Plasticity and Function of Dopamine Circuits Regulating the Transition to Habit

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Habits and motor skills are essential to survival, allowing for the fast, fluid, and automatic execution of actions that have repeatedly proved beneficial. Despite their utility, habits and motor skills come at a cost: a loss of behavioral flexibility. Automated actions that were previously beneficial can become maladaptive if action- outcome contingencies shift. Because automated actions are hard to adjust once established, maladaptive behaviors can persist, as is hypothesized to occur in obsessive-compulsive disorder (OCD) and addiction, for example. A major long-term goal of my laboratory is to understand how and why actions become automated through the closely related processes of habit formation and motor skill acquisition. What is the normal process of automation and how may it go awry in psychiatric disorders? Previous studies have identified a key role for the dorsolateral striatum (DLS), but it remains unclear how the DLS becomes engaged in behavior over time as goal-directed actions are repeated and automated. Existing theories have been difficult to test empirically, stalling the field. This project takes advantage of recent technological advancements in neural circuit tracing, intersectional genetic targeting of cell types, and optogenetics and fiber photometry, innovatively combined, to bring new data to bear on the problem and to inspire work on fresh hypotheses. Our main objective in this proposal is to characterize the neural circuits controlling dopaminergic input to the DLS, which is critical for regulating synaptic plasticity in this brain region. We will identify synaptic plasticity mechanisms in the dopaminergic midbrain that underlie changes in DLS dopamine release related to habit formation and motor skill acquisition, and empirically test a long-standing hypothesis in the field, the Ascending Spiral Hypothesis, which posits that activity in goal-directed regions of the striatum disinhibits DLS dopamine release. We will reformulate the Ascending Spiral Hypothesis as needed based on new data. Our innovative approach integrates circuit tracing, electrophysiology, optogenetics, fiber photometry, and behavioral studies across three specific aims, spanning levels of analysis from detailed subcellular synaptic input mapping to in vivo circuit function. With the successful completion of this project, we will provide a robust characterization of the Ascending Spiral circuit and its role in controlling DLS dopamine dynamics before, during, and after action automation. This research will have a broad impact as it will answer fundamental questions about the neural mechanisms underlying action automation. By understanding the brain circuit activity allowing transitions from goal-directed control to habits and motor skills, we will unlock a new point of entry into studying how complex polygenic diseases such as OCD and addiction emerge from the confluence of genetic and environmental factors on circuit function.