Synaptic plasticity of local connections in rat motor cortex

This paper reviews studies that investigated mechanisms of the induction of long-term synaptic efficacy increase in local horizontal connections in slices of adult rat motor cortex. Long-term potentiation (LTP) could be induced by electrical stimulation of afferents using theta burst stimulation (TBS) conditionally, when synaptic inhibition was transiently blocked by focal application of GABA(A) receptor antagonist. Robust, long-lasting enhancement of synaptic transmission in horizontal connections was induced by brief application of the potassium channel blocker, tetraethylammonium (TEA, 25 mM), to the incubation medium. This TEA-LTP could be blocked by nifedipine, a voltage-dependent calcium channel blocker. A transient exposure of slices to elevated extracellular calcium (5 mM) resulted in a long-lasting enhancement of responses, termed Ca-LTP, which could be blocked by the antagonist of NMDA receptors, APV. The induction of both TEA-LTP and Ca-LTP, could be prevented by inhibitors of the extracellular signal regulated kinase (ERK) cascade U0126 and PD98059. A transient activation of the ERK, 15 min after application of TEA or elevated [Ca2+], was demonstrated using immunofluorescence. Both forms of plasticity could also be prevented by the inhibitor of cAMP-dependent protein kinases (PKA), Rp-cAMPS. These studies indicate the involvement of the ERK and PKA signaling mechanisms in synaptic plasticity of the motor cortex in vitro. Since LTP in horizontal connections of the motor cortex has previously been shown to be related to the acquisition of a motor skill, it is suggested that the ERK and PKA signaling pathways may be involved in motor learning.     

Distinguishable brain activation networks for short- and long-term motor skill learning

The acquisition of a new motor skill is characterized first by a short-term, fast learning stage in which performance improves rapidly, and subsequently by a long-term, slower learning stage in which additional performance gains are incremental. Previous functional imaging studies have suggested that distinct brain networks mediate these two stages of learning, but direct comparisons using the same task have not been performed. Here we used a task in which subjects learn to track a continuous 8-s sequence demanding variable isometric force development between the fingers and thumb of the dominant, right hand. Learning-associated changes in brain activation were characterized using functional MRI (fMRI) during short-term learning of a novel sequence, during short-term learning after prior, brief exposure to the sequence, and over long-term (3 wk) training in the task. Short-term learning was associated with decreases in activity in the dorsolateral prefrontal, anterior cingulate, posterior parietal, primary motor, and cerebellar cortex, and with increased activation in the right cerebellar dentate nucleus, the left putamen, and left thalamus. Prefrontal, parietal, and cerebellar cortical changes were not apparent with short-term learning after prior exposure to the sequence. With long-term learning, increases in activity were found in the left primary somatosensory and motor cortex and in the right putamen. Our observations extend previous work suggesting that distinguishable networks are recruited during the different phases of motor learning. While short-term motor skill learning seems associated primarily with activation in a cortical network specific for the learned movements, long-term learning involves increased activation of a bihemispheric cortical-subcortical network in a pattern suggesting "plastic" development of new representations for both motor output and somatosensory afferent information.     

Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning

Movement representations within the human primary motor and somatosensory cortices can be altered by motor learning. Decreases in local GABA concentration and its release may facilitate this plasticity. Here we use in vivo magnetic resonance spectroscopy (MRS) to noninvasively measure serial changes in GABA concentration in humans in a brain region including the primary sensorimotor cortex contralateral to the hand used for an isometric motor sequence learning task. Thirty minutes of motor sequence learning reduced the mean GABA concentration within a 2 x 2 x 2-cm3 voxel by almost 20%. This reduction was specific to motor learning: 30 min of similar, movements with an unlearnable, nonrepetitive sequence were not associated with changes in GABA concentration. No significant changes in GABA concentration were found in the primary sensorimotor cortex ipsilateral to the hand used for learning. These changes suggest remarkably rapid, regionally specific short-term presynaptic modulation of GABAergic input that should facilitate motor learning. Although apparently confined to the contralateral hemisphere, the magnitude of changes seen within a large spectroscopic voxel suggests that these changes occur over a wide local neocortical field.     

