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

Shuai-Shuai Wang; Xing-Feng Mao; Zhi-Shen Cai; Wen Lin; Xiu-Xiu Liu; Bei Luo; Xiang Chen; Yue Yue; Heng-Yu Fan; Takuya Sasaki; Kohji Fukunaga; Wen-Bin Zhang; Ying-Mei Lu; Feng Han

doi:10.34133/research.0484

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

Research (Wash D C). 2024 Oct 2:7:0484. doi: 10.34133/research.0484. eCollection 2024.

Authors

Shuai-Shuai Wang¹, Xing-Feng Mao², Zhi-Shen Cai¹, Wen Lin¹, Xiu-Xiu Liu¹, Bei Luo³, Xiang Chen¹, Yue Yue¹, Heng-Yu Fan⁴, Takuya Sasaki⁵, Kohji Fukunaga⁵, Wen-Bin Zhang³, Ying-Mei Lu^{2

6}, Feng Han^{1

7

8

9}

Affiliations

¹ Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
² Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
³ Department of Functional Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China.
⁴ Life Sciences Institute and Innovation Center for Cell Biology, Zhejiang University, Hangzhou 310058, China.
⁵ Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
⁶ Key Laboratory of Modern Toxicology of Ministry of Education, Nanjing Medical University, Nanjing 211166, China.
⁷ Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215009, China.
⁸ Institute of Brain Science, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China.
⁹ The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian 223300, China.

Abstract

Cognitive dysfunction stands as 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. Here, we provide the first evidence for abnormal functional connectivity across olfactory bulb (OB) and piriform cortex (PC) or entorhinal cortex (EC) by clinical fMRI, and dysfunction of neural coherence in the olfactory system in PD mice. Moreover, we discovered that 2 subpopulations of mitral/tufted (M/T) cells in OB projecting to anterior PC (aPC) and EC precisely mediated the process of cognitive memory respectively by neural coherence at specific frequencies in mice. In addition, the transcriptomic profiling analysis and functional genetic regulation analysis further revealed that biorientation defective 1 (Bod1) may play a pivotal role in encoding OB^M/T-mediated cognitive function. We also verified that a new deep brain stimulation protocol in OB ameliorated the cognitive function of Bod1-deficient mice and PD mice. Together, aberrant coherent activity in the olfactory system can serve as a biomarker for assessing cognitive function and provide a candidate therapeutic target for the treatment of PD.