Michaelides Lab at the NIDA/NIH
Michaelides Lab at the NIDA/NIH
Biobehavioral Imaging &
Molecular Neuropsychopharmacology
Laboratory
at the National Institute on Drug Abuse/NIH
Intramural Research Program
Who we are
We are a group of scientists working to understand the brain and its involvement in disease with a focus on substance use and comorbid disorders
We use mechanistic neuropharmacology to decipher drug mechanisms and to develop translational chemical tools for mapping and modulating the brain
I was born in Greece and raised in a small town in Greece and in New York City. I received my PhD degree in Integrative Neuroscience from Stony Brook University in 2010 and completed postdoctoral training at the Departments of Pharmacology, Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai in 2015. My laboratory combines techniques spanning behavioral neuroscience, in vitro and in vivo pharmacology, imaging, molecular and synthetic biology, and neuromodulation to (I) study the molecular and brain circuit basis of substance use and comorbid disorders, (II) decipher drug mechanisms, and (III) develop novel pharmaceuticals, molecular imaging agents, and neuromodulation technologies.
Juan L. Gomez, Ph.D. - Research Fellow
2015-present
A statement about my-[science]-self: I have a curiosity driven by the need to explore; doing my best to improve upon methods and techniques to devise a better way to catch that roadrunner.
Thoughts on experience: High School - An introduction to the lab, samples, and 96-wells. As a junior, I volunteered my school breaks and weekends to assist a biology graduate collecting and analyzing water/soil samples from rivers in Arizona. I was one of the few high school students among undergraduates to present our findings at the annual Arizona State University poster day. I was hooked. Undergraduate (B.S.) - An undergrad is only an undergrad by name in the lab of Cheryl Conrad at Arizona State University (ASU) where I received a degree in Psychology. These early experiences sharpened my lab work ethic and expectations as a future academic. Graduate (Ph.D.) - Good work with those that work good with you. Mentored by Victoria Luine, we worked with Michael Lewis and others at Hunter College of CUNY (HC) on my dissertation. Collaborations were an integral part of my graduate career, and almost every lab at HC contributed to my development as a scientist, for which I am grateful. Postdoc #1 – Envy has no place in productive endeavors. At my first postdoc in the Behavioral Neuroscience department at Oregon Health & Science University (OHSU), I was exposed to a new level of research and opportunities. Working with Andrey Ryabinin I learned the value of independent research and perseverance during difficult times. Postdoc #2 - Further research is needed… I joined the BIMN lab in 2015. Thus far, the radioactive signal may show me the way.
Oscar Solís, Ph.D. - IRTA Postdoctoral Fellow
2019-present
I was born and raised in the tropical state of Guerrero in Mexico. After high school, I moved to Puebla, where I obtained a BSc in Biochemistry and a MSc degree in Physiology at the Autonomous University of Puebla. During my undergraduate studies, with Dr. Gonzalo Flores at the Physiology Institute, I worked on the alterations of cortical and striatal neurons in a rodent model of Parkinson disease. Then, after being accepted into the Ph.D. program in Neuroscience in Madrid, Spain, I joined the Neurobiology of Basal Ganglia Lab at Cajal Institute. Under the guidance of Prof. Rosario Moratalla, I studied the behavioral and molecular/structural/functional traits relevant to L-DOPA-induced dyskinesia and drug addiction. In my free time, I enjoy playing football, running, traveling and spending time with my family and friends.
Marjorie Levinstein, Ph.D. - IRTA Postdoctoral Fellow
2021-present
I grew up in Virginia where I also earned my bachelor’s in Psychology from James Madison University (2011). However, my first research experience was as a summer internship after my sophomore year on developmental neuroscience at the University of South Carolina. Once back at JMU, I ran several health psychology experiments and volunteered at Western State Hospital. Nevertheless, I realized I was interested in understanding the mechanisms behind behavior and enrolled in a master’s in experimental psychology at Seton Hall University (2013). There, I studied the effect of immune system activity on ethanol consumption. I then joined René Hen’s lab at Columbia University as a research technician. I focused on the pharmacological and biological mechanisms behind several antidepressants. In 2015, I moved across the country to Seattle, Washington where I earned my PhD from the University of Washington in Neuroscience (2020). Mentored under John F. Neumaier, I investigated gene expression changes in the lateral habenula after stress or chemogenetic activation. The east coast called me back, and I moved to Baltimore to join the BIMN lab. Outside of the lab, I enjoy crochet and rooting for the oft-losing Chicago Cubs.