Strengthening of horizontal cortical connections following skill learning

Learning a new motor skill requires an alteration in the spatiotemporal pattern of muscle activation. Motor areas of cerebral neocortex are thought to be involved in this type of learning, possibly by functional reorganization of cortical connections. Here we show that skill learning is accompanied by changes in the strength of connections within adult rat primary motor cortex (M1). Rats were trained for three or five days in a skilled reaching task with one forelimb, after which slices of motor cortex were examined to determine the effect of training on the strength of horizontal intracortical connections in layer II/III. The amplitude of field potentials in the forelimb region contralateral to the trained limb was significantly increased relative to the opposite 'untrained' hemisphere. No differences were seen in the hindlimb region. Moreover, the amount of long-term potentiation (LTP) that could be induced in trained M1 was less than in controls, suggesting that the effect of training was at least partly due to LTP-like mechanisms. These data represent the first direct evidence that plasticity of intracortical connections is associated with learning a new motor skill.     

Adaptive Plasticity in Primate Motor Cortex as a Consequence of Behavioral Experience and Neuronal Injury

It is now clear that the motor cortex of adult mammals is capable of widespread functional reorganization. After specific types of motor skill training, the cortical representations of the movements used to perform the task expand, invading adjacent motor representations. After peripheral nerve injury, representations of unaffected muscles expand, invading those of the denervated muscles. After focal cortical injury, representations in the uninjured, adjacent cortical tissue undergo widespread alterations. Specific changes are dependent upon the use of the affected limb during the postinjury period. It now appears likely that motor map alterability results from changes in synaptic efficacy of intrinsic horizontal connections within motor cortex. Taken together, these studies suggest that the neurophysiological circuitry underlying muscle and movement maps within primary motor cortex is continually remodeled throughout an individual's life. The functional organization of motor cortex is constantly reshaped by behavioral demands for the learning of new motor skills.     

Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects

There is good evidence that synaptic plasticity in human motor cortex is involved in behavioural motor learning; in addition, it is now possible to probe mechanisms of synaptic plasticity using a variety of transcranial brain-stimulation protocols. Interactions between these protocols suggest that they both utilise common mechanisms. The aim of the present experiments was to test how well responsiveness to brain-stimulation protocols and behavioural motor learning correlate with each other in a sample of 21 healthy volunteers. We also examined whether any of these measures were influenced by the presence of a Val66Met polymorphism in the BDNF gene since this is another factor that has been suggested to be able to predict response to tests of synaptic plasticity. In 3 different experimental sessions, volunteers underwent 5-Hz rTMS, intermittent theta-burst stimulation (iTBS) and a motor learning task. Blood samples were collected from each subject for BDNF genotyping. As expected, both 5-Hz rTMS and iTBS significantly facilitated MEPs. Similarly, as expected, kinematic variables of finger movement significantly improved during the motor learning task. Although there was a significant correlation between the effect of iTBS and 5-Hz rTMS, there was no relationship in each subject between the amount of TMS-induced plasticity and the increase in kinematic variables during motor learning. Val66Val and Val66Met carriers did not differ in their response to any of the protocols. The present results emphasise that although some TMS measures of cortical plasticity may correlate with each other, they may not always relate directly to measures of behavioural learning. Similarly, presence of the Val66Met BDNF polymorphism also does not reliably predict responsiveness in small groups of individuals. Individual success in behavioural learning is unlikely to be closely related to any single measure of synaptic plasticity.     

Direct-current-dependent shift of theta-burst-induced plasticity in the human motor cortex

