CHOLINERGIC DENERVATION AND REINNERVATION IN AGING

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DESCRIPTION (Investigator's Abstract): Although it has been shown that the adult central nervous system is capable of a plastic response to injury, the mechanisms that regulate compensatory sprouting in the CNS are poorly understood, and a great deal of knowledge regarding the development of this plastic response in the adult cortex, and its loss with aging, is still lacking. New preliminary data from this laboratory have revealed an age-related loss of cholinergic fiber density, innervating the cerebral cortex in a "patchy" fashion. These data suggest lack of compensatory sprouting in the remaining cholinergic fibers, that could contribute to the erratic modifications in attention and cognition present in otherwise normal aged individuals. To answer some of these questions, I specifically will seek to understand the extent and time course of denervation and reinnervation of the cholinergic fibers, following loss of the basal forebrain cholinergic neurons, in the young adult and aged rat. Cell specific lesions of the basal forebrain cholinergic system cause partial cortical ChAT loss, which recovers with time, but it is not clear what happens to individual cholinergic axons across this time course. I will examine the extent of axonal injury and determine whether recovery of ChAT levels reflects axonal ingrowth, by quantifying the effects of basal forebrain lesions on ChAT and NGFR immunoreactive innervation density. After lesions of the basal forebrain cholinergic system, aged rats have an impaired capacity for regeneration; it is not clear whether this is due to a permanent down-regulation of the cholinergic markers or to an inability to generate sprouting fibers. Two experimental paradigms are proposed: the first is aimed at measuring the cholinergic ChAT- and NGFR- immunoreactive axonal denervation and sprouting in the entorhinal cortex, after excitotoxic lesions of cholinergic cells in the HDB. The second paradigm is intended to examine the size of cortical terminal fields of individual neurons in the HDB, and to measure its modifications during aging, when the rat brain increases in size. Injections of different colored fluorescent tracers, spaced between 0.5 and 2.5 mm apart, will be made into the cortex of rats at different ages, and the percentage of double-labeled cells at different intervals will be plotted as a measure of terminal field size. My immediate aim is, therefore, to produce a rat model in which to study cholinergic cortical denervation and reinnervation, by measuring the time course of the effects that lesions of the cholinergic basal forebrain nuclei have on the cholinergic innervation of the cerebral cortex, across the aging spectrum. My long term goal is to apply this model to dissect the cellular and molecular mechanisms that may be involved in cholinergic fiber sprouting (or lack thereof in old age.