Study Rationale:
Parkinson’s Disease (PD) patients have difficulty in key components of cognition, such as the ability to estimate time intervals as well as learn from negative outcomes. Preclinical models of PD indicate that timing and other cognitive impairments result from the loss of dopamine neurons in an underappreciated PD-affected brain region (ventral tegmental area, VTA). Different types of VTA dopamine neurons exist and we will identify the specific dopamine cell-types and their brain pathways that control PD cognitive symptoms.
Hypothesis:
PD results in the loss of a specific type of VTA dopamine neuron sensitive to timing and aversive events, leading to imbalanced dopamine signals from a surviving, differently sensitive type of VTA dopamine neuron. Our hypothesis is that rebalancing VTA dopamine cell-type and network-related signals will rescue PD cognitive symptoms.
Study Design:
In human patients and preclinical models of PD, we will identify how dopamine cell-types and dopamine receiving neurons across VTA networks are altered in cognition-related signals as well as physiologically and genetically altered in PD models. In a series of experiments using different intervention strategies, we will reverse PD-induced cognitive symptoms in preclinical models by rebalancing VTA dopamine cell-type and pathway specific cognitive signals.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Our research will 1) broaden attention to how PD affects cognition and its regulation by VTA; 2) pinpoint the specific dopamine cell-types, networks, and modifications to rescue cognitive symptoms; 3) test strategies for eventual human intervention; and 4) develop a computational model to predict optimal intervention strategies based on heterogeneous cognitive symptoms.
Next Steps for Development:
If successful, we will 1) extend our intervention strategies in other preclinical PD models before eventual human trials and 2) expand our computational models to additional patients in order to predict optimal cell-type and pathway specific interventions.