Zachary Frangos, Ph.D. - IRTA Postdoctoral Fellow
2023-present
I grew up on the Central Coast of New South Wales in Australia. After finishing high school, I moved to Sydney to attend The University of Sydney where I obtained a Bachelor of Medical Science (Honors) majoring in pharmacology and neuroscience. It was during my undergraduate study that I developed a passion for understanding how the brain functions, dysfunctions, and how we can use drugs to fix it. This led me to join the Transporter Biology Group at The University of Sydney to complete my PhD. Under the supervision of Prof. Robert Vandenberg, I studied the molecular pharmacology of novel bioactive lipids thought to be useful in the treatment of neuropathic pain. Outside of the lab I enjoy hiking through National Parks, travelling with my wife and waking up early to video chat with family and friends back home in Australia.
Reece Budinich B.S. - IRTA Postbaccalaureate Fellow
2021-present
I was born and raised in Federal Way, Washington, a short drive from Seattle. For my undergraduate degree I attended Western Washington University in Bellingham, basically the furthest northwest corner of the beautiful Pacific Northwest. While at WWU, I developed an interest in Psychology. After nearly finishing my degree, I discovered a passion for Behavioral Neuroscience and spent an extra year at university to double major. During this 5th year I joined Dr. Josh Kaplan's Pharmacology of Cannabinoids research lab, where I studied the acute anxiolytic effects of commercial CBD vape products in a mouse model. Throughout my undergraduate degree I found myself in several mentoring positions, both as a Teaching Assistant for multiple classes and an officer in the Neuroscience Research Driven Students Club (NeRDS).
Outside of academia, I spend my time honing my photography skills and making fancy coffee like a true Seattleite. I love cats, astronomy, and I consume an abysmal amount of cheese.
Fallon Curry B.S. - IRTA Postbaccalaureate Fellow
2022-present
I grew up in Pittsburgh, PA, also referred to as the City of Bridges, or the Steel City, depending on who you ask. Seeking new horizons, I decided to travel down country roads to Virginia Tech. While there, I pursued a B.S. in Neuroscience with minors in Spanish and Public Health. While in school, I wanted to take my education beyond the book, and sought out research opportunities to do so. I joined the lab of Dr. Michelle Olsen during my junior year, where I studied astrocyte development and morphology. Additionally, I had the opportunity to partake in a summer research fellowship before my senior year. I studied under Dr. Shannon Farris, who examines the role of hippocampal area CA2 in encoding social memory. When not in the lab, I love to listen to music, bake, and cheer on the Pittsburgh Penguins.
Leila Ghaffari - Research Intern
2021-present
I grew up in Frederick, Maryland and moved to Baltimore to attend the University of Maryland, Baltimore County (UMBC), and I am currently in my third year. Beginning in high school, I pursued my passion for research and medicine. I interned in the NGHRI of the NIH and shadowed in the Clinical Center. During the Summer after my freshman year, I interned in the Chemical Engineering Department of the University of Virginia, where I understood the impact computers can have on molecular design and peptide synthesis. Throughout this time I am also involved in my sustained research lab on campus studying behavioral neuroscience in drosophila melanogaster under the guidance of Dr. Fernando Vonhoff. Since the fall of 2021, I have been an undergraduate intern in Dr. Michaelides' lab. At UMBC, I am majoring in biological sciences and minoring in computer science and vocal performance. I am interested in behavioral neuroscience and the interdisciplinary studies conducted through biology and computer science. After college I aspire toward a career as a physician scientist. Outside academics I enjoy music, art, and playing with my dog.
