Objective: To investigate the role of corticostriatal synucleinopathy on behavioral function in an alpha-synuclein preformed fibril (a-Syn PFF) rat model of Parkinson’s disease (PD).

Background: Cognitive and neuropsychiatric dysfunction are common non-motor symptoms in PD that can severely impact quality of life for patients. While much is understood about the underlying pathology associated with motor symptoms in PD, less is known about the pathophysiology and mechanisms associated with these non-motor symptoms. Both cortical Lewy body pathology and striatal dopamine (DA) deficiency have been correlated with executive dysfunction in PD, however the individual contribution of each remains unknown.

Method: Male Fischer 344 rats received bilateral a-syn PFF injections to either the substantia nigra (SNc; n=20) or striatum (Str; n=19). Controls received injections of aSyn monomer (n=20). At 4-6 months post-injection animals were behaviorally assessed using a battery of tests that measured multiple cognitive domains including executive function, spatial memory, and object recognition. Emotional reactivity was measured to determine the effect on neuropsychiatric function and sensorimotor function was assessed using tests for movement initiation, somatosensory responses, and spontaneous activity. Postmortem analysis included quantification of nigral degeneration and phosphorylated a-Syn (pSyn) accumulation.

Results: Both PFF rat groups exhibited equivalent loss (~60%) loss of nigral DA neurons. Accumulation of cortical pSyn pathology was only observed in rats receiving intrastriatal PFF injections, including significant accumulation in the anterior cingulate, insular and orbital cortices. Rats with cortical pSyn pathology displayed significant impairments in set-shifting, requiring more trials to reach criterion in set cue and set shift aspects of an operant task compared to controls. Rats with cortical pSyn pathology also spent significantly less time in the open arms of the elevated plus maze, indicating and enhanced fear response. No behavioral differences were observed between SNc PFF rats (no cortical pathology) and controls.

Conclusion: The results suggest that cortical pSyn accumulation is necessary for the development of cognitive and neuropsychiatric dysfunction in the a-Syn PFF rat model of PD.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/cognitive-and-neuropsychiatric-dysfunction-is-associated-with-corticostriatal-synucleinopathy-in-the-alpha-synuclein-preformed-fibril-rat-model-of-parkinsons-disease/