Dopamine is a neurotransmitter critical to normal brain function and has been implicated in a diverse array of brain disorders, including schizophrenia, depression, ADHD, addiction and others. The specific etiology of dopamine dysfunction in the different disorders has in turn been associated with distinct behavioral deficits. Thus, the clinical literature has ascribed to dopamine a wide array of behavioral and cognitive roles, including working memory, attention, motivation, learning, and many more. Contrary to this view, in the neurobiological literature, it has been a long-standing consensus that dopamine has a limited behavioral role: the processing of a reward prediction error signal. Thus, there is a fundamental gap between the clinical and neurobiological fields which must be bridged in order to understand the function of the dopamine system and to enable the development of improved therapeutics for the treatment of the different types of dopamine dysfunction. Studies showing that dopamine neurons comprise a functionally homogenous population whose activity could be well explained as a reward prediction error signal were mostly performed using simple cue-reward association behaviors. Recently I showed that during complex behavior, dopamine neurons divide into distinct, anatomically organized, functional subpopulations that mediate different aspects of the behavior. This diversity of function of the dopamine population could potentially underlie the diversity of behavioral roles attributed to dopamine in the clinical literature and suggests that dopamine neurons may flexibly encode a diverse array of behavioral variables via distinct functional subpopulations that emerge in response to behavioral demands. The goal of this project is to study the neural basis of the newly discovered diversity in dopamine function, and the precise behavioral role of the different functional dopaminergic subpopulations. In the mentored stage (K99) I will combine the use of deep-brain two-photon imaging with an array of precise behavioral tasks in virtual- reality to determine the relationship between behavioral complexity and the degree of functional diversity in the population of dopamine neurons (Aim 1). I will then leverage the power of two-photon imaging for recording the same neurons across days in order to study whether the specialized dopaminergic subpopulations generalize their functional role across task conditions (Aim 2, K99 phase). In this stage I will also learn the use of subregion- specific optogenetic techniques, which will allow me to probe the causal role of these subpopulations in behavior (Aim 2, R00 phase). Finally, I will uncover the neural basis of the functional diversity of dopamine neurons by recording and causally manipulating specific inputs to dopamine neurons during complex behavior (Aim 3, R00 phase). By using state-of-the art neurophysiological tools and expanding the study of dopamine to complex behavior, these studies will greatly advance our understanding of the dopamine system and may pave the way for the design of new approaches to target and treat dopamine dysfunction.
Clinically, dopamine has been shown to be critical for mediating a diverse array of cognitive functions, yet direct study of dopamine neurons have shown evidence for a very limited behavioral role. In order to bridge this gap, this proposal will investigate a newly discovered property of dopamine neurons: their diversity of function during complex behavior. By delineating the role of the behavioral context and the different input pathways in mediating dopaminergic functional diversity, this research ultimately seeks to uncover new therapeutic targets for the development of treatments for dopamine dysfunction evidenced in a wide variety of brain disorders.