Research
Mechanistic Neuropharmacology
We employ a wide array of complementary in vitro and in vivo pharmacological approaches for dissecting the in vivo mechanism of action of popular CNS medications and recreational drugs.Examples of some of the medications we work on are listed below.Ketamine & enantiomers
Ketamine is a controlled substance, has abuse potential, and can induce undesirable side effects. Nevertheless, it is considered to be generally safe and is a widely-used dissociative anesthetic and rapid-acting pain medication. The recent discovery that a single subanesthetic dose of racemic ketamine produces rapid and long-lasting antidepressant effects has been hailed as a key psychiatric breakthrough. (S)-ketamine (esketamine, SpravatoTM) was recently approved by the FDA as an intranasal formulation for treatment-resistant depression and human trials assessing efficacy of (R)-ketamine in depression are currently underway. As depression shares strong comorbidity with substance use disorders, we are working to better understand the precise in vitro and in vivo pharmacological properties and the abuse liability of its enantiomers.
(2R,6R)-Hydroxynorketamine
(2R,6R)-hydroxynorketamine (HNK) is a ketamine metabolite implicated in ketamine's efficacy in preclinical models of depression. We are working on the pharmacological characterization of (2R,6R)-HNK, for which human trials are underway.
Oliceridine (TRV-130)
Oliceridine is an FDA-approved pain medication. We are working on its in vivo pharmacological characterization and abuse liability profile.
Methadone & enantiomers
Racemic methadone is used for treatment of substance abuse. The efficacy of racemic methadone is attributed to (R)-methadone. (S)-methadone is being developed as a treatment for depression. We are working on the pharmacological characterization of (R)-methadone and (S)-methadone as well as their liability for abuse.
Drug Discovery & Development
We are working on discovery and preclinical development of selective mu opioid receptor agonists for treatment of pain with low abuse liability and adverse effect profiles.
Figure: Pharmacological screening (% binding or activity inhibition) of a novel selective mu opioid receptor ligand across many receptors and enzymes.
Molecular imaging & PET radiotracer development
A large portion of our research program involves the use of molecular imaging via PET. We perform PET studies by employing a variety of radioligands depending on experimental need. These can be procured commercially or are custom made to perform noninvasive, quantitative, and longitudinal assessments of brain metabolic activity, neuroinflammation, neurotransmitter displacement, and receptor occupancy/target engagement of candidate compounds or other processes. We co-implement chemogenetic, optogenetic, pharmacological, ultrasound, or electrical stimulation with PET imaging in awake, freely-moving animals either in an exploratory fashion, to determine whole-brain functional networks recruited during behaviorally-relevant contexts, or to corroborate functional connectivity or target engagement of a defined neuron-type, region, or pathway. We use such approaches to map functional anatomy related to a variety of cell-types/projections in distinct brain regions in basic and translational research.
Radioligands we currently use:
[18F]FDG - Glucose analog used for brain metabolic mapping
[11C]Raclopride - Displaceable dopamine D2/D3 receptor antagonist
[18F]Fallypride - Displaceable dopamine D2/D3 receptor antagonist
[18F]FE-DPN - Displaceable mu opioid receptor antagonist
[18F]FES - Estradiol analog for estrogen receptor and opsin imaging
[18F]JHU37107 - DREADD agonist
[11C]clozapine - atypical antipsychotic and DREADD agonist
[18F]ASEM - Nicotinic alpha7 receptor antagonist and PSAM4 agonist
Figure: PET image coregistered to MRI showing non-invasive assessment of dopamine D2/D3 receptors using [11C]raclopride in mouse brain.
Chemogenetics
We have developed chemogenetic ligands with high affinity and potency that can be used for both in vivo neuromodulation and non-invasive imaging of chemogenetic receptors.
Figure: Precision medicine offers considerable advantages over conventional medical treatment. Within precision medicine, theranostics comprises a strategy that combines THERApeutic and diagNOSTIC strategies to provide a personalized treatment approach encompassing disease diagnosis, drug delivery, and disease/therapy monitoring using a single agent. Such interventions are particularly timely given recent developments in neuromodulatory technologies. One such technology, called chemogenetics, offers the unprecedented ability to control neuronal activity in a cell type-specific manner without the need for chronically-implantable devices. A key feature of chemogenetic technologies is that they can be combined with clinical molecular imaging diagnostic methods such as positron emission tomography (PET). This particular combination extends the therapeutic component of chemogenetics to encompass its use in precision medicine-based neurotheranostics.
