Early Sociability and Social Memory Impairment in the A53T Mouse Model of Parkinson’s Disease Are Ameliorated by Chemogenetic Modulation of Orexin Neuron Activity


Parkinson’s disease (PD) is a multi-layered progressive neurodegenerative disease. Signature motor system impairments are accompanied by a variety of other symptoms such as mood, sleep, metabolic, and cognitive disorders. Interestingly, social cognition impairments can be observed from the earliest stages of the disease, prior to the onset of the motor symptoms. In this study, we investigated age-related reductions in sociability and social memory in the A53T mouse model of PD. Since inflammation and astrogliosis are an integral part of PD pathology and impair proper neuronal function, we examined astrogliosis and inflammation markers and parvalbumin expression in medial pre-frontal cortex (mPFC), part of the brain responsible for social cognition regulation. Finally, we used DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) for the stimulation and inhibition of orexin neuronal activity to modulate sociability and social memory in A53T mice. We observed that social cognition impairment in A53T mice is accompanied by an increase in astrogliosis and inflammation markers, in addition to loss of parvalbumin neurons and inhibitory pre-synaptic terminals in the mPFC. Moreover, DREADD-induced activation of orexin neurons restores social cognition in the A53T mouse model of PD.

Significance Statement

Social cognition is severely affected in the early stages of Parkinson’s disease. In this study, we identified the A53T mouse as a model of social cognitive impairment in PD. Observed alterations in sociability and social memory are accompanied by loss of parvalbumin positive neurons and loss of inhibitory input to mPFC. Stimulating orexin neurons using a chemogenetic approach (DREADDs) ameliorated social cognitive impairment. This study identifies a role for orexin neurons in social cognition in PD and suggests potential therapeutic targets for PD-related social cognition impairments.

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We would like to thank the Department of Neuroscience Mouse Behavior Core at the University of Minnesota for their support of the behavioral studies; the University of Minnesota Imaging Centers for their support of the confocal imaging; Dr. Chuanfeng Wang, MD, PhD from the Minneapolis VA Health Care System for providing the Stereo Investigator software and Axio Imager M2 fluorescence microscope; and Cagla Eroglu, PhD, Duke university for providing the Puncta Analyzer plugin for ImageJ software.


This work was supported by Department of Veterans Affairs (5I01RX000441-04 to CMK), the National Institute of Health (5R01DK100281-03).

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MS: conceived and designed research, performed experiments, analyzed data, interpreted results of experiments, prepared figures, drafted manuscript.

JPP: performed experiments, prepared figures.

AV: performed experiments, prepared figures.

CK: conceived and designed research, interpreted results of experiments, edited and revised manuscript, approved final version of manuscript.

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Correspondence to Milos Stanojlovic.

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Stanojlovic, M., Pallais Yllescas, J.P., Vijayakumar, A. et al. Early Sociability and Social Memory Impairment in the A53T Mouse Model of Parkinson’s Disease Are Ameliorated by Chemogenetic Modulation of Orexin Neuron Activity. Mol Neurobiol 56, 8435–8450 (2019). https://doi.org/10.1007/s12035-019-01682-x

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  • Parkinson’s disease
  • Orexin
  • Social cognition
  • Neuromodulation
  • mPFC