Deep brain stimulation-induced normalization of hippocampal synchrony in a transgenic rat model of Alzheimer's disease.

Abstract

Background and Aim: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by disrupted neural network dynamics and neuronal loss. Deep brain stimulation (DBS) may restore network function and abate cognitive deficits. In a transgenic rat model of AD, we investigated the dependence of hippocampal neuronal activity on a range of DBS parameters, aiming to identify stimulation conditions that transiently restore impaired network function. Material and Methods: We used 16-month-old TgF344-AD and NTg rats under light anesthesia and performed simultaneous DBS and high-resolution intracerebral recordings in the hippocampus using a linear multielectrode array. DBS was delivered in bipolar mode, at varying frequencies, amplitudes and duration, while monitoring local field potentials (LFP) and spiking activity. Phase-amplitude coupling (PAC), neuronal power, and firing rates were analyzed prior to and following DBS. Linear mixed effects models were used to evaluate the influence of genotype, sex, and stimulation parameters on the electrophysiological markers. Results: With increasing DBS frequency and amplitude, hippocampal power and PAC rose in all rats, particularly within the delta-theta range. When compared to NTgs, TgAD rats showed attenuated power but increased PAC responses to DBS. Low frequency DBS induced higher entrainment in the post- relative to during-DBS period in all animals. Compared to their non-transgenic littermates, TgAD rats showed reduced entrainment responses. Conclusions: These findings demonstrate that hippocampal responses to DBS have a parameter-dependent profile that is differentially modulated by AD pathology. Our study provides a foundation for tailoring DBS parameters to compensate for distinct neuronal deficits in established AD, supporting the use of electrophysiological biomarkers to guide individualized neuromodulation strategies.