Olfactory-to-Entorhinal Network Dysrhythmias Drive Parkinson's Cognitive Impairment Through Frequency-Specific Oscillatory Decoupling.

Abstract

Parkinson's disease (PD)-associated cognitive decline is heralded by olfactory dysfunction, but the network mechanisms bridging sensory and cognitive impairments remain poorly defined. Combining chronic multisite electrophysiology, behavioral tracking, and machine learning in PD models, a hierarchical disintegration of oscillatory dynamics across the olfactory network that mechanistically drives disease progression is uncovered. Early-stage PD mice are identified to show attenuated odor discrimination, accompanied by hyperexcitability of mitral/tufted (M/T) cells. Causally linking these deficits, aberrant gamma oscillation in the cross-olfactory network is identified as a causal factor underlying olfactory deficits. Notably, cognitive impairment emerged at later stages, correlating with abnormal theta oscillations in the cross-olfactory network. Pharmacological modulation of the olfactory bulb (OB)-lateral entorhinal cortex (LEC) pathway ameliorated cognitive deficits and restored cross-network theta oscillation. Collectively, the findings establish cross-olfactory network oscillations as dual diagnostic and therapeutic targets for PD cognitive impairment, providing a mechanism-guided framework for early intervention.