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Jeffrey A Kleim

Publications and source records attributed to Jeffrey A Kleim.

At least 19 recordsLinked to original sources
PubMed2006

Motor training induces experience-specific patterns of plasticity across motor cortex and spinal cord.

The motor cortex and spinal cord possess the remarkable ability to alter structure and function in response to differential motor training. Here we review the evidence that the corticospinal system is not only plastic but that the nature and locus of this plasticity is dictated by the specifics of the motor experience. Skill training induces synaptogenesis, synaptic potentiation, and reorganization of movement representations within motor cortex. Endurance training induces angiogenesis in motor cortex, but it does not alter motor map organization or synapse number. Strength training alters spinal motoneuron excitability and induces synaptogenesis within spinal cord, but it does not alter motor map organization. All three training experiences induce changes in spinal reflexes that are dependent on the specific behavioral demands of the task. These results demonstrate that the acquisition of skilled movement induces a reorganization of neural circuitry within motor cortex that supports the production and refinement of skilled movement sequences. We present data that suggest increases in strength may be mediated by an increased capacity for activation and/or recruitment of spinal motoneurons while the increased metabolic demands associated with endurance training induce cortical angiogenesis. Together these results show the robust pattern of anatomic and physiological plasticity that occurs within the corticospinal system in response to differential motor experience. The consequences of such distributed, experience-specific plasticity for the encoding of motor experience by the motor system are discussed.

Action Potentials↗
PubMed2006

BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex.

Motor training can induce profound physiological plasticity within primary motor cortex, including changes in corticospinal output and motor map topography. Using transcranial magnetic stimulation, we show that training-dependent increases in the amplitude of motor-evoked potentials and motor map reorganization are reduced in healthy subjects with a val66met polymorphism in the brain-derived neurotrophic factor gene (BDNF), as compared to subjects without the polymorphism. The results suggest that BDNF is involved in mediating experience-dependent plasticity of human motor cortex.

Adult↗
PubMed2006

Induction of neocortical long-term depression results in smaller movement representations, fewer excitatory perforated synapses, and more inhibitory synapses.

Long-term depression (LTD) is one of the most widely investigated models of the synaptic mechanisms underlying learning and memory. Previous research has shown that induction of LTD in the neocortex decreases measures of pyramidal cell dendritic morphology in both layers III and V. Here, we investigated the effects of LTD induction on 1) the time course of recovery of synaptic efficacy, 2) movement representations, 3) cortical thickness and layer V neuron density, and 4) the density of excitatory and inhibitory synapses in layer V of sensorimotor neocortex. Rats carried a stimulating electrode in the midline corpus callosum and a recording electrode in the right sensorimotor neocortex. Each rat received either low-frequency stimulation composed of 900 pulses at 1 Hz or handling daily for a total of 20-25 days. Callosal-neocortical evoked potentials were recorded in the right hemisphere before and after stimulation or handling. Our results show that LTD induction lasts for 3 weeks and results in smaller motor maps of the caudal forelimb area. We did not observe any reduction in neocortical thickness or neuron density. There was a reduction in the density of excitatory perforated synapses and an increase in the density of inhibitory synapses in layer V of the sensorimotor neocortex, thereby providing a general mechanism for the reduction in motor map size. This study sheds light on the interaction between an artificial model of learning, receptive field characteristics, and synaptic number in the sensorimotor cortex.

Animals↗
PubMed2006

FGF-2-induced cell proliferation stimulates anatomical, neurophysiological and functional recovery from neonatal motor cortex injury.

Infant rats treated with basic fibroblast growth factor-2 (FGF-2) after postnatal day (P)10 motor cortical injury, show functional improvement in adulthood relative to those that do not receive FGF-2. In this study we used a combination of behavioural, immunohistochemical, electrophysiological, electron microscopic and teratological approaches to investigate possible mechanisms by which FGF-2 may influence functional recovery. We show that subcutaneous injections of FGF-2 following bilateral lesions to the motor cortex at P10 in the rat leads to filling of the lesion area with migrating neuroblasts and cycling cells. We assessed the functionality of this tissue in adulthood, and show that cells from the filled region spontaneously fire and form synapses. Behavioural analysis shows enhanced motor performance in the FGF-2-treated lesion rats in comparison to vehicle-treated lesion rats, and this improvement is reversed by removal of the tissue from the previously lesioned area or by blocking cortical regeneration by embryonic treatment with bromodeoxyuridine (BrdU). The results show that FGF-2 stimulates filling of the lesion cavity with cells after neonatal motor cortex lesions, that the new tissue has anatomical and physiological properties similar to control tissue, and that the filled region supports motor behaviour.

