Dynamic acetylcholine regulation in flexible learning and restorative interventions in Parkinson’s disease
Learning requires a precise balance of acetylcholine and dopamine, a balance disrupted in Parkinson’s disease. Brain Resilience Scholar Fei Deng’s research explores how restoring acetylcholine regulation could improve cognitive flexibility and learning ability.
Research Summary
Flexible learning, the ability to adapt in changing environments, declines during normal aging. Moreover, this decline is exacerbated in patients with Parkinson's disease (PD), a common neurodegenerative disorder, affecting not only movement but also cognitive abilities. Imbalance in dopamine (DA) and acetylcholine (ACh) within the striatum underlie the cognitive deficits and is a key target for PD therapeutics. However, several major questions remain unknown: How do these neuromodulators facilitate flexible learning in health? Why does their disorder lead to cognitive deficits in PD? And how can we restore those deficits?
I aim to understand how phasic (sub-second) and tonic (minutes-to-hours) changes in ACh levels facilitate learning in mice and how disruptions in these dynamics contribute to the cognitive decline in PD. In addition to the loss of DA, the activity of cholinergic interneurons (ChIs), the main source of striatal ACh, is also altered in PD. The “burst-pause-burst” activity pattern, which is believed to be crucial for synaptic plasticity and learning facilitation, is disrupted in PD models.
Therefore, I hypothesize that phasic ACh dynamics are crucial for flexible learning in animals, while the loss of DA regulation in PD impairs flexible learning by “flattening” ACh dynamics, leading to inefficient learning, and restoring ACh dynamics could improve learning abilities in PD. To test these hypotheses, I will use cutting-edge genetically encoded sensors to monitor ACh and related downstream signaling in the striatum during mouse flexible learning task, and leverage powerful optogenetic tools to manipulate ACh signaling in the mouse striatum during foraging task, both in healthy and diseased states. By elucidating the role of ACh dynamics in flexible learning and evaluating the therapeutic potential of restoring these dynamics, this research may provide valuable insights into potential treatments for cognitive deficits in PD, ultimately improving the quality of life for PD patients.
