Abigail Polter, PhD, associate professor of pharmacology and physiology, recently received a grant from the Aligning Science Across Parkinson’s (ASAP) initiative to study a small, but integral part of the mid-brain, called the ventral tegmental area responsible for executive function that she believes holds the key to some of the cognitive symptoms of Parkinson’s Disease. The Michael J. Fox Foundation for Parkinson’s Research (MJFF) is ASAP’s funding and strategic partner.
The three-year, $2,156,172 grant, “Ventral Tegmental Area Dopamine Neuron Subtype-specific Roles in Parkinson’s Disease-related Cognitive Symptoms,” seeks to study the interactions among neurons in the ventral tegmental area (VTA) to uncover how Parkinson’s reconfigures the VTA and identify future targets for treatment.
The grant is part of a larger award from ASAP for a multi-site Parkinson’s study led by David Root, PhD, associate professor of behavioral neuroscience at the University of Colorado. Through this award, Polter, Root, and the rest of their team join ASAP’s Collaborative Research Network, an international, multidisciplinary, multi-institutional network working to address high-priority research questions about Parkinson's disease.
For her study, Polter’s lab is looking at what happens to the VTA as Parkinson’s disease progresses, particularly in the processes involved in cognition. Researchers want to understand how the disease changes the way different types of dopamine neurons communicate with other cells, and whether those changes contribute to problems with executive function and decision making.
The VTA sits in the midbrain and serves as the home for dopamine production, often described as the brain chemical responsible for pleasure or happiness. The truth, according to Polter, is more complex.
“What dopamine is actually for,” she explained, “is telling you what in your environment is important and guiding your behavior in response to that.”
Polter said dopamine plays a role not just in identifying and guiding behaviors, but also in learning from them, particularly “with more complex tasks, things we would classify more as cognitive or executive function” such as motivation, learning, addiction, and processing emotion.
Parkinson’s research has traditionally centered on another nearby group of dopamine-producing neurons, the substantia nigra. Those neurons are closely tied to movement, and their degeneration is responsible for many of the motor symptoms associated with Parkinson’s.
“We absolutely know that it’s essential to the development of Parkinson’s disease, and the substantia nigra is largely responsible for the motor symptoms,” said Polter.
But the VTA is right next door, and it is affected by Parkinson’s, too. The difference, Polter added, is that the damage is not spread evenly across the region. “There’s been evidence that there are different cell types in the VTA; some degenerate and some do not. You’ve lost an essential part of it completely, not that you’ve lost half of the whole thing.”
That distinction gives Polter’s team a way to ask a more specific question: What happens to individual cell types, and how do those changes affect the circuits responsible for cognition?
Through the study, Polter and her team will examine how dopamine cell types and dopamine-receiving neurons across VTA networks change in Parkinson’s models, both genetically and physiologically. They will also look at how the neurons respond to signals related to cognition.
Polter’s thought is that Parkinson’s may reduce the sensitivity of some neurons involved in executive function and decision-making to dopamine. If that balance can be restored, the researchers want to know whether cognitive symptoms could improve.
“This is something that is a real problem in Parkinson’s patients,” she said of the cognitive symptoms. “As the disease progresses, it becomes more likely that they’ll develop impairment or dementia.”
Current treatments, including L-Dopa and deep brain stimulation, can alleviate many of the motor symptoms of Parkinson’s, however, they don’t directly address many non-motor symptoms, particularly cognitive impairment.
“My lab is going to explore the electrical function of dopamine neurons, and of the post-synaptic neurons they target,” Polter said. “That’s going to tell us things about synaptic receptors and ion channels and neuromodulatory receptors, all of which [could be] druggable targets.”