Animals↗
PubMed2005

A quantitative comparison of synaptic density following perfusion versus immersion fixation in the rat cerebral cortex.

The main objective of the present study was to perform an unbiased comparison of immersion vs. perfusion techniques to assess whether we could use the former to quantify synapses through electron microscopy (EM). Using the immersion technique is ideally suited for instances in which the specimen under study could not be perfused under the standard EM protocol. Our results suggest that, despite suboptimal qualitative results, fixation by immersion allows for adequate quantification of synapses.

Animals↗
PubMed2005

Limits on recovery in the corticospinal tract of the rat: partial lesions impair skilled reaching and the topographic representation of the forelimb in motor cortex.

Although evidence suggests that there are impairments in skilled movements following very large lesions of the pyramidal component of the corticospinal tract, the behavioral and electrophysiological effects of partial lesion has not received equal attention. Here, rats with complete lesions or partial lesions (medial, central, or lateral third) of the pyramidal tract at the medullary pyramids were evaluated for their quantitative and qualitative postsurgical performance on a skilled reaching task, following which the topographic representation of their forelimb was mapped with intracortical microstimulation (ICMS). Complete lesions impaired reaching success, impaired the qualitative features of reaching movements, and abolished ICMS evoked movement from the forelimb region of motor cortex. Although partial lesions did not impair reaching success, they did impair qualitative aspects of limb movement including forepaw aiming, supination, and food pellet release. ICMS indicated a reduction in the size of the forelimb area, especially the distal area of the caudal forelimb area (CFA), of the motor map. The behavioral and electrophysiological impairments did not vary with lesion location within the pyramidal tract. The incomplete recovery, as measured both behaviorally and electrophysiologically, demonstrates that plasticity within the corticospinal system is limited even with lesions that permit substantial sparing of pyramidal tract fibers.

Animals↗
PubMed2005

In search of the motor engram: motor map plasticity as a mechanism for encoding motor experience.

Motor skill acquisition occurs through modification and organization of muscle synergies into effective movement sequences. The learning process is reflected neurophysiologically as a reorganization of movement representations within the primary motor cortex, suggesting that the motor map is a motor engram. However, the specific neural mechanisms underlying map plasticity are unknown. Here the authors review evidence that 1) motor map topography reflects the capacity for skilled movement, 2) motor skill learning induces reorganization of motor maps in a manner that reflects the kinematics of acquired skilled movement, 3) map plasticity is supported by a reorganization of cortical microcircuitry involving changes in synaptic efficacy, and 4) motor map integrity and topography are influenced by various neurochemical signals that coordinate changes in cortical circuitry to encode motor experience. Finally, the role of motor map plasticity in recovery of motor function after brain damage is discussed.

Animals↗
PubMed2004

Preserved ipsilateral-to-lesion motor map organization in the unilateral 6-OHDA-treated rat model of Parkinson's disease.

The classic view of dopamine (DA) loss in Parkinson's disease is that it produces a functional deafferentation in striatal-cortical circuitry that, in turn, contributes to sensorimotor deficits. The present study examines this view in the rat by assessing how DA-depletion affects the intracortical microstimulation (ICMS) topographic representation of movement in the rostral and caudal motor areas of the motor cortex. The ICMS map is used as an index of motor cortex function because it has been shown to reflect motor function and experience. Groups of rats received no training or skilled reach training and were then given unilateral 6-hydroxydopamine (6-OHDA) or sham lesions of the nigrostriatal bundle to deplete nigrostriatal DA. Lesion success was confirmed by abnormalities in skilled reaching, by apomorphine-induced rotation, and by loss of DA neurons in the substantia nigra. The size and threshold of the motor map in naive and skilled reach trained DA-depleted rats were preserved. In addition, there was an increase in distal limb representation in the caudal forelimb area (CFA) in the DA-depleted rats suggesting a possible plastic response to the behavioral effects of DA-depletion. The presence of preserved size and modified map organization in DA-depleted rats is discussed in relation to the hypothesis that preserved motor cortex functionality despite DA loss underlies the spared motor abilities of DA-depleted rats.

