Prefrontal neural modulation to restore cognitive deficits in an Alzheimer's Disease rat model

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Project Summary Alzheimer’s disease (AD) is characterized by memory impairments and underlying neuropathology, including plaques, amyloid-β peptides, tau, in conjunction with neuroinflammation, and neuronal injury/loss, particularly in the medial temporal lobe. Recent studies, however, suggest neurophysiological alterations in the prefrontal cortex (PFC) evident in AD patients prior to gross neuropathology which may contribute to deficits in cognitive processing early in AD. Given that the PFC contributes to top-down control of memory processing necessary for optimal decision-making, dysfunction within the PFC may contribute to suboptimal decision-making which often precedes gross memory loss in AD patients. Optimal decision-making requires functioning working memory processes (i.e., using information “online” to guide choices) and flexible behavior (the ability to shift behavior in response to changing consequences). Critically, early-stage AD may target brain circuits that underlie these prefrontal dependent processes leading to early impairment in optimal cognitive processing. As such, understanding neural circuits that are affected in AD underlie complex cognitive deficits may lead to earlier and effective screening for AD risk and serve as an important therapeutic target for improving the quality of life AD patients. The rat prelimbic cortex (PrL) is heavily implicated in working memory and flexible behavior necessary for online decision-making. AD rats that were developed to show age-dependent neuropathological signatures (plaques, tau) consistent with AD are impaired in PrL-dependent cognitive tasks prior to accumulation of neuropathology. Critically, these deficits in PrL-dependent tasks precede behavioral deficits in other memory tasks that do not depend on PrL function. As such, targeting the PrL function in vivo may restore these cognitive processes in the AD rat model. Here, we aim to use noninvasive brain stimulation that modulates neural oscillations to restore PrL-hippocampal neural activity (Aim 1) and PrL-orbitofrontal cortex neural activity (Aim 2) in working memory (delay nonmatch to position task) and flexible behavior (reversal learning), respectively.