This project seeks to identify the cellular mechanisms that regulate neurite outgrowth and synapse replacement in the striatum (ST) in response to injury and the effect of aging on these processes. Studies conducted during the previous funding period support the belief that the cellular basis of reactive synaptogenesis involves the activation of specific sets of partially overlapping developmental signals that are cell type, brain region and lesion specific, and that these responses may be differentially affected by age. However, while previous anatomical studies have readily demonstrated the ability of neurons to form new synaptic circuits in response to brain injury the cellular mechanisms that regulate reactive synaptogenesis remain unclear. The studies proposed are a direct extension of the work completed previously and will test four general hypotheses: 1) that different sets of growth associated proteins regulate neurite outgrowth in corticostriatal neurons in response to different deafferentation lesions: 2) that the time course for debris removal, terminal proliferation and synapse replacement in the ST after injury is influenced by age and the type of lesion involved; 3) that the new pattern of synaptic innervation that is formed in the ST is different after lesions of the cortex, substantia nigra or both, and are reflected in the pharmacological properties of the synaptic input on striatal neurons; and 4) that chronic dietary restriction or treatment with the dopamine agonist pergolide to manipulate the effects of aging in the ST (i.e., reactive astrocytosis, loss of D2 receptors) will reverse the effects of aging on dendrite remodeling and neurite outgrowth found after the cortex lesion. We will use experimental deafferentation lesions in young (4 mos) and old (24 mos) rats to model different combinations of neurotransmitter deficits that may effect neurite outgrowth and synapse replacement in the ST following brain injury. In addition, we will screen aged rats prior to surgery, using the balance beam test, to identify subsets of old rats with nigrostriatal deficits that may alter their ability to respond to the lesion. We will also assess the rate of functional recovery to correlate with our morphological and molecular data. Morphological remodeling of afferent input to the ST will be evaluated using ultrastructural methods; while synaptic physiology of the anatomically reorganized ST will be examined by electrophysiological analysis. In addition, we will use in in situ hybridization and western blot methods to define the time course of changes in the levels of mRNAs and proteins that we hypothesize are associated with the promotion of neurite outgrowth and synapse replacement in the ST (i.e., SCG-10, GAP-43, BDNF, GDNF, etc.).

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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University of Southern California
Los Angeles
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