UC San Diego

Neural plasticity - the capacity of the brain to change - has been described at almost every level of the nervous system. These include changes at the single neuron level in gene expression, protein phosphorylation and cellular distribution of proteins; changes in the morphology of spines and dendrites; changes in the synaptic signaling efficacy between different populations of neurons; and finally, large-scale changes in the organization or function of entire brain regions. This last type, denoted as cortical reorganization or map plasticity, is of special importance because it is believed to represent the large-scale integration of the many plastic changes that occur at the cellular and systems levels. functional maps of these areas of the brain before and after different experimental manipulations. One of the first examples of such cortical reorganization was demonstrated in the somatosensory cortex following digit amputation in macaque monkeys [1]. Further studies demonstrated somatosensory cortical reorganization following other peripheral manipulations [2], skilled training on a tactile paradigm [3, 4], and recovery of function after a cortical injury [5]. It was first surmised that the neural correlates of map plasticity would be the same, regardless of whether such plasticity occurred following cortical injury, peripheral injury or behavioral training [6]. Thus, a finding describing the importance of acetylcholine for map plasticity following skilled motor learning [7] was taken as evidence that acetylcholine was necessary for all forms of cortical map plasticity. In this dissertation, we challenged that assertion. Specifically, we have shown that the neural processes underlying cortical map plasticity vary depending on the experimental paradigm used to elicit it. Further, we demonstrate that certain aspects of this plasticity are specific to behavioral experience. We used the motor cortex of rats as a model system to study cortical reorganization following different types of injuries (both peripheral and central), as well as different types of behavioral experiences, including motor development during the juvenile period and skilled motor learning in adulthood. We first studied the role acetylcholine plays in these different types of motor cortical plasticity. We found that the basal forebrain cholinergic system, the primary source of acetylcholine in the cortex, is required in adult animals for behaviorally driven forms of cortical plasticity, but not for plasticity that occurs spontaneously following nervous system injury. We also found that this cholinergic system is necessary for the normal development of the cortical motor system. We next proceeded to study whether cortical reorganization is ever associated with axonal plasticity of the corticospinal tract at the level of the spinal cord. As axonal plasticity of other fibers has been described following cortical lesions, these neurons were traced following a cortical injury and rehabilitation paradigm previously developed in the lab. We found no evidence of plasticity of the corticospinal tract system following either a brain injury alone, or a brain injury in conjunction with rehabilitation training. Map plasticity of the motor cortex occurs in many contexts, and is thus not by itself an indication of skilled motor behavior. In searching for a paradigm to study motor cortex plasticity that occurs primarily in the context of skilled motor behavior, we adopted a stimulation paradigm used by others to evoke higher-level encoding of motor movements. Using this long-term stimulation paradigm, we found a form of cortical plasticity that occurs only in the context of rehabilitation following a cortical lesion. Plasticity of these complex movement maps correlated with the functional recovery of the animals, validating their behavioral relevance. We conclude that there are many different neural correlates underlying map plasticity of the motor cortex. In order to utilize this knowledge to enhance recovery following injury, it is essential to understand which neural changes have behavioral and functional relevance. 1. Merzenich, M.M., et al., Somatosensory cortical map changes following digit amputation in adult monkeys. J Comp Neurol, 1984. 224(4): p. 591-605. 2. Merzenich, M.M. and W.M. Jenkins, Reorganization of cortical representations of the hand following alterations of skin inputs induced by nerve injury, skin island transfers, and experience. J Hand Ther, 1993. 6(2): p. 89-104. 3. Recanzone, G.H., et al., Topographic reorganization of the hand representation in cortical area 3b owl monkeys trained in a frequency- discrimination task. J Neurophysiol, 1992. 67(5): p. 1031- 56. 4. Recanzone, G.H., C.E. Schreiner, and M.M. Merzenich, Plasticity in the frequency representation of primary auditory cortex following discrimination training in adult owl monkeys. J Neurosci, 1993. 13(1): p. 87-103. 5. Xerri, C., et al., Plasticity of primary somatosensory cortex paralleling sensorimotor skill recovery from stroke in adult monkeys. J Neurophysiol, 1998. 79(4): p. 2119-48. 6. Cruikshank, S.J. and N.M. Weinberger, Evidence for the Hebbian hypothesis in experience-dependent physiological plasticity of neocortex: a critical review. Brain Res Brain Res Rev, 1996. 22(3): p. 191-228. 7. Conner, J.M., et al., Lesions of the Basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron, 2003. 38(5): p. 819-29