Thursday, May 21, 2009

Enhancing circuit perfomance in injured spinal cord



Dr. Lorne Mendell's talk at Emory, May 21, 2009


Smashed spinal cord
- cell death
- activity-based therapy

Encouraging functional recovery

- reducing cell death
- replace absent cells
- enhancing performance of sensory circuit
a) training
b) neurotrophine-induced synaptic potentiation

Neonatal transection: Step training can enhance stepping performance
- trained animals can walk when they grew up
- shape of the movement is slightly different (less force?)
- ankle angle

Recovery reverses transection-induced changes in monosynaptic EPSPs and AHP
- Change in population of EPSP size and AHP
a) transection reduced the overall size of EPSPs (more small EPSPs than large EPSPs)
b) shift of EPSP population to have more large EPSPs
c) much more large EPSPs than control
d) AHP became larger, but became smaller after training.

Improved stepping performance correlated with change in motoneuron
- Change in AHP depth indicates the ability to fire at high frequency
- Change in EPSP amplitude indicate changes in the sensory feedback from muscle spindle (ankle)

NT-3 (&BNDF)
- motor improvement
= both mimicked by NT-3?
- electrophysiological changes (EPSP, AHP)

NT-3 is required for motoneuronal projections to muscle spindle
Acute sensitization by NTs
- neurotrophic factor (NT-3) sensitize motoneurons.
- for example, it sensitize GluR

Chronic effects of NT-3 on the strength of the mo...

NT-3 strengthen projections of injured & developing spindle afferent to motoneurons
- intraneural NT-3 enhance synapses for axotmized neurons.

Substitute NT-3 for training
- virus that has NT-3 is injected into muscle

Delivery of neurotrophines to intact preparations without trauma: Viral vectors
- AAV/NT-3; expression, 150 days

NT-3 expression profiles differ according to the preparation, and physiological effects differ accordingly
- Cord NT-3 was plotted against DRG NT-3.
- In spinal cord, NT-3 expression is larger in the intact than transected animal.
- In the intact prep, EPSPs became smaller after transection (probably by increase of the motoneuron's size).
- Appearance of large EPSPs for transected animals (by sprouting by presynaptic afferent neurons = DRG neuron)

Input resistance of motor neuron was reduced
- by increase of the motoneuron's size
- contribute to the reduction of the EPSP size

AAV/NT-3 decreases motoneuronal input resistance
- in intact animal, it reduced both EPSP size and Rm
- in transected animal, it only reduced Rm size, but increased the EPSP size.

Ventrolateral white matter (VLF?) synapses persist on motoneurons in chronically transected preparation

Changes after AAV/NT-3 in intact preparations
- the change in EPSP size was synapse specific

Trained animals are different from AAV/NT-3 treated
- Trained animal shows both increase in Rm and EPSP size in the motoneurons.
- c-fos

AVV/NT-3 enhances the stretch-reflex by increased performance in stepping

NT-3 strengthens MG strech pathway by increased EPSP size.


- K. Pearson Exp Br Res (2003)

- Chen Y et al., 2006, JNsc26: 12537.

- Modeling stepping function by a model: Yakovenko et al., (2004)
Stretch reflex enhances stability of CPG circuit

Neurotropin treatment of adult transected preparations (preliminary results).

Monday, May 18, 2009

Homeostatic synapse-driven membrane plasticity in nucleus accumbens neurons

By Ishikawa,M.; Mu,P.; Moyer,J.T.; Wolf,J.A.; Quock,R.M.; Davies,N.M.; Hu,X.T.; Schluter,O.M.; Dong,Y.


Abstract:

- Homeostatic mechanisms balances the input-output/synapse-membrane interaction at nucleus accumbens neurons.
- Studies on nucleus accumbens (NAc) neurons revealed a novel form of synapse-to-membrane homeostatic regulation (hSMP), homeostatic synapse-driven membrane plasticity (hSMP).
- Through hSMP, NAc neurons adjusted their membrane excitability to functionally compensate for basal shifts in excitatory synaptic input.
- hSMP is triggered by synaptic NMDA receptors.

Introduction:
- Homeostatic plasticity is an important cellular mechanism through which neurons use the neuroplasticity mechinery to maintain stable functional output in an ever-changing internal and external environment (Turrigiano and Nelson, 2004).
- The functional output of a neuron relies on dynamic integration of synaptic inputs and intrinsic membrane excitability.
- It has long been known that homeostatic plasticity can occur independently at either synapses (Turrigiano and Nelson, 2004) or the membrane excitability (Zhang and Linden, 2003).

Results:
- hSMP in NAc slice cultures: NAc mediam spiny neuron (MSNs) increased excitability in slice culture.
- NMDA receptor mediates hSMP. DCS (D-cycloserine).
- hSMP in acute brain slices.
- Synapse-specific hSMP.
- SK channels mediate the expression of hSMP.
- Implication of hSMP in cocaine -induced membrane adaptation.

Homeostatic and nonhomeostatic modulation of learning in human motor cortex

By Patric Jung and Ulf Ziemann

Introduction
- Motor learning is of crucial importance throughout life for acquisition of new skills and reaccquisition of formerly known but, attributable to brain lesion, lost skills (Sanes, 2003; Krakauer, 2006).

- There is now substantial evidence that many types of motor learning occur in the primary motor cortex (M1) and involve synaptic plasticity in the form of long-term potentiation (LTP) (Rioult-Pedotti et al., 2000; Monfils and Teskey, 2004).

Neocortical mechanisms in motor learning



by
Jerome N Sanes

- Incontrovertible evidence: Many neocortical regions, including the motor-related areas, exhibit plasticity and are likely to contribute to motor- skill learning.

Leaning mechanisms

- Candidate mechanisms include fundamental modification in neural-spiking properties, the formation of new intrinsic or extrinsic synaptic contacts, the long-term potentiation or long-term depression of network synapses, and changes in intracortical processing.

- LTP and LTD have been proposed as mechanisms for learning and memory functions throughout the brain, although definitive proof of the relationship between synaptic plasticity and learning often is lacking.

Sunday, May 17, 2009

Voltage-dependent switching of sensorymotor integration by a lobster central pattern generator

By Romuald Nargeot

- Repeated sensory nerve stimulation gradually and long-lastingly strengthened the bursting of the LP neuron to the detriment of sensory-elicited inactivation.

- This strengthening of pyloric-timed rhytmic activity as enhanced by experimental depolarization of the neuron.

- When the LP neuron was hyperpolarized, the same sensory stimulation paradigm now gradually increased the susceptibility of the pyloric-timed bursting of the network neuron to sensory-elicited inactivation.

- Modulation of depolarization-activated and hyperpolarization-activated ionic conductances that underlie the intrinsic bursting properties of the LP neuron may contribute via differential voltage-dependent recruitment and effects to the respective adaptive processes.

Neuromodulatory inputs maintain expression of a lobster motor pattern-generating network in a modulation-dependent state:

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.

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.

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.

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.