Animal studies using polarising currents have shown that induction of synaptic long-term potentiation (LTP) and long-term depression (LTD) by bursts of patterned stimulation is affected by the membrane potential of the postsynaptic neurone. The aim of the present experiments was to test whether it is possible to observe similar phenomena in humans with the aim of improving present protocols of inducing synaptic plasticity for therapeutic purposes. We tested whether the LTP/LTD-like after effects of transcranial theta-burst stimulation (TBS) of human motor cortex, an analogue of patterned electrical stimulation in animals, were affected by simultaneous transcranial direct-current stimulation (tDCS), a non-invasive method of polarising cortical neurones in humans. Nine healthy volunteers were investigated in a single-blind, balanced cross-over study; continuous TBS (cTBS) was used to introduce LTD-like after effects, whereas intermittent TBS (iTBS) produced LTP-like effects. Each pattern was coupled with concurrent application of tDCS (<200 s, anodal, cathodal, sham). Cathodal tDCS increased the response to iTBS and abolished the effects of cTBS. Anodal tDCS changed the effects of cTBS towards facilitation, but had no impact on iTBS. Cortical motor thresholds and intracortical inhibitory/facilitatory networks were not altered by any of the stimulation protocols. We conclude that the after effects of TBS can be modulated by concurrent tDCS. We hypothesise that tDCS changes the membrane potential of the apical dendrites of cortical pyramidal neurones and that this changes the response to patterned synaptic input evoked by TBS. The data show that it may be possible to enhance LTP-like plasticity after TBS in the human cortex.     

Links from complex spikes to local plasticity and motor learning in the cerebellum of awake-behaving monkeys

The hypothesis of cerebellar learning proposes that complex spikes in Purkinje cells engage mechanisms of plasticity in the cerebellar cortex; in turn, changes in the cerebellum depress the simple-spike response of Purkinje cells to a given stimulus and cause the adaptive modification of a motor behavior. Many elements of this hypothesis have been supported by prior experiments, and correlations have been found [corrected] between complex spikes, simple-spike plasticity and behavior [corrected] during the learning process. We carried out a trial-by-trial analysis of Purkinje cell responses in awake-behaving monkeys and found evidence for a causal role for complex spikes in the induction of cerebellar plasticity during a simple motor learning task. We found that the presence of a complex spike on one learning trial was linked to a substantial depression of simple-spike responses on the subsequent trial, at a time when behavioral learning was expressed.     

Addition of inhibition in the olivocerebellar system and the ontogeny of a motor memory

The developmental emergence of learning has traditionally been attributed to the maturation of single brain regions necessary for learning in adults, rather than to the maturation of synaptic interactions within neural systems. Acquisition and retention of a simple form of motor learning, classical conditioning of the eyeblink reflex, depends on the cerebellum and interconnected brainstem structures, including the inferior olive. Here, we combined unit recordings from Purkinje cells in eye regions of the cerebellar cortex and quantitative electron microscopy of the inferior olive to show that the developmental emergence of eyeblink conditioning in rats is associated with the maturation of inhibitory feedback from the cerebellum to the inferior olive. The results are consistent with previous work in adult animals and indicate that the maturation of cerebellar inhibition within the inferior olive may be a critical factor for the formation and retention of learning-specific cerebellar plasticity and eyeblink conditioning.     

Skilled-learning-induced potentiation in rat sensorimotor cortex: a transient form of behavioural long-term potentiation

The relation between the acquisition of a skilled motor task and synaptic plasticity in the sensorimotor cortex of the awake, freely behaving rat was examined. Skilled-motor training was previously found to induce a functional reorganization of the caudal forelimb area, and to induce an increase in synaptic efficacy, measured in vitro, on the side contralateral to the reaching forelimb. Here, we repeatedly measured neocortical evoked potential recordings in awake, freely behaving rats to examine whether skilled training would induce changes in polysynaptic efficacy on the side contralateral to the reaching forelimb. We found that the increase in task proficiency, but not the acquisition of task requirements or the maintenance of task proficiency, induced an increase in synaptic efficacy on the side contralateral to the reaching forelimb. We also tested the hypothesis that skilled learning induced potentiation shares similar mechanisms to long-term potentiation (LTP) and long-term depression by artificially manipulating polysynaptic efficacy in skilled rats with high- and low-frequency stimulation. We observed that, compared with the ipsilateral side, less potentiation but more depression could be induced on the side contralateral to the reaching forelimb. We conclude that a transient, network-based LTP-like mechanism operates during the learning of a skilled motor task.     

