle
Is there a sensitive period for post-injury plasticity and recovery potential?
- Behavioral training is most effective if done within 1 week.
Conclusions
- A disruption of cortical motor network triggers a major reassembly of inter- and intra-areal cortical networks.
- Post-injury behavioral experience appears to be crucial to the reassemby of adaptive modules.
- Basic intracortical wiring plan is substancially altered.
- Intact tissue undergoes structural and functional changes that could play a substantial role in neurological recovery after focal injury to the cerebral cortex.
- Waves of growth promotion and inhibition modulate the self-repair processes of the brain.
- Entire cortical networks participate in the recovery process.
Early demonstrasions of post-injury plasticity
- Behavioral experience is a potent modulator of post-injury cortical plasticity.
New insights into the cellular and molecular mechanisms underlying local reorganization
- Neurite outgrowth in the peri-infarct region (increased GAP-43 immunoreactivity).
- Synaptogenesis (elevated synaptophysin staining).
- Axonal sprouting (traact-tracting methods).
- Surviving neurons becme hyperexcitable with upregulation of NMDA receptors and downregulation of GABAA receptors.
- Growth-promoting gene expression.
- Exploiting this new understanding of cellular and molecular events following injury might provide new treatment approaches for recovery after CNS injury.
Plastic events remotes from the cortical injury
- The excitability of areas remote from the site of infarct is altered for significant periods of time after injury by upregulation of NMDA receptors and downregulation of GABAA receptors.
- Alteration of intercortical wiring patterns among different cortical fields.
- Dendritic arborization and synaptogenesis (2 weeks ~ 1 month) in contralateral side.
- role of neural stem cells is still unclear.
Re-emmergence of the mass action principle
Is there a sensitive period for post-injury plasticity and recovery potential?
- Behavioral training is most effective if done within 1 week.
Conclusions
- A disruption of cortical motor network triggers a major reassembly of inter- and intra-areal cortical networks.
- Post-injury behavioral experience appears to be crucial to the reassemby of adaptive modules.
- Basic intracortical wiring plan is substancially altered.
PLASTICITY OF THE SPINAL NEURAL CIRCUITRY AFTER INJURY
By V. Reggie Edgerton, Niranjala J.K. Tillakaratne, Allison J. Bigbee, Ray D. de Leon, and Roland R. Roy
- A high level of functional recovery can be achieved following a complete spinal cord injury (SCI).
- The level of recovery in motor function is defined by the level and types of motor training or experience following the injury (Edgerton et al. 2001a, Wernig et al. 1995).
- Insight into the mechanisms of recovery and motor learning depends on a basic understanding of
the neural control of motor functions in the uninjured compared to the injured nervous system.
AUTOMATICITY IN POSTURE AND LOCOMOTION: SOME BASIC NEUROBIOLOGICAL PRINCIPLES OF MOTOR CONTROL BEFORE AND AFTER SCI
- Evolutionary learning in shaping the mammalian neural systems that control posture and locomotion.
- The automaticity within the spinal cord becomes even more critical for the CPG circuitry to successfully process sensory inputs.
Supraspinal Control of Posture and Locomtion
- The specific control features of each of the descending spinal tracts in controlling locomotion are poorly understood.
Spinal Control of Posture and Locomotion
1) CPG
2) SENSORY INPUT
- We propose that the spinal cord processes and interprets proprioception in a manner similar to how our visual system processes information (pattern recognition?).
- At any instant, the spinal cord receives an ensemble of information from all receptors throughout the body that signals a proprioceptive "image" that represents time and space.
- The importance of the CPG is not simply its ability to generate repetitive cycles, but also to receive, interpret, and predict the appropriate sequences of actions during any part of the step cycle, i.e., "state-dependence."
- The injured spinal cord interprets sensory changes in load and speed
- SCI patients can voluntarily initiate locomotion
3) THE INJURED SPINAL CORD IS AN "ALTERED" SPINAL CORD
- The spinal cord processes input and generates motor output in a different manner as a result of injury-related adaptations.
- Spasticity is a sign of activity in the spinal circuitry
MOTOR OUTPUT IS ENHANCED BY REPETITIVE TRAINING
Chronic Motor Training Modulates Spinal Plasticity to Enhance Motor Output After SCI
- Experiments with spinal cats using chronic locomotor training paradigms sugget that the ability to learn and successfully perform a motor task is dependent on repetitive practice.
- The functional state of the cord is shaped by specific locomotor training regimes.
- Although the mechanisms underlying locomotor training-enhanced plasticity is not well understood, it is clear that the physiological state of the cord can be affected by activity-dependent processes that can influence its ability to learn and perform a specified motor behavior.
The Spinal Cord Can Respond to Novel, Acute Perturbation
- An example of an object placed in front of a spinal cat stepping on a treadmill, a learning and memory-type phenomenon may be taking place ("smartness" of the spinal cord).