Gomez, Bonaventura et al. 2017
Magnus, Lee et al., 2019
Bonaventura, Eldridge, Hu, et al., 2019
Hu, Morris Bonaventura, et al., 2020
Roseboom, et al., 2021
Song, et al., 2021
Optogenetics
Optogenetics is a widely-used technology consisting of light-activatable ion channels expressed in neural tissue which upon light stimulation can either activate or inhibit neurons with exquisite temporal precision. Optogenetics has had a strong impact on basic neuroscience research. However, its use in translational applications has been limited. One reason for this, is that to date, opsins have not been able to be visualized noninvasively in intact subjects. To address this, we are developing a noninvasive reporter detection system for optogenetics. This scalable system consists of (i) chimeric opsins tagged with a small human protein epitope and (ii) an FDA-approved PET radioligand and permits both optogenetic neuromodulation and noninvasive, quantitative, and longitudinal detection of opsins in the brain.
Figure: A novel chimeric opsin called ChRERa (pronounced "carrera") that consists of Channelrhodopsin-2 and the ligand binding domain (LBD) of human estrogen receptor alpha (ERa).
For more details our "Hot Topics" presentation at the ACNP 2019 meeting can be found here
Synaptic Zinc
Synaptic zinc is transported into synaptic vesicles via the ZnT3 (Slc30a3) transporter and is co-released from presynaptic terminals along with glutamate. Synaptic zinc is essential for normal neurobiological functioning. Studies have shown that people with substance and alcohol use disorders have abnormal zinc levels. Nevertheless, the precise involvement of synaptic zinc in normal neurobiology, and in substance and alcohol use disorders are not well understood. The dopamine transporter is the principal target for cocaine and contains four zinc binding sites on its extracellular domain. We recently showed that synaptic zinc potentiates the effects of cocaine on dopamine neurotransmission and behavior. We are currently working to better understand the role of synaptic zinc in modulating neurochemistry and behavior and the extent to which this is relevant to substance and alcohol use disorders.
Ongoing efforts involve development of a ZnT3-cre mouse, dissecting the role of ZnT3-expressing neurons in behaviors relevant to substance use disorder, and development of ZnT3-selective small molecules.
Figure: (Top) At physiological concentrations, zinc increases the binding of the cocaine analog [3H]WIN35,428 as well as of cocaine itself at the dopamine transporter. (Bottom) [3H]WIN35,428 autoradiography in a coronal mouse brain section showing that zinc increases binding of [3H]WIN35,428 in the striatum.Publications
Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?
2024
Sex Dependence of Opioid-mediated Responses to Subanesthetic Ketamine in Rats
2024
Unique Pharmacodynamic Properties and Low Abuse Liability of the µ-Opioid Receptor Ligand
(S)-Methadone.2023
DREADD-mediated Amygdala Activation is Sufficient to Induce Anxiety-like
Responses in Young Nonhuman Primates
2023
A Non-Canonical Striatopallidal “Go” Pathway that Supports Motor Control
2023
Tools & Resources
Chemogenetics & Optogenetics
Radioligands & Imaging Agents
Our lab has pioneered the use of the agents below for non-invasive localization of chemogenetic and optogenetic switches in various species with the ultimate goal being human application.
[3H]ASEM - In vitro PSAM4-GlyR & PSAM4-5HT3 quantification
[18F]ASEM - Longitudinal In vivo PSAM4-GlyR & PSAM4-5HT3 quantification
[3H]Clozapine - In vitro hM3Dq/hM4Di quantification
[3H]Compound 13 (C13) - In vitro hM3Dq/hM4Di quantification
[18F]JHU37107 (J07) - Longitudinal In vivo hM3Dq/hM4Di quantification
[18F]fluoroestradiol (FES) - Longitudinal In vivo Opsin quantification (coming soon)
Publications
Gomez, Bonaventura et al. 2017
Chemogenetic agonists
Our lab has developed the first DREADD agonists that exhibit high affinity, high in vivo potency, and high brain penetrance in several species, which favors clinical translation. These compounds require very low systemic doses (<0.1 mg/kg) to facilitate rapid and remote activation of chemogenetic switches in the brain.
