Distinct Olfactory Bulb-Cortex Neural Circuits Coordinate Cognitive Function in Parkinson Disease

摘要

Objective:Cognitive dysfunction is a prevalent and consequential non-motor manifestation in Parkinson's Disease (PD).Although dysfunction of the olfactory system has been recognized as an important predictor of cognitive decline,the exact mechanism by which aberrant olfactory circuits contribute to cognitive dysfunction in PD is unclear.Methods:We used clinical fMRI to assess functional connectivity (FC) in olfactory regions,behavioral tests for phenotyping,patch-clamp and in vivo electrophysiology to record mitral/tufted (M/T) cell activity,virus tracing for circuit mapping,and optogenetics/DBS for intervention.Transcriptomic profiling explored the molecular basis.Results:(1) We found abnormal FC across olfactory regions in PD patients.(2) We discovered that two subpopulations of M/T cells in OB projecting to anterior PC (aPC) and entorhinal cortex (EC) precisely mediated the process of cognitive memory respectively by neural coherence at specific frequencies.(3) We revealed that Bod1 may play a pivotal role in encoding OBM/T-mediated cognitive function.(4) We verified that a new DBS protocol in OB ameliorated the cognitive function of Bod1-deficient mice and PD mice.Conclusion:Aberrant coherent activity in the olfactory system may serve as a biomarker for cognitive function and a therapeutic target for PD.

关键词

cognitive dysfunction / olfactory circuits / neural oscillation / Bod1