- Spinal cord is "solving" problems in real time based on the continually changing state of incoming peripehral information to elicit a nearly constant behavior, even though the means to the endpoint differ.
- These studies imply that spinal learning can occur in a very short period of time, and a type of memory trace allows for quicker adaptation upon reexposure to a given perturbation (Liu et al., 2003).
- The underlying cellular mechanisms are unknown.
- Hippocampal learning-like phenomena can occur in the spinal cord, but largely unknown.
Biochemical and Phamacological Evidence for Spinal Cord Plasticity After Injury
- The functinally recovered spinal animals showed no evidence of regeneration of descending pathways (Joynes et al. 1999) or showed minimal changes in hindlimb skeletal muscle properties to account for the recoery characteristics, the functinal behavior exhibited by these animals must have been mediated by the plasticity in existing spinal pathways.
- This plasticity may occur at any of many spinal cord regions or cell types such as motoneurons, premotor pattern-generating neurons, and/or nonneuronal celly types.
- There could also be anatomically altered synaptic connections, increased active zones of synapses, altered sensitivities of neurotoransmitter receptors, or altered pruduction of neurotransmitters.
- Data showed a significant role for these neurotransmitter systems in facilitating locomotor activity and thus suggest that these agents might be useful for inducing locomotion in SCI animals.
- Administration of 5-HT, its precursor 5-HTP, or the 5-HT agonists are also effective in improving locomotion in cats (Barbeau & Rossignol 1990, 1991) and rats (Feraboli-Lohnherr et al. 1999, Kim et al. 2001).
- The mechanism is unknown.
- The improvement of motor recovery upon the administration of of strychnine or bicuculline may occur by facilitating neuronal excitation by blocking the abnormally high levels of general inhibition resulting from a complete SCI (de Leon et al. 1999b).
- Nontrained spinal rats have increased GABA synthetic enzyme GAD67 and glycine and GABAA receptors in the lumbar spinal cord, whereas step-trained spinal rats have near-normal levels (Edgerton et al. 2001a, Tillakaratne et al. 2000).
- Training spinal cats to weight-bear also appears to reduce GABA signaling in some spinal interneurons.
- The amount of these enzymes depends on the type of training.
- These finding suggest that the inability of stand-trained spinal animals to step is closely linked to an elevated level of inhibition of flexor motor pools.
- The elevated level of a GABAA receptor subunit returns toward nearly undetectable control levels after six weeks of step training.
- Plasticity of spinal circuit may also be mediated by activity-dependent induction of neurotrophins.
Effects of Electrical Stimulation on Locomotor Recovery After SCI
HUMAN SCI: A PERSPECTIVE
Treadmill Training and the Recovery of Walking Ability After SCI
Use of Pharmacological Therapies in Enhancing Walking after SCI
CONCLUSION
- Training to stand improves standing ability and training to step improves stepping ability.
- One of the biochemical consequences of a complete SCI is an upregulation of inhibitory neurotransmitter systems, and step training reverses this effect.
- Physiological and biochemical state of the spinal conrd will affect how it respond to any given therapeutic intervention.
- A high level of functional recovery can be achieved following a complete spinal cord injury (SCI).
- The level of recovery in motor function is defined by the level and types of motor training or experience following the injury (Edgerton et al. 2001a, Wernig et al. 1995).
- Insight into the mechanisms of recovery and motor learning depends on a basic understanding of
the neural control of motor functions in the uninjured compared to the injured nervous system.
AUTOMATICITY IN POSTURE AND LOCOMOTION: SOME BASIC NEUROBIOLOGICAL PRINCIPLES OF MOTOR CONTROL BEFORE AND AFTER SCI
- Evolutionary learning in shaping the mammalian neural systems that control posture and locomotion.
- The automaticity within the spinal cord becomes even more critical for the CPG circuitry to successfully process sensory inputs.
Supraspinal Control of Posture and Locomtion
- The specific control features of each of the descending spinal tracts in controlling locomotion are poorly understood.
Spinal Control of Posture and Locomotion
1) CPG
2) SENSORY INPUT
- We propose that the spinal cord processes and interprets proprioception in a manner similar to how our visual system processes information (pattern recognition?).
- At any instant, the spinal cord receives an ensemble of information from all receptors throughout the body that signals a proprioceptive "image" that represents time and space.
- The importance of the CPG is not simply its ability to generate repetitive cycles, but also to receive, interpret, and predict the appropriate sequences of actions during any part of the step cycle, i.e., "state-dependence."
- The injured spinal cord interprets sensory changes in load and speed
- SCI patients can voluntarily initiate locomotion
3) THE INJURED SPINAL CORD IS AN "ALTERED" SPINAL CORD
- The spinal cord processes input and generates motor output in a different manner as a result of injury-related adaptations.
