Cognitive and Affective Network Dysfunction and Neuromodulation in Aging and Synucleinopathy

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Synucleinopathies such as Lewy body dementia (LBD) and Parkinson’s disease dementia (PDD), both Alzheimer’s disease-related disorders (ADRD), are some of the most common and fastest growing types of dementia in the world. In addition, synuclein pathology is increasingly appreciated as contributing to mixed pathology in dementias such as Alzheimer’s disease. Although synuclein-associated ADRDs are commonly thought of as causing tremor, slowness, and stiffness from degeneration of the motor structures of the nigrostriatal network, the accumulation of the protein alpha- synuclein fibrils is also seen in cognitive and affective brain networks, leading to dementia. Patients and their families struggle with a host of cognitive and affective symptoms, usually referred to as ‘non-motor symptoms”, with significant impact on their quality of life. By 2040 there will be close to 20 million patients world-wide with cognitive impairment, impulsivity, hallucinations, and anxiety, and other features of dementia just from synuclein-associated ADRDs alone, with few effective therapies for these non-motor symptoms. A common feature of all synuclein-related dementias is that age is the most significant risk factor. Despite the role of age as a risk factor, however, the specific interactions between age and a-synuclein in cognitive and network dysfunction remain largely unstudied and an important unmet need in understanding the mechanisms of age-dependent dementia and neurodegeneration. Moreover, synuclein animal models used to study pathophysiologic mechanisms of LBD and PDD are usually young adults, and rarely take age into account. Published and preliminary data show that experimental seeding of synuclein preformed fibrils (PFF) induces changes in oscillations in the cortex of young adult mice, that synuclein pathology affecting the mesocorticolimbic network can induce cognitive and affective deficits, and that mesocorticolimbic network function is also compromised in normal aging. Moreover, non-invasive, gamma-band neuromodulation improves cognition and delays progression of neuropathology in mouse models of Alzheimer’s disease. The establishment of aged rat models and PFF injections in our lab have particular value in assessing the cognitive and affective effects of the interaction between aging and synuclein pathology. Rats have a rich behavioral repertoire for assessment of cognitive and behavioral dysfunction. The injection of preformed synuclein fibrils into the ventral tegmental area allows for the targeting of a rapidly progressive pathology at a given timepoint to a mesocorticolimbic structure known to show synuclein pathology, which is analogous to human LBD and PDD non-motor disease and progression. The objective of this proposal is to is to develop an experimental approach that recapitulates behavioral, pathological, and neural network signatures of cognitive and affective dysfunction in LBD and PDD, determine the interacting effects of advanced age and a-synuclein pathology on cognitive/motivational and neural network outcomes relevant for synuclein-related dementias, and test a neuromodulatory therapy for these non-motor symptoms based on gamma-band therapies efficacious in Alzheimer’s disease mouse models. Our rationale is that these experiments will help to establish the role of the mesocorticolimbic network in cognitive symptoms in age-related synucleinopathy, and identify a framework for therapeutic neuromodulation in future studies that addresses synuclein-associated dementias.