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One or more keywords matched the following properties of Melikian, Haley
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keywords Dopamine
keywords Dopamine Transporter
overview

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.

Post Docs

I am seeking an accomplished and motivated Ph.D. neurobiologist with significant biochemistry expertise, to undertake an investigation identifying proteins in complex with the cocaine-sensitive transporter, and their role in dopamine transporter regulation and DA-dependent behaviors. This is an exciting opportunity to leverage cutting edge intersectional strategies that integrate proteomic and transgenic mouse approaches to link molecular mechanisms to behaviors. Candidates will have a strong track record of productivity from their doctoral research, with excellent verbal and written skills, with expertise in neurobiology and biochemistry. Interested candidates should forward a cover letter, curriculum vitae, and the names and contact information of three references via e-mail to:  

Haley E. Melikian, Ph.D.

Brudnick Neuropsychiatric Research Institute

UMASS Medical School

haley.melikian@umassmed.edu

Post Docs

I am seeking an accomplished and motivated Ph.D. electrophysiologist to study the impact of dopamine transporter trafficking and regulation on dopaminergic neurotransmission. This is an exciting opportunity to integrate state-of-art optogenetic, chemogenetic and transgenic mouse approaches to link molecular mechanisms to synaptic physiology. Candidates will have a strong track record of productivity from their doctoral research, with excellent verbal and written skills, with expertise in ex vivo brain slice electrophysiological approaches. Interested candidates should forward a cover letter, curriculum vitae, and the names and contact information of three references via e-mail to:  

Haley E. Melikian, Ph.D.

Brudnick Neuropsychiatric Research Institute

UMASS Medical School

haley.melikian@umassmed.edu

Rotation Projects

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 ResponsesRecent 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.
 
 
One or more keywords matched the following items that are connected to Melikian, Haley
Item TypeName
Academic Article The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines.
Academic Article Amphetamine-induced decreases in dopamine transporter surface expression are protein kinase C-independent.
Academic Article Dopamine transporter endocytic determinants: carboxy terminal residues critical for basal and PKC-stimulated internalization.
Academic Article The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking.
Academic Article Dopamine transporter endocytic trafficking in striatal dopaminergic neurons: differential dependence on dynamin and the actin cytoskeleton.
Academic Article Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization.
Academic Article Insertion of tetracysteine motifs into dopamine transporter extracellular domains.
Concept Dopamine Uptake Inhibitors
Concept Dopamine Plasma Membrane Transport Proteins
Academic Article Brain slice biotinylation: an ex vivo approach to measure region-specific plasma membrane protein trafficking in adult neurons.
Academic Article Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant.
Academic Article Dopamine Transporter Amino and Carboxyl Termini Synergistically Contribute to Substrate and Inhibitor Affinities.
Grant Dopamine Transporter Cell Surface Dynamics
Academic Article The Dopamine Transporter Recycles via a Retromer-Dependent Postendocytic Mechanism: Tracking Studies Using a Novel Fluorophore-Coupling Approach.
Academic Article Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function.
Grant Dopamine Transporter Cell Surface Dynamics
Grant Dopamine Transporter: Tools for in vivo molecular replacement
Academic Article Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact.
Academic Article In Situ Regulated Dopamine Transporter Trafficking: There's No Place Like Home.
Academic Article Dopaminergic Ric GTPase activity impacts amphetamine sensitivity and sleep quality in a dopamine transporter-dependent manner in Drosophila melanogaster.
Academic Article Presynaptic Gq-coupled receptors drive biphasic dopamine transporter trafficking that modulates dopamine clearance and motor function
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  • Dopamine