Plasmids
For translational and clinical gene therapy applications, chemogenetic/optogenetic switches need to be optimized to drive efficient expression and trafficking to the cell membrane, where their respective actuators would achieve maximum efficacy. For this reason, our goal has been to optimize existing chemogenetic/optogenetic gene therapy constructs for optimal expression and targeting. One way of doing this is to strip bulky and potentially toxic fluorescent reporters, typically used in such designs, and which are not useful for translational and clinical applications. Our strategy is to leverage the use of our translational PET-based reporters for non-invasive and longitudinal quantification of chemogenetic/optogenetic switches along with small epitopes (e.g. HA-tag) whenever in vitro detection would be necessary.
Highlights
The role of the estrogen receptor in COVID-19
Our recent work highlighted in the journal Nature Italy. Interview by first author Dr. Oscar Solis.
December 12 2022
Cooperative Research and Development Agreement (CRADA) with Attune Neurosciences, Inc.
Mike Michaelides to serve as a co-PI on a CRADA with Attune Neurosciences, Inc. to develop focused ultrasound applications for neuromodulation
December 22 2021
Cooperative Research and Development Agreement (CRADA) with Redpin Therapeutics, Inc.
Mike Michaelides to serve as a PI on a CRADA with Redpin Therapeutics, Inc. to develop chemogenetic applications for translational applications
June 16 2021
NIH Scientists Redesign Neurons to Enable Targeted Therapies
Our recent work highlighted in the NIH I am Intramural Blog
March 17 2021
Presentation at the Brain Initiative's "Chemogenetic Innovations in the Manipulation & Monitoring of Labeled Neurons Workshop"
Mike presented at this NIH Brain Initiative Workshop
December 10 2019
Presentation at the ACNP 2019 Annual Meeting describing our optogenetics molecular imaging technology
Mike presented at the ACNP 2019 "Hot Topics"
December 10 2019
"Changing the Locks" article and interview for Chemistry World about our work and that of others on chemogenetics.
Mike's interview at Chemistry World
May 20 2019
Interview for Science magazine: Could deep brain stimulation help zap diabetes?
Mike's interview for Science
May 23 2018
Interview for the American Psychiatric Association (APA): DREADDs Could Guide More Targeted Treatments in Future
Mike's interview for Psychiatric News
March 16 2018
Research highlight about our recent work on chemogenetics
Our recent work highlighted in the journal Nature Methods
September 29 2017
Research highlight about our recent work on chemogenetics
Our recent work highlighted in the journal Nature Chemical Biology
September 19 2017
Alumni
Emilya Ventriglia, B.S., M.S.
RTA Postbaccalaureate Fellow
2020-2023
Current - Ph.D. student
Brown Universtiy-NIH GPP Program
Matthew Boehm, Ph.D.
PhD Student, NIH GPP Program/Brown University
2017-2022
Current -
Meghan Carlton, B.S.
IRTA Postbaccalaureate Fellow
2019-2021
Current - PhD student
Albert Einstein School of Medicine
Jordi Bonaventura, Ph.D.
Research Fellow
2019-2021
IRTA Postdoctoral Fellow
2016-2019
Current - Assistant Professor
University of Barcelona
Sherry Lam, B.S.
Research Technician
2019-2020
IRTA Postbaccalaureate Fellow
2017-2019
Current - M.A. student
Rutgers University
Theresa Kopajtic, B.S.
Research Biologist
2018-2019
Current - Retired
Kelsey Wright, B.S.
IRTA Postbaccalaureate Fellow
2017-2019
Current - Ph.D. Student
Northwestern University
Dondre Marable, B.S.
IRTA Postbaccalaureate Fellow/Diversity Fellow
2017-2019
Current - Entrepreneur/Industry
Jatia Mills, B.S.
RTURP Research Fellow
Summer 2018
Current - Ph.D. student
Biomedical and Veterinary Sciences, Virginia Tech
Weilin Chan, B.S.
Special Volunteer/Summer Student
2016-2018
Current - M.D. Student
University of Buffalo
Randall J. Ellis, B.S.
