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.

[1]  Eric R Kandel,et al.  Local protein synthesis and its role in synapse-specific plasticity , 2000, Current Opinion in Neurobiology.

[2]  O. Witte,et al.  Use‐related gene expression patterns of rat motor cortex , 2002, Neuroreport.

[3]  J. Donoghue,et al.  Strengthening of horizontal cortical connections following skill learning , 1998, Nature Neuroscience.

[4]  Lawrence C Katz,et al.  Neurotrophin Regulation of Cortical Dendritic Growth Requires Activity , 1996, Neuron.

[5]  E Jankowska,et al.  The mode of activation of pyramidal tract cells by intracortical stimuli. , 1975, The Journal of physiology.

[6]  J. Kleim,et al.  Motor Learning-Dependent Synaptogenesis Is Localized to Functionally Reorganized Motor Cortex , 2002, Neurobiology of Learning and Memory.

[7]  Otto W Witte,et al.  Gene Expression Profiling in Perilesional and Contralateral Areas after Ischemia in Rat Brain , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  G. W. Huntley Differential Effects of Abnormal Tactile Experience on Shaping Representation Patterns in Developing and Adult Motor Cortex , 1997, The Journal of Neuroscience.

[9]  Joseph E LeDoux,et al.  Memory Consolidation of Auditory Pavlovian Fear Conditioning Requires Protein Synthesis and Protein Kinase A in the Amygdala , 2000, The Journal of Neuroscience.

[10]  R. Nudo,et al.  Effects of Postlesion Experience on Behavioral Recovery and Neurophysiologic Reorganization after Cortical Injury in Primates , 2000, Neurorehabilitation and neural repair.

[11]  T. Brown,et al.  On the Instability of a Cortical Point , 1912 .

[12]  E. Welker,et al.  Upregulation of BDNF mRNA Expression in the Barrel Cortex of Adult Mice after Sensory Stimulation , 1996, The Journal of Neuroscience.

[13]  C. Epstein Applications of transcranial magnetic stimulation , 1999, Proceedings of the First Joint BMES/EMBS Conference. 1999 IEEE Engineering in Medicine and Biology 21st Annual Conference and the 1999 Annual Fall Meeting of the Biomedical Engineering Society (Cat. N.

[14]  Y. Dudai,et al.  Memory Extinction, Learning Anew, and Learning the New: Dissociations in the Molecular Machinery of Learning in Cortex , 2001, Science.

[15]  T. Deacon,et al.  Chronic cognitive deficits and amyloid precursor protein elevation after selective immunotoxin lesions of the basal forebrain cholinergic system , 1998, Neuroreport.

[16]  R. Racine,et al.  Changes in field potentials and membrane currents in rat sensorimotor cortex following repeated tetanization of the corpus callosum in vivo. , 1998, Cerebral cortex.

[17]  E. Fetz,et al.  Comparable patterns of muscle facilitation evoked by individual corticomotoneuronal (CM) cells and by single intracortical microstimuli in primates: evidence for functional groups of CM cells. , 1985, Journal of neurophysiology.

[18]  Mark Hallett,et al.  Plasticity of the human motor cortex and recovery from stroke , 2001, Brain Research Reviews.

[19]  Yi Liu,et al.  Grafts of BDNF-Producing Fibroblasts Rescue Axotomized Rubrospinal Neurons and Prevent Their Atrophy , 2002, Experimental Neurology.

[20]  Stefano Tamburin,et al.  Abnormal somatotopic arrangement of sensorimotor interactions in dystonic patients. , 2002, Brain : a journal of neurology.

[21]  D. Buonomano,et al.  Cortical plasticity: from synapses to maps. , 1998, Annual review of neuroscience.

[22]  T. Powell,et al.  The intrinsic connections of the cortex of area 4 of the monkey. , 1978, Brain : a journal of neurology.

[23]  Donald M. Wilson,et al.  Post-activation potentiation and depression in the neocortex of the rat: II. Chronic preparations , 1994, Brain Research.

[24]  M Hallett,et al.  Plasticity of movement representation in the human motor cortex. , 1999, Electroencephalography and clinical neurophysiology. Supplement.

[25]  M. A. Matthews,et al.  The effect of intraocular injection of tetrodotoxin on fast axonal transport of [3H]proline- and [3H]fucose-labeled materials in the developing rat optic nerve , 1985, Neuroscience.

[26]  M. Ehlers Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system , 2003, Nature Neuroscience.

[27]  M. Merzenich,et al.  Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  KM Jacobs,et al.  Reshaping the cortical motor map by unmasking latent intracortical connections , 1991, Science.

