Mechanisms of hippocampal network-targeted stimulation to rescue memory impairment due to Alzheimer's disease

补充项目摘要/摘要

Supplement Project Summary/Abstract The purpose of this administrative supplement for our ongoing grant “Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation” (R01-NS11380) is to use the innovative translational brain stimulation methods developed under the ongoing parent grant to test whether and how they rescue memory impairments in the next-generation rodent model of Alzheimer’s disease (AD), TgF344-AD. AD produces memory impairment by affecting the function of the distributed network of the hippocampus. Our ongoing project investigates the mechanisms whereby electrical brain stimulation targeting the hippocampal network can improve its function. By performing companion in vivo electrophysiological experiments in healthy young adult rodents and in human neurosurgical cases with depth electrodes in regions homologous to those implanted in the rodents, the ongoing project takes a highly translational approach to identify similarities across species in how the hippocampal network responds to brain stimulation. This approach thereby enhances the relevance to human function of the mechanistic insights offered by rodent in vivo and in vitro electrophysiology experiments performed for the ongoing project. This administrative supplement will expand our translational model of hippocampal network brain stimulation to address memory impairment due to AD. We first will behaviorally characterize young (5-6 mo.) and aged (20-23 mo.) F344 wild-type and aged TgF344-AD rats (a rodent model of AD) using the spatial Morris water maze task. Aged F344 rats will be categorized based on performance of this task into age-unimpaired (AU) and age-impaired (AI) subgroups, such that comparisons among the four groups (young, AU, and AI F344 rats and aged TgF344-AD rats) will be able to differentiate variation in stimulation efficacy based on aging, on typical aging-related memory impairment, and on AD pathology. In each of these groups, we will then compare the effects of locking stimulation to the ongoing phase of the hippocampal theta rhythm (versus non-phase-locked control conditions) on hippocampal network in vivo electrophysiology and on performance on the paired associate learning (PAL) touchscreen task, which is hippocampal dependent in both rodents and humans. Across-group comparisons will be used to determine whether phase-locked stimulation is maximally beneficial for hippocampal network electrophysiology and PAL performance in TgF344-AD rats relative to AI rats, with comparisons between AI and AU groups and between AU and young groups used to differentiate the effects of AD from those of aging with versus without memory impairment. Notably, although brain stimulation has shown moderate efficacy for memory impairment in aging and AD, very little data are available regarding mechanisms. These experiments will thus yield important and highly novel data on how brain stimulation targeting the hippocampal network influences its function in animals with AD. Results will be useful in tailoring brain stimulation for memory rescue in human AD patients owing to the highly translational nature of the experimental animal brain stimulation model that we have developed.