Developmental regulation of cognitive abilities: modified composition of a molecular switch turns on associative learning

N-methyl-D-aspartate receptors (NMDARs) act as molecular coincidence detectors and allow for association or dissociation between pre- and postsynaptic neurons. NMDA receptors are central to remodeling of synaptic connections during postnatal development and associative learning abilities in adults. The ability to remodel neural networks is altered during postnatal development, possibly due to a change in the composition of NMDARs. That is, as forebrain systems (and cerebellum) develop, synaptic NR2B-containing NMDARs (NR2B-NMDARs) are replaced by NR2A-containing NMDARs (NR2A-NMDARs) and NR2B-NMDARs move to extrasynaptic sites. During the initial phase of the switch, synapses contain both NR2A- and NR2B-NMDARs and both long-term potentiation and long-term depression are enhanced. As NMDAR subunit expression decreases and NR2A-NMDARs come to predominate in the synapse, channel function and synaptic plasticity are reduced, and remodeling ability dissipates. The end result is a balance of plasticity and stability that is optimal for information processing and storage. Associative learning abilities involving different sensory modalities emerge sequentially, in accordance with synaptic maturation in related cortical and underlying brain structures. Thus, developmental alterations in NMDAR composition that occur at different ages in various brain structures may explain the protracted nature of the maturation of various associative learning abilities.     

Effects of short-term training on sensory and motor function in severed nerves of long-term human amputees

Much has been studied and written about plastic changes in the CNS of humans triggered by events such as limb amputation. However, little is known about the extent to which the original pathways retain residual function after peripheral amputation. Our earlier, acute study on long-term amputees indicated that central pathways associated with amputated peripheral nerves retain at least some sensory and motor function. The purpose of the present study was to determine if these functional connections would be strengthened or improved with experience and training over several days time. To do this, electrodes were implanted within fascicles of severed nerves of long-term human amputees to evaluate the changes in electrically evoked sensations and volitional motor neuron activity associated with attempted phantom limb movements. Nerve stimulation consistently resulted in discrete, unitary, graded sensations of touch/pressure and joint-position sense. There was no significant change in the values of stimulation parameters required to produce these sensations over time. Similarly, while the amputees were able to improve volitional control of motor neuron activity, the rate and pattern of change was similar to that seen with practice in normal individuals on motor tasks. We conclude that the central plasticity seen after amputation is most likely primarily due to unmasking, rather than replacement, of existing synaptic connections. These results also have implications for neural control of prosthetic limbs.     

Substantia nigra dopamine regulates synaptic plasticity and membrane potential fluctuations in the rat neostriatum, in vivo

The spiny projection neurons of the neostriatum are a site at which dopamine inputs from the substantia nigra converge with excitatory inputs from the cerebral cortex. These two systems interact in certain learning and motor control mechanisms of the brain. We investigated these interactions using intracellular recording from spiny striatal neurons in urethane-anaesthetized rats. We found that acute dopamine depletion was associated with long-term depression of corticostriatal synaptic input. Electrical stimulation of the cortex which mimicked synchronous cortical input to striatal neurons also induced long-term depression of corticostriatal inputs. In intact control animals, but not in dopamine-depleted animals, this depression was prevented or reversed by concomitant stimulation of the substantia nigra. In agreement with previous in vitro studies, our in vivo findings show that long-term depression occurs in the corticostriatal pathway, and in addition show that it is regulated by dopaminergic inputs from the substantia nigra. This form of synaptic plasticity may therefore be important for understanding disturbances of the motor system seen in humans with Parkinson's disease.     

Synaptic proliferation in the motor cortex of adult cats after long-term thalamic stimulation.

