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Haley E Melikian PhD

TitleProfessor
InstitutionUMass Chan Medical School
DepartmentNeurobiology
AddressBrudnick Neuropsychiatric Research Institute
364 Plantation Street, LRB 726
Worcester MA 01605
Phone774-455-4308
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentBiochemistry and Molecular Biotechnology

    InstitutionT.H. Chan School of Medicine
    DepartmentNeurobiology

    InstitutionT.H. Chan School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionT.H. Chan School of Medicine
    DepartmentPsychiatry
    DivisionBrudnick Neuropsychiatric Research Institute

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentNeuroscience

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentPostbaccalaureate Research Education Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentTranslational Science

    InstitutionUMass Chan Programs, Centers and Institutes
    DepartmentBrudnick Neuropsychiatric Research Institute


    Collapse Biography 
    Collapse education and training
    University of Massachusetts Amherst, Amherst, MA, United StatesBA
    University of Massachusetts Amherst, Amherst, MA, United StatesBSBiochemistry
    Emory University, Atlanta, GA, United StatesDOCA
    Howard Hughes Medical Institute, Emory University, Atlanta, GAPostdoctoralGenetics/Neurobiology
    Emory University, Atlanta, GA, United StatesPHDNeuroscience
    Harvard Medical School, Boston, MAPostdoctoralNeurobiology

    Collapse Overview 
    Collapse 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.


    Collapse 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.
     
     

    Collapse 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




    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



    Collapse Research 
    Collapse research activities and funding
    R01DA035224     (MELIKIAN, HALEY E)May 1, 2013 - Jan 31, 2018
    NIH
    Dopamine Transporter Cell Surface Dynamics
    Role: Principal Investigator

    R01DA035224-06A1     (Haley Melikian)Apr 1, 2018 - Mar 31, 2023
    NIH/NIDA
    Dopamine Transporter Cell Surface Dynamics

    R21DA049057     (Haley Melikian)Apr 1, 2020 - Mar 31, 2022
    NIH/NIDA
    Dopamine Transporter: Tools for in vivo molecular replacement

