Cortical Pathophysiology of Parkinsonism

Study Rationale: Specific brain circuits that are highly melanized (build-up of the dark pigment neuromelanin) with age are primarily affected, particularly early, in Parkinson’s disease (PD). Models incorporating this aspect of PD have only been developed recently and show that increased neuromelanin production causes neurodegenerative changes consistent with Parkinson’s. The regulators of cellular neuromelanin metabolism have not been determined, the effect of neuromelanin on normal activity in these pathways has not been defined, the potential for neuromelanin aggregates to increase alpha-synuclein accumulation has not been evaluated, and the impact of extracellular neuromelanin on detrimental inflammatory processes has not been assessed. Hypothesis: Activity in melanized brain circuits is a dominant factor in the initiation of PD and sustains its progression by seeding pathology in connected regions and providing the stimulus for chronic inflammation. Manipulating neuromelanin production and/or brain circuit activity can ameliorate these deficits.  Study Design: Parallel experiments will be performed in mice and non-human primates in which neuromelanin production has been induced for comparison with neuromelanin-producing neurons in people with prodromal and early Parkinson’s. To test whether activity in melanized brain circuits is a dominant factor in the initiation of PD, spatiotemporal activity mapping, imaging, and other techniques will be used, and manipulating neuromelanin production and/or brain circuit activity will be assessed as potential treatments. To determine if neurons spread PD pathology through their connectivity, seeding experiments will be performed and impacts on behavior and neurodegeneration assessed. To determine how non-neuronal mechanisms are involved in disease progression, high-resolution microscopy and cell-specific details of changes in extracellular spaces and infiltration of non-neuronal cells into the brain will be assessed. Impact on Diagnosis: Diagnosis of neuromelanin changes in the brain are already being assessed for their diagnostic potential, but this study will determine their focus and rate of change with respect to neural activity and clinical features. Team Vila will also identify if reducing neuromelanin levels stabilizes pathology and restores brain activity.

Study Rationale: Parkinson’s disease (PD) begins decades before it compromises the ability to move about in the world and sleep through the night. Understanding how the dysfunction of brain circuits begins and then evolves to cause difficulty in moving and sleeping will allow researchers to diagnose PD earlier—increasing the chances of halting disease progression—and to better treat the disease once it appears. Hypothesis: The progressive damage to dopamine-releasing neurons results in staged disruption of neural circuits in larger and larger parts of the brain, ultimately leading to both motor and sleep deficits characteristic of PD. Study Design: Team Surmeier's plan is to study a new genetically engineered mouse model that manifests a progressive, levodopa-responsive parkinsonism. Importantly, this mouse faithfully reproduces the human staging of pathology in key brain circuits. Using the most advanced methods available for studying and manipulating genetically defined brain circuits, the causal linkage between circuit dysfunction and motor and sleep behavior will be determined.  Impact on Diagnosis: A better understanding of how the circuit dysfunction underlying PD is staged should allow earlier diagnosis—enhancing the potential benefit of disease-modifying therapies—and better treatment strategies for later-stage patients.

Study Rationale: People with Parkinson’s disease have long been known to display remarkable motor abilities under special circumstances, such as smooth walking with certain visual or auditory cues. This phenomenon is called paradoxical kinesia. In addition, placebos can be surprisingly effective in treating the motor signs of the disease. Team Strick hypothesizes that a specific neuroanatomical substrate supports paradoxical kinesia and the placebo effect. The team plans to define this substrate and investigate its functional organization. Hypothesis: Team Strick hypothesizes that a specific neural circuit supports paradoxical kinesia and the placebo effect. Study Design: Team Strick will use cutting-edge techniques to reveal the two distinct brain circuits that enable the basal ganglia to influence the control of voluntary movement in primates. Next, the team will record the electrical and chemical activity of basal ganglia neurons in the best animal model of Parkinson’s disease. In addition, Team Strick will determine the molecular signatures of basal ganglia neurons that are affected by the disease and those that are left intact. Finally, the team will image neural activity in human subjects affected by the disease to determine the full range of strategies that could be used to improve basal ganglia function. Impact on Diagnosis: Team Strick's results could re-shape paradigms for therapeutic development and attempts to influence disease progression. Importantly, the team's results have the potential to use basal ganglia circuits that are untouched by the disease to promote recovery of more normal motor function..