Dopamine Signaling in Neuropsychiatric Disorders and Addiction
Dopamine (DA) signaling in the brain is requisite for a number of key behaviors, including motivation, reward, motor function, and learning. Multiple neurological and neuropsychiatric disorders exhibit aberrant DA signaling, including addiction, schizophrenia, autism spectrum disorder (ASD), Parkinson's disease, and attention-deficit/hyperactivity disorder (ADHD). Despite the association of these disorders with dopaminergic dysfunction, the molecular mechanisms and neuronal circuits involved in these processes are not well defined. In order to investigate these pressing questions, we leverage a variety of approaches that span from molecules to behavior in mouse models, including in vivo monitoring of neuronal activity and DA signaling using genetically encoded tools. We currently are pursuing multiple lines of investigation:
Regulation of the Cocaine-Sensitive DA Transporter (DAT): Our laboratory is interested in the circuit- and molecular-specific mechanisms that regulate DA signaling and DA-dependent behaviors. Once released, extracellular DA is temporally and spatially restricted by presynaptic DA reuptake facilitated by the DA transporter (DAT). In addition to its central role in basal synaptic transmission, DAT is the primary target for addictive psychostimulants, cocaine and amphetamine, as well as therapeutic psychoactive drugs, such as methylphenidate (Ritalin) and bupropion (Wellbutrin/Zyban). These agents block DAT activity and thereby enhance extracellular DA levels and drive dysfunction in DA-depndent behaviors.
Given DAT’s importance in DAergic neurotransmission and as a psychoactive drug target, cellular mechanisms that impact DAT function are likely to have significant impact on DA signaling and neuropsychiatric disorders. Multiple DAT coding variants have been identified in ADHD and autism patients, further supporting that altered DAT function is linked to significant behavioral consequences. Work from our lab investigates the cellular and molecular mechanisms that regulate DAT. Endocytic trafficking dynamically controls DAT plasma membrane availability, and a variety of cellular signaling pathways and psychostimulant drugs rapid alter DAT trafficking, surface expression and function. We have identified multiple key players that govern DAT trafficking. Using a variety of cutting edge approaches, such as viral-mediated gene expression, gene silencing (RNAi), optogenetics and chemogenetics, we are investigating how DAT regulation impacts DA neurotransmission and DA-associated behaviors.
Role of modulatory glutamate signaling in motor function, novelty, and reward: Glutamate is the major excitatory neurotransmitter in the brain, but also has a modulatory role by signaling through metabotropic glutamate receptors (mGluRs). Recent work from our laboratory revealed that selective expression of mGluR5 in DA neurons is required for several DA-dependent behaviors and DA signaling. However, the circuit- and mechanistic-specific underpinnings of these processes have not been elucidated. Using a novel conditional knockout model, we are leveraging several intersectional approaches to determine how DAergic mGluR5 impacts DA neuron function and DA-dependent behaviors.
Potential Rotation Projects
1. The Role of Dopamine Transporter (DAT) Trafficking in Psychostimulant Addiction: This project is to determine whether membrane trafficking of the dopamine transporter is required for cocaine and amphetamine addiction. Our lab has developed a novel, AAV-mediated, in vivo molecular replacement strategy, that replaces wildytpe DAT with DAT trafficking dysregulated mutants in adult mice. Rotation students will assist in behaviorally assessing replacement mice as compared to controls, and will additionally use immumohistochemical approaches to validate mutant protein expression in dopamine neurons in situ. Students will gain experience in mouse behavior, brain dissection, preparation of brain slices, and immunhistochemical techniques in mouse brain.
2. The Role of Distal Translation in Acute DAT Regulation and Cocaine Responses. Recent studies suggest that many proteins that are key for synaptic transmission and synaptic plasticity are locally translated in distal processes, such as axons and dendrites. However, it is currently unknown whether DAT is regulated by local translation in striatal terminals and, if so, how cocaine addiction may impact this process. Rotation students will directly test this possibility by examining DAT biosynthesis in striatal tissue. Students will gain experience in brain dissection, protein biosynthesis studies, and quantitative immunoblotting.