Prefrontal Microcircuits and Cognitive Symptoms of Parkinson s Disease
Abstract
U.S. military Service Members are particularly vulnerable to Parkinson s disease (PD) because of their risk of toxin exposure, pesticide exposure, traumatic brain injury (TBI), and chemical exposure. Up to 80% of the millions of Parkinson s patients worldwide will develop cognitive symptoms and nearly 30% of PD patients will have cognitive dysfunction at initial diagnosis. Cognitive dysfunction in PD predicts a malignant disease course leading to loss of employment, loss of independence, early nursing home placement, and death. These events drive societal cost and suffering for PD patients. There are few treatments for these aspects of PD. Thus, cognitive symptoms in PD can pose a major challenge for the U.S. military, and there is a critical need to better understand the basic mechanisms of cognitive function and dysfunction in PD. Our long-term goal is to develop new targeted therapies that improve cognition in PD. In this proposal, we study how the neurotransmitter dopamine affects key cognitive areas in the prefrontal cortex. Dopamine has been studied extensively in motor circuits but has been studied far less in cognitive circuits. We focus on the D1-type dopamine receptor, which is expressed on both pyramidal neurons (output neurons of the prefrontal cortex), and interneurons (local processing neurons of the prefrontal cortex). D1-type dopamine receptors are expressed on both pyramidal neurons and interneurons. Our past work and preliminary data clearly show that these receptors play a key role in cognition. Here, we leverage neurotoxins to study dopamine and cognitive circuits in rodent models where we can use cutting-edge tools to dissect these circuits with incredibly precise detail. We will combine intersectional genetics and optogenetics to study prefrontal D1DR+ pyramidal vs. interneurons during cognitive tasks in mice with cell type-specific methods. Our hypothesis is that prefrontal D1DR+ pyramidal neurons orchestrate cognitive processing via 4-Hz oscillations. In Aim 1 we will determine how silencing D1DR+ pyramidal neurons or interneurons disrupt prefrontal networks. In Aim 2 we will characterize D1DR+ pyramidal neurons and interneurons interactions with prefrontal networks. In Aim 3 we will determine if closed-loop 4-Hz stimulation rescues dopamine-dependent cognitive deficits. We have engineered adaptive algorithms that analyze and adjust in real time to dynamically deliver maximally effective brain stimulation. This research is specifically relevant to the DOD and to the Neurotoxin Exposure Treatment Parkinson s program. PD involves midbrain dopaminergic neurons. We focus on cognitive symptoms of PD and specifically model neurotoxin exposure in Aim 3. We explore highly targeted interventions to mitigate the effects of these exposures. Although our work is in rodent models, because prefrontal 4-Hz rhythms are dysfunctional in human PD patients, our work to understand the circuit basis of prefrontal 4-Hz rhythms may lead to new biomarkers or to targeted therapies that improve cognitive function in PD patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110851
Entities
People
- Nandakumar Narayanan
Organizations
- United States Army
- University of Iowa