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    Newest   |   Oldest   |   Most Cited   |   Most Discussed   |   Timeline   |   Field Summary   |   Plain Text
    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Kearny, P.J, Kahuno, E., Conklin, T., Martin, G.E., Lubec, G., and Melikian, H.E. Presynaptic Gq-coupled receptors drive biphasic dopamine transporter trafficking that modulates dopamine clearance and motor function . Biorxiv. 2022. View Publication.
    2. Fagan RR, Kearney PJ, Luethi D, Bolden NC, Sitte HH, Emery P, Melikian HE. Dopaminergic Ric GTPase activity impacts amphetamine sensitivity and sleep quality in a dopamine transporter-dependent manner in Drosophila melanogaster. Mol Psychiatry. 2021 12; 26(12):7793-7802. PMID: 34471250.
      Citations: 2     Fields:    Translation:AnimalsCells
    3. Fagan RR, Kearney PJ, Melikian HE. In Situ Regulated Dopamine Transporter Trafficking: There's No Place Like Home. Neurochem Res. 2020 Jun; 45(6):1335-1343. PMID: 32146647.
      Citations: 6     Fields:    Translation:HumansAnimalsCells
    4. Fagan RR, Kearney PJ, Sweeney CG, Luethi D, Schoot Uiterkamp FE, Schicker K, Alejandro BS, O'Connor LC, Sitte HH, Melikian HE. Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact. J Biol Chem. 2020 04 17; 295(16):5229-5244. PMID: 32132171.
      Citations: 5     Fields:    Translation:HumansAnimalsCells
    5. Sweeney CG, Kearney PJ, Fagan RR, Smith LA, Bolden NC, Zhao-Shea R, Rivera IV, Kolpakova J, Xie J, Gao G, Tapper AR, Martin GE, Melikian HE. Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function. Neuropsychopharmacology. 2020 01; 45(2):384-393. PMID: 31277075.
      Citations: 9     Fields:    Translation:HumansAnimalsCells
    6. Wu S, Fagan RR, Uttamapinant C, Lifshitz LM, Fogarty KE, Ting AY, Melikian HE. The Dopamine Transporter Recycles via a Retromer-Dependent Postendocytic Mechanism: Tracking Studies Using a Novel Fluorophore-Coupling Approach. J Neurosci. 2017 09 27; 37(39):9438-9452. PMID: 28847807.
      Citations: 26     Fields:    Translation:HumansAnimalsCells
    7. Sweeney CG, Tremblay BP, Stockner T, Sitte HH, Melikian HE. Dopamine Transporter Amino and Carboxyl Termini Synergistically Contribute to Substrate and Inhibitor Affinities. J Biol Chem. 2017 01 27; 292(4):1302-1309. PMID: 27986813.
      Citations: 13     Fields:    Translation:HumansCells
    8. Wu S, Bellve KD, Fogarty KE, Melikian HE. Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant. Proc Natl Acad Sci U S A. 2015 Dec 15; 112(50):15480-5. PMID: 26621748.
      Citations: 30     Fields:    Translation:HumansCells
    9. Gabriel LR, Wu S, Melikian HE. Brain slice biotinylation: an ex vivo approach to measure region-specific plasma membrane protein trafficking in adult neurons. J Vis Exp. 2014 Apr 03; (86). PMID: 24747337.
      Citations: 14     Fields:    Translation:AnimalsCells
    10. Gabriel LR, Wu S, Kearney P, Bellvé KD, Standley C, Fogarty KE, Melikian HE. Dopamine transporter endocytic trafficking in striatal dopaminergic neurons: differential dependence on dynamin and the actin cytoskeleton. J Neurosci. 2013 Nov 06; 33(45):17836-46. PMID: 24198373.
      Citations: 43     Fields:    Translation:HumansAnimalsCells
    11. Gabriel L, Lvov A, Orthodoxou D, Rittenhouse AR, Kobertz WR, Melikian HE. The acid-sensitive, anesthetic-activated potassium leak channel, KCNK3, is regulated by 14-3-3?-dependent, protein kinase C (PKC)-mediated endocytic trafficking. J Biol Chem. 2012 Sep 21; 287(39):32354-66. PMID: 22846993.
      Citations: 14     Fields:    Translation:HumansAnimalsCells
    12. Navaroli DM, Stevens ZH, Uzelac Z, Gabriel L, King MJ, Lifshitz LM, Sitte HH, Melikian HE. The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking. J Neurosci. 2011 Sep 28; 31(39):13758-70. PMID: 21957239.
      Citations: 46     Fields:    Translation:HumansAnimalsCells
    13. Navaroli DM, Melikian HE. Insertion of tetracysteine motifs into dopamine transporter extracellular domains. PLoS One. 2010 Feb 09; 5(2):e9113. PMID: 20161733.
      Citations: 2     Fields:    Translation:HumansAnimalsCells
    14. Gabriel L, Stevens Z, Melikian H. Measuring plasma membrane protein endocytic rates by reversible biotinylation. J Vis Exp. 2009 Dec 23; (34). PMID: 20032927.
      Citations: 12     Fields:    Translation:Cells
    15. Boudanova E, Navaroli DM, Stevens Z, Melikian HE. Dopamine transporter endocytic determinants: carboxy terminal residues critical for basal and PKC-stimulated internalization. Mol Cell Neurosci. 2008 Oct; 39(2):211-7. PMID: 18638559.
      Citations: 37     Fields:    Translation:AnimalsCells
    16. Boudanova E, Navaroli DM, Melikian HE. Amphetamine-induced decreases in dopamine transporter surface expression are protein kinase C-independent. Neuropharmacology. 2008 Mar; 54(3):605-12. PMID: 18164041.
      Citations: 38     Fields:    Translation:AnimalsCells
    17. Holton KL, Loder MK, Melikian HE. Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization. Nat Neurosci. 2005 Jul; 8(7):881-8. PMID: 15924135.
      Citations: 72     Fields:    Translation:HumansAnimalsCells
    18. Melikian HE. Neurotransmitter transporter trafficking: endocytosis, recycling, and regulation. Pharmacol Ther. 2004 Oct; 104(1):17-27. PMID: 15500906.
      Citations: 82     Fields:    Translation:HumansAnimals
    19. Loder MK, Melikian HE. The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines. J Biol Chem. 2003 Jun 13; 278(24):22168-74. PMID: 12682063.
      Citations: 109     Fields:    Translation:HumansAnimalsCells
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