Bidirectional plasticity supports learning and post-ischemic functional recovery in the rat striatum.

摘要

While stroke-related deaths have decreased in recent years, stroke is still the leading cause of long-term disability in the United States. Adequate rehabilitation is dependant upon plasticity, a multidimensional and adaptive process underlying recovery of function in both the human and rodent brain. The complexity of processes underlying plasticity in the central nervous system is still largely unknown, but manipulating this spontaneous state of the healing brain is of the utmost importance as it will allow maximum therapeutic effect. Characterization of lesion-induced local and remote rewiring, initial behavioral deficit and their long-term relationships to behavioral outcome are required to fill some of the gaps in our understanding of brain repair mechanisms after stroke. The experiments outlined in this dissertation take advantage of hypothesized neuroplasticity foundations of learning and memory, as well as an established model of forelimb motor cortex injury in rats in order to examine changes in the striatal target regions of the disrupted and intact corticofugal tracts as well as within the uninjured homotopic sensorimotor cortex. Ultimately, these studies enhance those changes and their behavioral correlates through skilled training.;Our work investigates the molecular underpinnings of unilateral skilled reach task acquisition in the rat. The findings demonstrate that striatal shifts in glutamate receptor subunit phosphorylation and composition, known to support changes in synaptic strength and efficacy, accompany learning in an experience-dependent fashion. As task-specific rehabilitation is a critical component of stroke-related disability treatment, an increasing understanding of neurotransmission alterations that occur during novel motor sequence practice can play a valuable role in the pursuit of adjuvant therapies.;Results presented show that naive learning and post-ischemic re-learning share molecular support phenomena. Bi-directional (&agr;-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA and (N-methyl D-aspartate) NMDA receptor changes are associated with behavioral recovery from lesion-induced impairments in an ordinal and training-dependent manner. Substantial skilled task experience, likely accompanied by morphological growth at active corticostriatal synapses, allows glutamate receptor-modulated long-term plasticity thresholds to stabilize, thereby promoting an insaturable learning environment. While loss of cortical input to the denervated striatum is likely the source of abnormal patterns of glutamate receptor expression in the hemisphere subject to lesion, disregulated inhibition within the intact cortex may initiate these changes along the corticostriatal pathway of the non-injured hemisphere. Initial behavioral deficit is an indication of both extent of lesion and underlying neurotransmitter transmission and receptor expression.;Medium spiny neuron (MSN) synaptic plasticity can contribute to improved functional motor output variably in the context of different experimental paradigms. This flexibility is appropriate for the striatum's critical role in both motor learning and recovery, as it simultaneously promotes physiological adaptability and homeostasis. One of the fundamental sources of support for this elegant and malleable system may be the capacity for bi-directionality at glutamate receptors. Future studies will continue to uncover the potential for modifying these characteristics for use in innovative and effective clinical strategies.