IRTA Postbaccalaureate Fellow
2015-2017
Current - Ph.D. student
Biophysics & Systems Pharmacology
Icahn School of Medicine at Mount Sinai
Lionel A. Rodriguez, B.S.
IRTA Postbaccalaureate Fellow
2015-2017
Current - Ph.D. student,
Neuroscience
Johns Hopkins University
Margaret Jokoh
RTURP Research Fellow
Summer 2016
Current - Student, Loyola University
Kat Daly, B.S.
Lab rotation, NIH GPP program
Spring 2016
Current - Ph.D. student
JHU/NIH GPP Program
Collaborators
Marcello Allegretti, Ph.D.
Dompé farmaceutici S.p.A
Veronica A. Alvarez, Ph.D.
National Institute on Alcohol Abuse & Alcoholism
Yeka Aponte, Ph.D.
National Institute on Drug Abuse
Michael J. Bannon, Ph.D.
Wayne State University
Michael Baumann, PhD
National Institute on Drug Abuse
Miriam E. Bocarsly, Ph.D.
Rutgers New Jersey Medical School
Jordi Bonaventura, Ph.D.
Universitat De Barcelona
Charles W. Bradberry, Ph.D.
National Institute on Drug Abuse
Luis De Lecea, Ph.D.
Stanford University
Sergi Ferré, M.D., Ph.D.
National Institute on Drug Abuse
Adriana Galvan, Ph.D.
Emory University/Yerkes
Cameron Good, Ph.D.
Attune Neurosciences, Inc. & NeuroLux, Inc.
Todd D. Gould, M.D.
University of Maryland Medical Center
Brandon K. Harvey, Ph.D.
National Institute on Drug Abuse
Andrew G. Horti, Ph.D.
Johns Hopkins University School of Medicine
Robert B. Innis, M.D., Ph.D.
National Institute of Mental Health
Sanjay K. Jain, M.D.
Johns Hopkins University School of Medicine
Ned H. Kalin, M.D.
University of Wisconsin Madison
Lorenzo Leggio, M.D., Ph.D.
National Institute on Drug Abuse
Carl R. Lupica, Ph.D.
National Institute on Drug Abuse
Stephen V. Mahler, Ph.D.
University of California at Irvine
Ruin Moaddel, Ph.D.
National Institute on Aging
Marisela Morales, Ph.D.
National Institute on Drug Abuse
Patrick J. Morris, Ph.D.
National Center for Advancing Translational Sciences
Sadegh Nabavi, Ph.D.
Aarhus University
Kendall W. Nettles, Ph.D.
Scripps Research Institute
Marco Pignatelli, M.D.
Washington University School of Medicine in St. Louis
Vsevolod Y. Polotsky, M.D., Ph.D.
Johns Hopkins University School of Medicine
Martin G. Pomper, M.D., Ph.D
Johns Hopkins University School of Medicine
Kenner C. Rice, Ph.D.
National Institute on Drug Abuse
Barry Richmond, M.D.
National Institute of Mental Health
Avi Z. Rosenberg, M.D., Ph.D.
Johns Hopkins University School of Medicine
Yavin Shaham, Ph.D.
National Institute on Drug Abuse
Lei Shi, Ph.D.
National Institute on Drug Abuse
David R. Sibley, Ph.D.
National Institute on Neurological Disorders and Stroke
Elliot A. Stein, Ph.D.
National Institute on Drug Abuse
Scott M. Sternson, Ph.D.
University of California, San Diego
Gianluigi Tanda, Ph.D.
National Institute on Drug Abuse
Craig J. Thomas, Ph.D.
National Center for Advancing Translational Sciences
Zheng-Xiong Xi, Ph.D.
National Institute on Drug Abuse
Menghang Xia, Ph.D.
National Center for Advancing Translational Sciences
Carlos A. Zarate Jr., M.D.
National Institute of Mental Health
Wei Zheng, Ph.D.
National Center for Advancing Translational Sciences
Where to find us
NIDA Intramural Research Program
Biomedical Research Center
251 Bayview Blvd
Baltimore MD 21224
tel: 1-443-740-2894
fax: 1-443-740-2122
BIMN Lab © 2017