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

## TL;DR

This study shows that specific brain wave patterns in the olfactory network are linked to early and later cognitive problems in Parkinson's disease, offering new diagnostic and treatment targets.

## Contribution

The study identifies frequency-specific oscillatory decoupling in the olfactory-entorhinal network as a novel mechanism driving cognitive decline in Parkinson's disease.

## Key findings

- Early-stage Parkinson's mice show olfactory deficits linked to gamma oscillation abnormalities in the olfactory network.
- Later cognitive impairments correlate with theta oscillation disruptions in the same network.
- Pharmacological modulation of the olfactory bulb-lateral entorhinal cortex pathway restores cognitive function and theta oscillations.

## 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.

Wang et al reveal that in the olfactory system, the selective impairment of gamma‐driven Barcode features underlying early olfactory deficits, while the selective impairment of theta‐driven Barcode features underlying later cognitive deficits, further establishing cross‐network gamma oscillations in the early stage as a biomarker of later cognitive deficits in Parkinson's disease pathogenesis.