Habits allow for the fast, fluid, nearly effortless execution of complex tasks, yet they can also be detrimental, for example in cases where they lead to compulsive behaviors in OCD or to behavioral patterns of drug abuse and relapse in addiction. Habit formation requires the striatum, the input nucleus of the basal ganglia, as well as dopamine inputs to the striatum from the substantia nigra pars compacta (SNc). However, a better understanding of the mechanisms by which striatal and SNc dopaminergic circuitry support habit formation will be a crucial next step in elucidating the roles of habit formation processes in health and disease. SNc dopamine neurons are readily divisible by their efferent projections to the dorsomedial striatum (DMS) or the dorsolateral striatum (DLS), regions that decades of research have shown play distinct roles in operant learning: the DMS mediates early goal-directed task acquisition, while the DLS mediates later habit formation. The fact that SNc dopamine neurons project only to the DMS or the DLS suggests that different signals may be relayed to each area, causing the DMS and DLS to experience dopamine-dependent plasticity at different time points during behavior. Indeed, we have found that DMS- and DLS-projecting SNc dopamine neurons respond oppositely to unconditioned aversive stimuli. Although striking, this finding leaves much to be understood about the independent dopaminergic information streams being sent to the DMS and the DLS, especially in the context of learning. The goal of this proposal is to establish the circuit dynamics controlling differential processing of salient stimuli in subpopulations of SNc dopamine neurons defined by their efferent targets in the DMS and DLS, with temporal specificity and cellular resolution, over the course a complex behavior: the slow transition from goal-directed reward-seeking to habitual responding. In service of this goal, three specific aims are proposed.
Each aim i s focusing on elucidating one of three crucial yet unknown aspects of SNc dopaminergic circuit dynamics: determinants of variability, evolution over the course of a behavioral shift, and afferent control. First, to determine whether efferent targets are the main determinant of variability within SNc subpopulation, we will perform in vivo two-photon calcium imaging of efferent-defined SNc dopamine neurons in awake mice. Second, we will perform in vivo multi-fiber photometry in freely behaving animals to assess natural dopaminergic projection dynamics in both the DMS and the DLS within a single animal over the course of a behavioral transition to habit. Third, we will combine photometry with optogenetics to dissect mechanisms of afferent modulation of efferent-defined SNc dopamine neurons. Collectively, these approaches will enable the first functional, circuit-focused investigations of SNc dopamine neurons' involvement in learning and habit formation, providing a necessary foundation for understanding how aberrations in dopaminergic circuit dynamics could underlie an array of neurological and psychiatric disorders including OCD and drug addiction. This research will be pursued at Stanford University, a leading R1 research institution with an impressive arsenal of material and intellectual resources available for postdoctoral fellows. The Stanford neuroscience faculty is made up of preeminent researchers in a broad array of neuroscience subfields and the neuroscience graduate program is consistently ranked among the nation's best. The Stanford neuroscience community is a highly productive environment where researchers with similar interests and complementary technical expertise freely collaborate. Stanford not only offers a world-class scientific research environment, but also provides invaluable resources for career and professional development. Stanford's resources will enable the candidate to pursue both her immediate career goals - the acquisition of additional experimental and data analysis techniques and the learning and honing of key skills necessary for independence such as grantsmanship, negotiation, resource budgeting, communication and mentorship - and her long-term career goal - to succeed as a tenured neuroscience professor at a strong biomedical research institution by developing an independent group studying the regulation of brain-wide dopaminergic signaling by dissecting circuits, testing their functionality, and determining how the properties of individual circuit components as well as the emergent properties of the system evolve with learning and differ with age, gender, stress, and health status.
This project addresses fundamental questions about the neural mechanisms underlying habit formation by revealing the functional properties of and dynamic interactions between two brain areas - the striatum and the substantia nigra - already known to individually contribute to habit formation. By clarifying how these two brain regions function together as repeated actions transition into habits, this project will provide an empirica basis for understanding for how habits form in the brain. If successful, this project will provide n important foundation for future studies of the roles that habit formation circuits play in a range f psychiatric diseases that are theorized to involve dysfunction of the habit system, including obsessive-compulsive disorder (OCD) as well as drug addiction and relapse.