1. One of the hypotheses for information storage in the CNS postulates the induction of structural changes in synaptic circuits. This postulate predicts that behavioral experiences produce changes in neural activity that subsequently induce synaptogenesis in the mature CNS. Available data indicate that the establishment of engrams for novel motor acts may involve alterations of synaptic interactions within the primary motor cortex. The present study examines the hypothesis that patterns of synaptic circuitry and of synaptic activation are rearranged after enhanced neural activity in pathways projecting to the motor cortex. 2. Electrodes implanted in the ventroposterolateral (VPL) nucleus of the thalamus were used for long-term stimulation (20 microA, 4 days) of afferents to the motor cortex in freely behaving, adult cats. This stimulation primarily affected corticocortical inputs from the somatosensory cortex (area 2) to area 4 gamma of the motor cortex. Electron microscopy and stereological procedures were used to compare the numerical density (Nv) of various types of synapses in layers II/III of the stimulated (experimental) motor cortex with the Nv of the corresponding synapses in the contralateral (control) hemisphere. 3. Long-term stimulation produced a significant increase (25.6%) in synaptic Nv in experimental motor cortex. This increase was due primarily to an increase in the Nv of asymmetrical synapses with dendritic spines. The numbers of symmetrical synapses, and of asymmetrical synapses with dendritic shafts, were not affected by long-term stimulation. 4. Synaptic active zones [calculated by measuring the lengths of postsynaptic densities (PSDs)] were significantly longer in experimental motor cortex. Lengthening of PSDs occurred selectively in asymmetrical synapses with dendritic shafts (28% increase). 5. The Nv of synapses having perforations in their PSDs (perforated synapses) was significantly higher in experimental hemispheres. Also increased was the incidence of synapse-associated polyribosomes, which are most commonly found at the base of dendritic spines. An increase in the number of perforated synapses and of polyribosomes are both morphological hallmarks of synaptogenesis. 6. The percentages of synapses having different curvatures (i.e., presynaptically concave, convex, or flat) were similar in experimental and in control motor cortex.(ABSTRACT TRUNCATED AT 400 WORDS)     

Primary motor cortical metaplasticity induced by priming over the supplementary motor area

Motor cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS) sometimes depends on the prior history of neuronal activity. These effects of preceding stimulation on subsequent rTMS-induced plasticity have been suggested to share a similar mechanism to that of metaplasticity, a homeostatic regulation of synaptic plasticity. To explore metaplasticity in humans, many investigations have used designs in which both priming and conditioning are applied over the primary motor cortex (M1), but the effects of priming stimulation over other motor-related cortical areas have not been well documented. Since the supplementary motor area (SMA) has anatomical and functional cortico-cortical connections with M1, here we studied the homeostatic effects of priming stimulation over the SMA on subsequent rTMS-induced plasticity of M1. For priming and subsequent conditioning, we employed a new rTMS protocol, quadripulse stimulation (QPS), which produces a broad range of motor cortical plasticity depending on the interval of the pulses within a burst. The plastic changes induced by QPS at various intervals were altered by priming stimulation over the SMA, which did not change motor-evoked potential sizes on its own but specifically modulated the excitatory I-wave circuits. The data support the view that the homeostatic changes are mediated via mechanisms of metaplasticity and highlight an important interplay between M1 and SMA regarding homeostatic plasticity in humans.     

Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation

Adaptation of ocular reflexes is a prototype of motor learning. While the cerebellum is acknowledged as the critical site for motor learning, the functional differences between the cerebellar cortex and nuclei in motor memory formation are not precisely known. Two different views are proposed: one that the memory is formed within the cerebellar flocculus, and the other that the memory is formed within vestibular nuclei. Here we developed a new paradigm of long-term adaptation of mouse horizontal optokinetic response eye movements and examined the location of its memory trace. We also tested the role of flocculus and inferior olive in long-term adaptation by chronic lesion experiments. Reversible bilateral flocculus shutdown with local application of 0.5 microl-5% lidocaine extinguished the memory trace of day-long adaptation, while it very little affected the memory trace of week-long adaptation. The responsiveness of vestibular nuclei after week-long adaptation was examined by measuring the extracellular field responses to the electrical stimulation of vestibular nerve under trichloroacetaldehyde anesthesia. The amplitudes and slopes of evoked monosynaptic field response (N1) of week-long adapted mice were enhanced around the medial vestibular nucleus compared with those of control mice. Chronic flocculus or inferior olive lesions abolished both day and week-long adaptations. These results suggest that the functional memory trace of short-term adaptation is formed initially within the cerebellar cortex, and later transferred to vestibular nuclei to be consolidated to a long-term memory. Both day and week-long adaptations were markedly depressed when neural nitric oxide was pharmacologically blocked locally and when neuronal nitric oxide synthase was ablated by gene knockout, suggesting that cerebellar long-term depression underlies both acquisition and consolidation of motor memory.     

