The longterm objective of this program is to determine if changes in the morphology and cholinergic phenotype of basal forebrain (BF) neurons and their targets in the hippocampus and neocortex as a consequence of perinatal choline treatment corollate with choline-induced facilitation of spatial memory in young adult and aged rats. First, we will use computer- assisted morphometry to characterize in young adult and aged rats the morphological changes in BF neurons immunoreactive for nerve growth factor receptor (NGFRir), which follow perinatal choline supplementation, and determine if the same treatment periods which elicit behavioral improvement also produce these morphological changes. Second, to test the hypothesis that morphological changes may result from prevention of naturally- occurring shrinkage during development and aging we will examine juvenile rats for the effects of perinatal choline treatment on morphology and size of NGFRir BF neurons. Third, to determine if this morphological plasticity is selective for cholinergic and/or septal neurons, we will evaluate BF and striatal neurons in young adult and aged rats morphometrically using immunocytochemistry of choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD). Fourth, to localize and quantify putative pre- and postsynaptic changes in cholinergic function within hippocampal and frontal cortex target areas, we will use autoradiography to analyse high affinity choline uptake sites and muscarinic receptors, respectively, in young adult and aged rats. Fifth, we will test the hypothesis that changes in cell size and/or redistribution of cells within nuclear boundaries may be related either to selective withdrawal of axon collaterals during development/aging or to altered cycles of mitosis within the BF, using double-labeling with retrograde tracers and (3)H-thymidine autoradiography in juvenile, young adult and aged rats. These studies will help elucidate the role of BF neuron size, collateral connectivity and cholinergic terminal activity in spatial memory function. Since cholinergic activity and memory function decline in Alzheimer's disease, evaluation of early treatments which may prevent these declines should assist in the design of interventions in young adults permitting similar enhancement of BF function.
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