Analysis of Variance↗
PubMed2004

Long-term potentiation induces expanded movement representations and dendritic hypertrophy in layer V of rat sensorimotor neocortex.

While long-term potentiation (LTP) is currently the most widely investigated model of the synaptic mechanisms underlying learning, there is a paucity of reports on the direct effects of LTP on cortical organization. Here we show that strengthening polysynaptic potentiation correlates with an expanded neocortical area that responds to intracortical microstimulation-induced movements of rat forelimb and increased dendritic material in layer V pyramidal cells. Rats carried a stimulating electrode in the corpus callosum (midline), and a recording electrode in the right caudal forelimb area (CFA). Each rat received 15 days of either high frequency stimulation (HFS) or handling. Evoked potentials of the transcallosal pathway were recorded in the right hemisphere before and after 15 days of stimulation or handling. Following the last stimulation, movement representations were determined in the left CFA using high-resolution intracortical microstimulation (ICMS) and then the brains were processed for Golgi-Cox staining. Our results show that synaptic modification results in a recruitment of more neocortical area into movement representations and increases in several measures of dendritic morphology in layers III and V. This study sheds light on the interaction between artificial models of learning, receptive field characteristics and dendritic morphology in the sensorimotor cortex.

Adaptation, Physiological↗
PubMed2004

Cortical synaptogenesis and motor map reorganization occur during late, but not early, phase of motor skill learning.

Extensive motor skill training induces reorganization of movement representations and synaptogenesis within adult motor cortex. Motor skill does not, however, develop uniformly across training sessions. It is characterized by an initial fast phase, followed by a later slow phase of learning. How cortical plasticity emerges during these phases is unknown. Here, we examine motor map topography and synapse number within rat motor cortex during the early and late phases of motor learning. Adult rats were placed in either a skilled or unskilled reaching condition (SRC and URC, respectively) for 3, 7, or 10 d. Intracortical microstimulation of layer V was used to determine the topography of forelimb movement representations within caudal forelimb area of motor cortex contralateral to the trained paw. Quantitative electron microscopy was used to measure the number of synapses per neuron within layer V. SRC animals showed significant increases in reaching accuracy after 3, 7, and 10 d of training. In comparison with URC animals, SRC animals had significantly larger distal forelimb representations after 10 d of training only. Furthermore, SRC animals had significantly more synapses per neuron than URC animals after 7 and 10 d of training. These results show that both motor map reorganization and synapse formation occur during the late phase of skill learning. Furthermore, synaptogenesis precedes map reorganization. We propose that motor map reorganization and synapse formation do not contribute to the initial acquisition of motor skills but represent the consolidation of motor skill that occurs during late stages of training.

Animals↗
PubMed2004

Evidence for bilateral control of skilled movements: ipsilateral skilled forelimb reaching deficits and functional recovery in rats follow motor cortex and lateral frontal cortex lesions.

Unilateral damage to cortical areas in the frontal cortex produces sensorimotor deficits on the side contralateral to the lesion. Although there are anecdotal reports of bilateral deficits after stroke in humans and in experimental animals, little is known of the effects of unilateral lesions on the same side of the body. The objective of the present study was to make a systematic examination of the motor skills of the ipsilateral forelimb after frontal cortex lesions to either the motor cortex by devascularization of the surface blood vessels (pial stroke), or to the lateral cortex by electrocoagulation of the distal branches of the middle cerebral artery (MCA stroke). Plastic processes in the intact hemisphere were documented using Golgi-Cox dendritic analysis and by intracortical microstimulation analysis. Although tests of reflexive responses in forelimb placing identified a contralateral motor impairment following both cortical lesions, quantitative and qualitative measures of skilled reaching identified a severe ipsilateral impairment from which recovery was substantial but incomplete. Golgi-impregnated pyramidal cells in the forelimb area showed an increase in dendritic length and branching. Electrophysiological mapping showed normal size forelimb representations in the lesioned rats relative to control animals. The finding of an enduring ipsilateral impairment in skilled movement is consistent with a large but more anecdotal literature in rats, nonhuman primates and humans, and suggests that plastic changes in the intact hemisphere are related to that hemisphere's contribution to skilled movement.

