Developmental, neurochemical and functional properties of the cholinergic basal forebrain complex in mice.

摘要

Basal forebrain (BF) neurons, including the neurons of the nucleus basalis magnocellularis (nBM), provide the major cholinergic innervation to the cerebral cortex in the rodent. During development, these projections modulate morphogenesis in the cerebral cortex; in the adult, they play a critical role in learning and memory. Furthermore, these projections are vulnerable to damage in Down syndrome (DS) and Alzheimer's disease (AD). The purpose of these studies was to investigate the relationship between the development and function of the BF in prenatal and adult mice: one study examined the development of the BF in euploid and trisomy (Ts)16 mice (an animal model for DS) and three studies examined behavioral deficits following lesions of the nBM in adult mice and pharmacological manipulations to reverse the lesion-induced deficits.; The neurogenesis of the basal forebrain in prenatal Ts16 and euploid mice was examined by combining ({dollar}sp3{dollar}H) thymidine autoradiography with acetylcholinesterase (AChE) histochemistry. AChE-positive neurons of the BF underwent terminal mitosis between days 11 and 15 of gestation, in both euploid and Ts16 mice. In Ts16 mice, however, hypocellularity of the BF was observed: particularly dramatic was the reduction of the population of nBM cells that expressed AChE.; In adult mice, nBM lesions produced reductions in cortical cholinergic markers and severe deficits on passive avoidance and the reversal phase of a spatial navigation task. These deficits were attenuated dramatically by a centrally-active AChE inhibitor, galanthamine. This drug improved performance in a dose-dependent fashion on both tasks with an optimal dose of 3.0 mg/kg. Galanthamine also improved performance in a time-dependent fashion, with peak performance four hours after a 5.0 mg/kg injection. Inhibition of cortical AChE activity and increased endogenous acetylcholine levels were associated with alterations in performance.; These studies suggest a critical role for the basal forebrain (nBM) cholinergic system in memory modulation. During development, the BF may regulate the formation of cortical circuitry necessary for associative memory processes. In the adult, these projections may be important not only in the maintenance of this circuitry but also in the plasticity necessary to modify previously learnd responses.