- Spasticity is a sign of activity in the spinal circuitry
MOTOR OUTPUT IS ENHANCED BY REPETITIVE TRAINING
Chronic Motor Training Modulates Spinal Plasticity to Enhance Motor Output After SCI
- Experiments with spinal cats using chronic locomotor training paradigms sugget that the ability to learn and successfully perform a motor task is dependent on repetitive practice.
- The functional state of the cord is shaped by specific locomotor training regimes.
- Although the mechanisms underlying locomotor training-enhanced plasticity is not well understood, it is clear that the physiological state of the cord can be affected by activity-dependent processes that can influence its ability to learn and perform a specified motor behavior.
The Spinal Cord Can Respond to Novel, Acute Perturbation
- An example of an object placed in front of a spinal cat stepping on a treadmill, a learning and memory-type phenomenon may be taking place ("smartness" of the spinal cord).
- Spinal cord is "solving" problems in real time based on the continually changing state of incoming peripehral information to elicit a nearly constant behavior, even though the means to the endpoint differ.
- These studies imply that spinal learning can occur in a very short period of time, and a type of memory trace allows for quicker adaptation upon reexposure to a given perturbation (Liu et al., 2003).
- The underlying cellular mechanisms are unknown.
- Hippocampal learning-like phenomena can occur in the spinal cord, but largely unknown.
Biochemical and Phamacological Evidence for Spinal Cord Plasticity After Injury
- The functinally recovered spinal animals showed no evidence of regeneration of descending pathways (Joynes et al. 1999) or showed minimal changes in hindlimb skeletal muscle properties to account for the recoery characteristics, the functinal behavior exhibited by these animals must have been mediated by the plasticity in existing spinal pathways.
- This plasticity may occur at any of many spinal cord regions or cell types such as motoneurons, premotor pattern-generating neurons, and/or nonneuronal celly types.
- There could also be anatomically altered synaptic connections, increased active zones of synapses, altered sensitivities of neurotoransmitter receptors, or altered pruduction of neurotransmitters.
- Data showed a significant role for these neurotransmitter systems in facilitating locomotor activity and thus suggest that these agents might be useful for inducing locomotion in SCI animals.
- Administration of 5-HT, its precursor 5-HTP, or the 5-HT agonists are also effective in improving locomotion in cats (Barbeau & Rossignol 1990, 1991) and rats (Feraboli-Lohnherr et al. 1999, Kim et al. 2001).
- The mechanism is unknown.
- The improvement of motor recovery upon the administration of of strychnine or bicuculline may occur by facilitating neuronal excitation by blocking the abnormally high levels of general inhibition resulting from a complete SCI (de Leon et al. 1999b).
- Nontrained spinal rats have increased GABA synthetic enzyme GAD67 and glycine and GABAA receptors in the lumbar spinal cord, whereas step-trained spinal rats have near-normal levels (Edgerton et al. 2001a, Tillakaratne et al. 2000).
- Training spinal cats to weight-bear also appears to reduce GABA signaling in some spinal interneurons.
- The amount of these enzymes depends on the type of training.
- These finding suggest that the inability of stand-trained spinal animals to step is closely linked to an elevated level of inhibition of flexor motor pools.
- The elevated level of a GABAA receptor subunit returns toward nearly undetectable control levels after six weeks of step training.
- Plasticity of spinal circuit may also be mediated by activity-dependent induction of neurotrophins.
Effects of Electrical Stimulation on Locomotor Recovery After SCI
HUMAN SCI: A PERSPECTIVE
Treadmill Training and the Recovery of Walking Ability After SCI
Use of Pharmacological Therapies in Enhancing Walking after SCI
CONCLUSION
- Training to stand improves standing ability and training to step improves stepping ability.
- One of the biochemical consequences of a complete SCI is an upregulation of inhibitory neurotransmitter systems, and step training reverses this effect.
- Physiological and biochemical state of the spinal conrd will affect how it respond to any given therapeutic intervention.
Sunday, April 19, 2009
Synaptic Bombardment Modulates Muscarinic Effects in Forelimb Motor Cortex
Niraj S. Desai and Elisabeth C. Walcott
Continuous synaptic bombardment with a complex barrage of excitatory and inhibitory inputs alter many aspects of neuronal responsiveness (by depolarizing neurons, increasing membrane conductance, and introducing fluctuations). This study shows how it shapes neuromodulation of postsynaptic responses by examining muscarinic modulation of forelimb motor cortex, a brain area in which cholinergic stimulation is known to be necessary for modifications during motor skill learning. Using a dynamic clamp system to inject simulated conductances
into pyramidal neurons, they mimicked in vivo-like activity by introducing a random background of excitatory and
inhibitory inputs. The presence of such background conductances strongly attenuated most muscarinic neuromodulatory effects, with the notable exception that sustained firing responses to trains of inputs were well preserved. This may be important for promoting plasticity in vivo.