Animals↗
PubMed2003

Long-Evans and Sprague-Dawley rats have similar skilled reaching success and limb representations in motor cortex but different movements: some cautionary insights into the selection of rat strains for neurobiological motor research.

Many rat strains are used for neurobiological studies of nervous system function and behavior. The most widely used strain for studies of the neural basis of movement is the out bred, pigmented Long-Evans strain, while the most widely used strains for the study of movement impairments in neurological disease are out bred albino rats, including Sprague-Dawley rats. Although previous research has indicated that there are strain differences in skilled movements displayed by different rat strains, there has been no explicit comparison of the Long-Evans and Sprague-Dawley strains. This was the purpose of the present study. The rats were video recorded as they learned to reach for single food pellets and the video records were subjected to frame-by-frame analysis. Component movements of reaching were scored using a system derived from Eshkol-Wachman Movement Notation (EWMN). The quality of movements was described using Laban Movement Analysis (LMA). Forelimb representations in motor cortex were defined electrophysiologically. Acquisition scores and success in reaching did not differ between the two strains, nor did the topographical representation of the forelimb in motor cortex. Long-Evans and Sprague-Dawley rats did differ in the movements used for reaching and on the quality of their movements. The movements of Sprague-Dawley rats resembled the movements of Long-Evans rats with motor system injury. That rat strains can show both quantitative and qualitative differences in movement is useful for the understanding of the genetic, neural, and behavioral organization of the motor system. The results are also relevant to the question of appropriateness of particular rat strains for studies of neurological diseases and the effects of albinism on motor behavior, and suggest that some of the most widely used rat strains for neurological investigations may be less than appropriate.

Animals↗
PubMed2003

Functional organization of adult motor cortex is dependent upon continued protein synthesis.

The functional organization of adult cerebral cortex is characterized by the presence of highly ordered sensory and motor maps. Despite their archetypical organization, the maps maintain the capacity to rapidly reorganize, suggesting that the neural circuitry underlying cortical representations is inherently plastic. Here we show that the circuitry supporting motor maps is dependent upon continued protein synthesis. Injections of two different protein synthesis inhibitors into adult rat forelimb motor cortex caused an immediate and enduring loss of movement representations. The disappearance of the motor map was accompanied by a significant reduction in synapse number, synapse size, and cortical field potentials and caused skilled forelimb movement impairments. Further, motor skill training led to a reappearance of movement representations. We propose that the circuitry of adult motor cortex is perpetually labile and requires continued protein synthesis in order to maintain its functional organization.

Age Factors↗
PubMed2003

Motor enrichment and the induction of plasticity before or after brain injury.

Voluntary exercise, treadmill activity, skills training, and forced limb use have been utilized in animal studies to promote brain plasticity and functional change. Motor enrichment may prime the brain to respond more adaptively to injury, in part by upregulating trophic factors such as GDNF, FGF-2, or BDNF. Discontinuation of exercise in advance of brain injury may cause levels of trophic factor expression to plummet below baseline, which may leave the brain more vulnerable to degeneration. Underfeeding and motor enrichment induce remarkably similar molecular and cellular changes that could underlie their beneficial effects in the aged or injured brain. Exercise begun before focal ischemic injury increases BDNF and other defenses against cell death and can maintain or expand motor representations defined by cortical microstimulation. Interfering with BDNF synthesis causes the motor representations to recede or disappear. Injury to the brain, even in sedentary rats, causes a small, gradual increase in astrocytic expression of neurotrophic factors in both local and remote brain regions. The neurotrophic factors may inoculate those areas against further damage and enable brain repair and use-dependent synaptogenesis associated with recovery of function or compensatory motor learning. Plasticity mechanisms are particularly active during time-windows early after focal cortical damage or exposure to dopamine neurotoxins. Motor and cognitive impairments may contribute to self-imposed behavioral impoverishment, leading to a reduced plasticity. For slow degenerative models, early forced forelimb use or exercise has been shown to halt cell loss, whereas delayed rehabilitation training is ineffective and disuse is prodegenerative. However, it is possible that, in the chronic stages after brain injury, a regimen of exercise would reactivate mechanisms of plasticity and thus enhance rehabilitation targeting residual functional deficits.

