Anxiety and depression in a nonhuman primate model of synucleinopathy

Intraneuronal inclusions of aggregated Synuclein (Syn), termed Lewy bodies (LBs), are a pathological hallmark of Parkinson’s disease (PD), PD dementia (PDD) and LB dementia (LBD). The amygdala is a preferential site for LB accumulation, suggesting that it is either highly vulnerable to the development of synucleinopathy or a primary area of αSyn ‘seeding’. Dysfunction of the amygdala has been linked to anxiety and depression, but little is known about its involvement in PD, PDD and LBD. Based de on the identification of anxiety and depression as a prodromal sign of PD, PDD and LBD, the heavy LB burden in the amygdala of these patients, and the multiple connections of the amygdala with critical brain areas affected by these disorders, the goals of this proposal are to establish a NHP model of αSyn pathology and test the primary hypothesis that αSyn pathology in the amygdala affects the regulation of anxiety and mood by altering amygdala neuronal signaling to its monosynaptic connected neurons of the ventral striatum and prefrontal cortex (e.g. Area 25, posterior OFC). To test this hypothesis, we propose three specific aims: 1) Assess time-dependent changes in anxiety- and depression-related behaviors and their associated neural correlates in rhesus macaques overexpressing αSyn in the amygdala. 2) Assess time-dependent changes in motor and non-motor behaviors and their associated neural correlates in rhesus macaques overexpressing αSyn in the SNpc. 3) Characterize αSyn burden and its distribution induced by primary targeted overexpression in the amygdala or SNpc. AAV-αSyn and AAV-mCherry (control) will be bilaterally injected into the amygdala or the SN using real-time intraoperative MRI methods. The animals’ motor and non-motor behaviors will be evaluated with a battery of validated tests, and functional brain connectivity will be assessed with fMRI; postmortem analyses will be performed 12 or 18 months after AAV surgery. This innovative proposal capitalizes on the combined expertise of the Emborg and Kalin labs to establish a primate model of αSyn pathology and investigate the role of amygdalar synucleinopathy in anxiety and depression. These highly translational results will inform future trials considering the amygdala as a target for neuroprotective strategies and for treatments against anxiety and depression in PD, PDD and LBD. Project Number: 1RF1NS138787-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: MARINA EMBORG (+1 co-PI) | Institution: UNIVERSITY OF WISCONSIN-MADISON, MADISON, WI | Award Amount: $3,064,072 | Activity Code: RF1 | Study Section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11128050