[29]  K. Svoboda,et al.  Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo , 2000, Nature.

[30]  E R Kandel,et al.  A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia. , 1986, Science.

[31]  D. Cain,et al.  The effect of water maze spatial training on posterior parietal cortex transcallosal evoked field potentials in the rat. , 1998, Cerebral cortex.

[32]  M. Tuszynski,et al.  Lesions of the Basal Forebrain Cholinergic System Impair Task Acquisition and Abolish Cortical Plasticity Associated with Motor Skill Learning , 2003, Neuron.

[33]  D. Jaffe,et al.  Protein Synthesis Inhibition Blocks the Induction of Mossy Fiber Long-Term Potentiation In Vivo , 2000, The Journal of Neuroscience.

[34]  Ian Q. Whishaw,et al.  The structure of skilled forelimb reaching in the rat: A proximally driven movement with a single distal rotatory component , 1990, Behavioural Brain Research.

[35]  E. Schuman,et al.  Protein synthesis in the dendrite. , 2002, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[36]  L. Maffei,et al.  BDNF Regulates the Maturation of Inhibition and the Critical Period of Plasticity in Mouse Visual Cortex , 1999, Cell.

[37]  D. C. Sterio The unbiased estimation of number and sizes of arbitrary particles using the disector , 1984, Journal of microscopy.

[38]  D. Amaral,et al.  An Analysis of Atrophy in the Medial Mammillary Nucleus Following Hippocampal and Fornix Lesions in Humans and Nonhuman Primates , 2000, Experimental Neurology.

[39]  K. Svoboda,et al.  Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex , 2002, Nature.

[40]  R. Porter,et al.  Morphology of neurons in area 4γ of the cat's cortex studied with intracellular injection of HRP , 1988 .

[41]  R. Cantello,et al.  Applications of Transcranial Magnetic Stimulation in Movement Disorders , 2002, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[42]  E. Shooter,et al.  BDNF overexpression increases dendrite complexity in hippocampal dentate gyrus , 2002, Neuroscience.

[43]  O. Steward,et al.  Protein synthesis at synaptic sites on dendrites. , 2001, Annual review of neuroscience.

[44]  Larry W. Swanson,et al.  Brain Maps: Structure of the Rat Brain , 1992 .

[45]  J. Kleim,et al.  Functional reorganization of the rat motor cortex following motor skill learning. , 1998, Journal of neurophysiology.

[46]  Marie-H Monfils,et al.  Motor map expansion following repeated cortical and limbic seizures is related to synaptic potentiation. , 2002, Cerebral cortex.

[47]  Mark G Packard,et al.  Post‐training reversible inactivation of hippocampus reveals interference between memory systems , 2002, Hippocampus.

[48]  H. Okado,et al.  Continual remodeling of postsynaptic density and its regulation by synaptic activity , 1999, Nature Neuroscience.

[49]  W. D. Thompson,et al.  Excitation of pyramidal tract cells by intracortical microstimulation: effective extent of stimulating current. , 1968, Journal of neurophysiology.

[50]  M. Merzenich,et al.  Repetitive microstimulation alters the cortical representation of movements in adult rats. , 1990, Somatosensory & motor research.

[51]  J. Kleim,et al.  Sensitivity of cortical movement representations to motor experience: evidence that skill learning but not strength training induces cortical reorganization , 2001, Behavioural Brain Research.

[52]  R. Nudo,et al.  Neural Substrates for the Effects of Rehabilitative Training on Motor Recovery After Ischemic Infarct , 1996, Science.

[53]  R. Lemon,et al.  The effects upon the activity of hand and forearm muscles of intracortical stimulation in the vicinity of corticomotor neurones in the conscious monkey , 2004, Experimental Brain Research.

[54]  M. Hallett,et al.  Plasticity of the Human Motor Cortex , 1993 .

[55]  Samuel Schacher,et al.  Synapse Formation in the Absence of Cell Bodies Requires Protein Synthesis , 2002, The Journal of Neuroscience.

[56]  J. Rauschecker Cortical map plasticity in animals and humans. , 2002, Progress in brain research.

[57]  E. Kandel,et al.  Synapse-Specific, Long-Term Facilitation of Aplysia Sensory to Motor Synapses: A Function for Local Protein Synthesis in Memory Storage , 1997, Cell.

[58]  J. Sarvey,et al.  Blockade of long-term potentiation in rat hippocampal CA1 region by inhibitors of protein synthesis , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.