Animals↗
PubMed2003

Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult.

Recovery of motor function following stroke is believed to be supported, at least in part, by functional compensation involving residual neural tissue. The present study used a rodent model of focal ischemia and intracortical microstimulation (ICMS) to examine the behavioral and physiological effects of cortical stimulation in combination with motor rehabilitation. Adult rats were trained to criterion on a single pellet reaching task before ICMS was used to derive maps of movement representations within forelimb motor cortex contralateral to the trained paw. All animals then received a focal ischemic infarct within the motor map. A cortical surface electrode was implanted over the motor cortex. Low levels of electrical stimulation were applied during rehabilitative training on the same reaching task for 10 days and ICMS used to derive a second motor map. Results showed that both monopolar and bipolar cortical stimulation significantly enhanced motor recovery and increased the area of cortex from which microstimulation movements could be evoked. The results demonstrate the behavioral and neurophysiological benefits of cortical stimulation in combination with rehabilitation for recovery from stroke.

Analysis of Variance↗
PubMed2002

Long-Evans rats have a larger cortical topographic representation of movement than Fischer-344 rats: a microstimulation study of motor cortex in naïve and skilled reaching-trained rats.

Intracortical microstimulation of the frontal cortex evokes movements in the contralateral limbs, paws, and digits of placental mammals including the laboratory rat. The topographic representation of movement in the rat consists of a rostral forelimb area (RFA), a caudal forelimb area (CFA), and a hind limb area (HLA). The size of these representations can vary between individual animals and the proportional representation of the body parts within regions can also change as a function of experience. To date, there have been no investigations of strain differences in the cortical map of rats, and this was the objective of the present investigation. The effect of cortical stimulation was compared in young male Long-Evans rats and Fischer-344 rats. The overall size of the motor cortex representation was greater in Long-Evans rats compared to Fischer-344 rats and the threshold required to elicit a movement was higher in the Fischer-344 rats. An additional set of animals were trained in a skilled reaching task to rule out the possibility that experiential differences in the groups could account for the result and to examine the relationship between the differences in topography of cortical movement representations and motor performance. The Long-Evans rats were quantitatively and qualitatively better in skilled reaching than the Fischer-344 rats. Also, Long-Evans rats exhibited a relatively larger area of the topographic representation and lower thresholds for eliciting movement in the contralateral forelimb. This is the first study to describe pronounced strain-related differences in the microstimulation-topographic map of the motor cortex. The results are discussed in relation to using strain differences as a way of examining the behavioral, the physiological, and the anatomical organization of the motor system.

Animals↗
PubMed2002

Learning-induced multiple synapse formation in rat cerebellar cortex.

Strengthening of synaptic connections has been proposed to underlie information storage in the brain, and experience-dependent increases in synapse number have been observed. However, the effect of these new synapses on the specific connectivity, and thus function, of a given brain area remains largely unknown. We report here that motor learning specifically induces the formation of multiple synapses--two post-synaptic contacts at a single pre-synaptic varicosity--in the cerebellum. Rats undergoing motor learning had more multiple synapses (two Purkinje cell spines contacting a given parallel fiber varicosity) per Purkinje cell than did active or inactive controls. The formation of multiple synapses provides an additional connection between a given parallel fiber and Purkinje cell, thereby enhancing particular pathways, and may constitute a fundamental mechanism of neural encoding.

Animals↗