The Journal of Neuroscience, February 22, 2006 • 26(8):2215–2226
Similar thing may be happening in the slug's CPG in the sea water. Most of my experiments testing neuromodulation have been done in HiDi saline, which suppresses anonymous synaptic bombardment.
Continuous synaptic bombardment with a complex barrage of excitatory and inhibitory inputs alter many aspects of neuronal responsiveness (by depolarizing neurons, increasing membrane conductance, and introducing fluctuations). This study shows how it shapes neuromodulation of postsynaptic responses by examining muscarinic modulation of forelimb motor cortex, a brain area in which cholinergic stimulation is known to be necessary for modifications during motor skill learning. Using a dynamic clamp system to inject simulated conductances
into pyramidal neurons, they mimicked in vivo-like activity by introducing a random background of excitatory and
inhibitory inputs. The presence of such background conductances strongly attenuated most muscarinic neuromodulatory effects, with the notable exception that sustained firing responses to trains of inputs were well preserved. This may be important for promoting plasticity in vivo.
The Journal of Neuroscience, February 22, 2006 • 26(8):2215–2226
Similar thing may be happening in the slug's CPG in the sea water. Most of my experiments testing neuromodulation have been done in HiDi saline, which suppresses anonymous synaptic bombardment.
Neurotrophins mediates a rapid switch in transmitter release
Bo Yang, John D. Slonimsky and Susan J. Birren
Brain-derived neurotrophic factor (BDNF) altered the neurotrasmitter release properties of sympathetic neuron-myocyte connections in rodent cell culture, leading to a rapid shift from excitatory norepinephrinic transmission to inhibitory cholinergic trasmission.
p75 neurotophin receptor mediates modulation of release of distinct neurotransmitter pools, resulting functinoal switch between excitatory and inhibitory neurotoransmission in individual neurons.
Nature Neuroscience 5(6) 539-545 (2002).
Thursday, April 16, 2009
From IPSPs to EPSPs: Transition to seizures in the mouse hippocampus
Transition to seizures in the isolated immature mouse hippocampus: a switch from dominant phasic inhibition to dominant phasic excitation.
M. Derchansky, S. S. Jahromi, M. Manami, D.S. Shin, A. Sik, and P. L. Carlen
Neuronal networks can display non-linear complex behaviours that result in multiple stable states, with the capacity to undergo spontaneous transition between these states. An in vitro model of temporal lobe epilepsy (TLE) generates recurrent seizure-like events. The authors studied the sequence of inhibitory and excitatory events during the preictal state.
In animal models of epilepsy, dendritic but not somatic GABAergic inhibition is decreased and it has been hypothesized that this is the mechanism responsible for ictal generation.
Anothor hypothesis for ictal generation is that interneurons might be involved in synchronizing large neuronal populatios. This synchronization is possible by their abundant connectivity to pyramidal cells. Excitation might be achieved by the alteration of the intracellular chloride gradient after prolonged high-frequency activation of GABA-A receptor.
During the preictal state, there was a total reversal in the polarity of the synaptic potentials in pyramidal cells, fast-spiking cells, and non-FS cells.
The hyperpolarizing potentials during preictal state are generated by recurrent IPSPs (Cl-).
However, the reversal is not due to the change in the reversal potential for Cl ion. The authors suggest that the excitatory drive was produced by a complex change in the synaptic interactions among pyramidal cells and interneurons.
J. Physiol. 586.2, 477-494 (2008).
M. Derchansky, S. S. Jahromi, M. Manami, D.S. Shin, A. Sik, and P. L. Carlen
Neuronal networks can display non-linear complex behaviours that result in multiple stable states, with the capacity to undergo spontaneous transition between these states. An in vitro model of temporal lobe epilepsy (TLE) generates recurrent seizure-like events. The authors studied the sequence of inhibitory and excitatory events during the preictal state.
In animal models of epilepsy, dendritic but not somatic GABAergic inhibition is decreased and it has been hypothesized that this is the mechanism responsible for ictal generation.
Anothor hypothesis for ictal generation is that interneurons might be involved in synchronizing large neuronal populatios. This synchronization is possible by their abundant connectivity to pyramidal cells. Excitation might be achieved by the alteration of the intracellular chloride gradient after prolonged high-frequency activation of GABA-A receptor.
During the preictal state, there was a total reversal in the polarity of the synaptic potentials in pyramidal cells, fast-spiking cells, and non-FS cells.
The hyperpolarizing potentials during preictal state are generated by recurrent IPSPs (Cl-).
However, the reversal is not due to the change in the reversal potential for Cl ion. The authors suggest that the excitatory drive was produced by a complex change in the synaptic interactions among pyramidal cells and interneurons.
J. Physiol. 586.2, 477-494 (2008).
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