Aberrant brain activation following motor skill learning in schizophrenic patients as shown by functional magnetic resonance imaging

BACKGROUND: Motor skill learning may be impaired in schizophrenia. While functional brain imaging studies have shown reduced activation during motor task performance in schizophrenic patients, brain activity changes with motor skill learning in these patients have not been studied by functional imaging. METHODS: A sequential complex motor task involving the right hand was performed by nine medicated schizophrenic patients and 10 age-matched healthy controls. Functional magnetic resonance images were obtained using a gradient echo, echoplanar imaging (EPI) pulse sequence before and after 1 week of training in performing the task. RESULTS: Bilaterally, patients showed significantly less blood oxygenation level-dependent (BOLD) signal response in the premotor area (PMA) before beginning motor training than controls. BOLD signal response increased in the left PMA of schizophrenic patients after 1 week of motor training; in contrast, the signal decreased in the left PMA of control subjects. Training effects concerning the number of finger movement sequences achieved did not differ between groups. Daily neuroleptic dose did not significantly affect changes with training in BOLD signal response in the PMA. CONCLUSIONS: These preliminary results suggest that schizophrenic patients have dysfunction of neural networks in areas including the PMA that are involved in executing a complex motor task. In terms of brain activity, motor learning may be less efficient or slower in the patients than in healthy subjects.     

Chronic inhibition of cyclooxygenase-2 induces dendritic hypertrophy and limited functional improvement following motor cortex stroke

The cyclooxygenase-2 (COX-2) enzyme is part of the inflammatory pathway and is induced within the brain by a variety of pathological events, including ischemia. Pharmacological agents that inhibit COX-2 have been found to be neuroprotective in a number of injury models, and long-term administration of these drugs has been shown to induce plastic changes in the brain. In the current experiment, we investigated the effectiveness of stimulating cortical plasticity following stroke injury through the administration of the COX-2 inhibitor drug NS398. Furthermore, we determined whether the induced plastic changes improved functional outcome following motor cortex stroke. Chronic drug administration was found to induce dendritic hypertrophy in cells in the parietal cortex, and this anatomical change was associated with the animals making significantly more reach attempts, as well as successful reaches during a skilled reaching task. Additional motor tests however revealed that the treatment did not affect the level of motor recovery, as the animals showed chronic impairments in the Schallert cylinder, and the forepaw inhibition tasks. Short-term administration of the drug, immediately following the stroke did not induce any dendritic changes, nor was it found to improve behavioral performance on any of the motor tasks. Based on these results we conclude that the plastic changes that are induced by long-term COX-2 inhibitor administration provide some benefit to functional outcome following ischemic cortical injury.     

The bidirectionality of motor learning in the vestibulo-ocular reflex is a function of cerebellar mGluR1 receptors

Bidirectional changes in synaptic transmission have the potential to optimize the control of movement. However, it can be difficult to establish a causal relationship between the bidirectionality of synaptic plasticity and bidirectional changes in the speed of actual movements. We asked whether metabotropic glutamate receptor 1 (mGluR1) receptors, which participate in cerebellar long-term depression (LTD), are necessary for bidirectional motor learning in the vestibulo-ocular reflex (VOR). Cerebellar LTD and long-term potentiation (LTP) are thought to cause increases and decreases, respectively, in the gain of the VOR; the direction of learning depends on the behavioral protocol. We injected either the mGluR1 agonist (S)-DHPG or the antagonist YM 298198 bilaterally into the flocculus of alert cats, and then induced motor learning. In the presence of YM 298198, the VOR gain decreased in gain-up, as well as in gain-down protocols. (S)-DHPG augmented gain-up learning. Gain-down learning was not significantly affected by either drug. These results supported the hypothesis that gain-up learning relies on cerebellar LTD, but gain-down learning relies on a different mechanism. In the absence of mGluR1 activity, cerebellar LTD may be replaced with LTP, permitting learning in only one direction.