Forty-hertz auditory stimulation restored hippocampal-prefrontal synchrony and attenuated hippocampal hyperexcitability in an STZ-induced Alzheimer's model.

Dysfunction of neuronal networks such as aberrant excitability and disrupted oscillatory activity, especially within theta and gamma bands, in memory-related areas including the hippocampus and prefrontal cortex, is increasingly recognized as an important contributor to cognitive impairment in Alzheimer's disease (AD). In this context, targeting network dysfunction via gamma sensory entrainment, such as 40 Hz auditory stimulation, has emerged as a promising non-invasive therapeutic approach; however, the therapeutic mechanisms by which 40 Hz auditory stimulation ameliorates network-level deficits remain poorly understood. We studied the effects of long-term 40 Hz auditory stimulation in STZ-induced AD rats on the hippocampal-prefrontal network activity. Daily auditory stimulation was applied for 21 days, and its impact was assessed using electrophysiological recordings, behavioral testing, histological staining, and molecular analyses. STZ-treated rats exhibited impaired theta-gamma coupling, reduced hippocampal-prefrontal theta coherence, increased interictal epileptiform discharges, and significant deficits in spatial memory. These network abnormalities were associated with Aβ accumulation, tau hyperphosphorylation, altered expression of insulin/PI3K/Akt pathway-associated genes, and reduced expression of neurogenesis-related markers. Remarkably, 40 Hz auditory stimulation reversed many of these impairments: it restored functional connectivity and cross-frequency coupling, reduced epileptiform activity, improved memory performance, attenuated Aβ and tau pathology, partially normalized insulin/PI3K/Akt pathway-associated gene expression, and upregulated genes related to adult neurogenesis. Our findings indicated that 40 Hz auditory stimulation can effectively target both neural circuit dysfunction and molecular markers of AD, highlighting its potential as a simple, accessible, and multifaceted therapeutic strategy.