Effects of social isolation and enrichment on communication impairment in a translational model of PD

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Abstract Parkinson disease (PD) is a complex, neurodegnerative disorder characterized by limb motor, sensorimotor, and non-motor features including anxiety, depression, and cognitive dysfunction. 90% of individuals with PD experience significant communication deficits that diminish quality of life. Vocal function, cognitive skill, and regulation of anxiety/depression are essential for meaningful social interactions; thus, individuals with PD often experience debilitating social isolation. How socially-isolating living conditions impact vocal communication, cognitive abilities, and well-being in PD, however, is not known, especially in early and mid-stage disease. Further, the underlying brain pathology that modulates these behaviors is not fully described. Because of these critical gaps in knowledge, deficits in communication, cognition, and anxiety/depression remain largely under- treated. We propose to study how social interaction relates to vocal function, cognition, well-being, and neuropathological progression using a validated rat model of early-onset PD (Pink1-/-). This model recapitulates vocal communication deficits with laryngeal and brainstem pathology that follows an onset and progressive timeline analogous to humans. Our central hypotheses are that social isolation further contributes to vocal degradation, and enhancing vocal opportunities with a social enrichment intervention will slow the onset and progression of vocal communication deficits, improve cognitive function, and decrease anxiety and anhedonia, a marker for depression. Further, we hypothesize that neurochemical content in areas critical for speech motor and cognitive/emotional control (the ventral tegmental area, medial prefrontal cortex, and substantia nigra) will be altered by social condition. We propose two specific aims: Aim 1 will quantify the impact of social condition on vocal communication, cognition, anxiety, and anhedonia in Pink1-/- and WT rats. Pink1-/- and wildtype (WT) control rats will be randomly assigned to 3 experimental treatment conditions: (1) control, (2) isolation, and (3) social enrichment (implemented 5x per week to facilitate social and vocal opportunities with conspecifics). Using established rat behavior tests, vocal communication, cognition, anxiety, and anhedonia will be quantified and statistically compared at the following disease stages: prodromal (2, 4 mo of age), early (6 mo), and mid-stage (8,10 mo). Additionally, Aim 2 will determine how social condition affects catecholamine concentrations in the ventral tegmental area, medial prefrontal cortex, and substantia nigra of Pink1-/- and WT rats. Brain tissue from these regions will be assayed for dopamine, norepinephrine, and serotonin concentrations using high pressure liquid chromatography at 10 mo. This work is timely and significant as it will lead to a better understanding of how social isolation contributes to the complex pathology of PD-related communication dysfunction and provide foundational knowledge of how social enrichment may attenuate these deficits and change brain neurochemistry. The overarching goal of my training is to provide a foundation to conduct research that has a direct translation to human health.