At the Hurd Lab, our multi-prong research is focused on understanding the contribution and interplay of genes and the environment to the development of addictive disorders, and providing neurobiological insights that innovate and advance treatment and intervention. Translational research is the principal feature of our lab. Led by Dr. Yasmin Hurd, the Director of the Addiction Institute at the Mount Sinai Behavioral Health System, the research lab consists of a multi-disciplinary team of scientists who study addiction through a myriad of lenses: Animal Behavior, Molecular Biology, Cell Biology, Pharmacology, Psychology, Neuroimaging, Bioinformatics and Biotechnology.
Dr. Yasmin Hurd is Professor in the Departments of Psychiatry, Neuroscience and Pharmacology and Systems Therapeutics. She is the Director of the Addiction Institute.
Areas of Research
At the Hurd Lab, our multi-prong research is focused on understanding the contribution and interplay of genes and the environment to the development of addictive disorders, and providing neurobiological insights that innovate and advance treatment and intervention. Translational research is the principal feature of our lab. Led by Dr. Yasmin Hurd, the Director of the Center for Addictive Disorders at the Mount Sinai Behavioral Health System, the research lab consists of a multi-disciplinary team of scientists who study addiction through a myriad of lenses: animal behavior, molecular biology, cell biology, pharmacology, psychology, neuroimaging, bioinformatics and biotechnology.
Genetic and Epigenetic Mechanisms
Combining standard molecular biological techniques such as in situ hybridization, qPCR, and biochemical assays with innovative methods such as next-generation sequencing and viral-mediated manipulations of discrete neuronal pathways, the Hurd lab investigates neurobiological disturbances associated addiction to variety of substances ( heroin, cannabis, cocaine). Epigenetic mechanisms including DNA methylation, histone modifications and microRNAs are also evaluated in relation to the regulation of gene expression within distinct neuronal populations of the mesocorticolimbic and striatal circuits.
Cutting-edge Molecular Neurobiology
Through our affiliation with the Friedman Brain Institute, the Hurd Lab has access to state-of-the-art technology in confocal and electron microscopy to analyze human and animal tissues at the single-cell level. Additionally, we use non-invasive neuroimaging techniques such as PET, fMRI and small animal MRI to determine real-time changes in neural activity, neurotransmitter levels and drug distribution, as well as structural changes in the brain. We pioneered the technique of DREAMM (DREADD-assisted metabolic mapping) combining molecular pharmacogenetic and in vivo imaging strategies to provide high-resolution quantitative mapping of functional brain circuits associated with disturbance of genes expressed in specific cell populations.
Animal Behavior Models
A large part of our research is committed to animal behavioral studies designed to mimic patterns of prenatal and adolescent THC exposure seen in humans in order to further explore the molecular basis for clinical symptoms observed in human subjects. The Hurd research group is a pioneering leader in the field studying developmental exposure to THC (the main psychoactive component of marijuana), and in particular, its transgenerational impact on neurocognitive development as it relates to vulnerability to addictive disorders and comorbid psychiatric disturbances such as anxiety and depression. We were the first to reveal that adolescent THC exposure may cause permanent changes in the mesocorticolimbic gene expression, receptor function and cellular activity transmitted through the parental germline to subsequent generations.
Human Brain Studies
Another significant part of our research engine is our long-standing translational efforts to study the neurobiological effects of human substance abuse through the direct examination of post-mortem human brain tissue. Through molecular, biochemical, and in vivo imaging studies of the human brain, we also work to understand the relationship of genetic polymorphisms to neurobiological systems underlying addictive and affective disorders.
Innovative translational research being the backbone of our research, some of our most exciting research efforts relate to clinical studies in addiction and intervention involving human subjects. Currently, we are conducting clinical research with cannabidiol, a cannabinoid compound from the marijuana plant that we identified from our animal studies to inhibit heroin-seeking behavior. We now study cannabidiol for its novel and potential role in preventing relapse in heroin and cocaine addiction, reducing anxiety, and improving overall cognitive function. We have successfully completed Phase I of this project and are carrying out Phase II studies.
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Ferland, J.N., and Hurd, Y.L. (2020). Deconstructing the neurobiology of cannabis use disorder. Nat Neurosci.
Hurd, Y.L (2020). Leading the Next CBD Wave-Safety and Efficacy. JAMA Psychiatry.
G.Egervari, Y.L.Hurd, et al. (2020). Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder. Nature Communications.
Hurd, Y. L., S. Spriggs, J. Alishayev, G. Winkel, K. Gurgov, C. Kudrich, A. M. Oprescu and E. Salsitz (2019). Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial. Am J Psychiatry: appiajp201918101191.
Miller, M. L., B. Chadwick, D. L. Dickstein, I. Purushothaman, G. Egervari, T. Rahman, C. Tessereau, P. R. Hof, P. Roussos, L. Shen, M. G. Baxter and Y. L. Hurd (2019). Cell- and layer-specific transcriptomic strategy for characterizing the molecular phenotype of rat cortical neurons using laser capture microdissection and massively parallel RNA sequencing. Mol Psychiatry 24(4): 473.
Calipari, E. S., A. Godino, M. Salery, D. M. Damez-Werno, M. E. Cahill, C. T. Werner, A. M. Gancarz, E. G. Peck, Z. Jlayer, J. Rabkin, J. A. Landry, A. C. W. Smith, P. Defilippi, P. J. Kenny, Y. L. Hurd, R. L. Neve, D. M. Dietz and E. J. Nestler (2019). Synaptic microtubule-associated protein EB3 and SRC phosphorylation mediate structural and behavioral adaptations during withdrawal from cocaine self-administration. J Neurosci.
Anderson, S.A.R., Oprescu, A.M., Calello, D.P., Monte, A., Dayan, P.S., Hurd, Y.L., Manini, A.F., and Tox, I.C.I. (2019). Neuropsychiatric Sequelae in Adolescents With Acute Synthetic Cannabinoid Toxicity. Pediatrics 144.
Bassir Nia, A., Mann, C.L., Spriggs, S., DeFrancisco, D.R., Carbonaro, S., Parvez, L., Galynker, II, Perkel, C.A., and Hurd, Y.L. (2019). The Relevance of Sex in the Association of Synthetic Cannabinoid Use With Psychosis and Agitation in an Inpatient Population. J Clin Psychiatry 80.
Hu, J., Ly, J., Zhang, W., Huang, Y., Glover, V., Peter, I., Hurd, Y.L., and Nomura, Y. (2019). Microbiota of newborn meconium is associated with maternal anxiety experienced during pregnancy. Dev Psychobiol 61, 640-649.
Hurd, Y.L., Manzoni, O.J., Pletnikov, M.V., Lee, F.S., Bhattacharyya, S., and Melis, M. (2019). Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects. J Neurosci 39, 8250-8258.
Egervari, G., Kozlenkov, A., Dracheva, S., and Hurd, Y.L. (2018b). Molecular windows into the human brain for psychiatric disorders. Mol Psychiatry.
Bassir Nia, A., and Hurd, Y.L. (2018). Cannabidiol, an Adjunct Player in the Antipsychosis Arsenal. Am J Psychiatry 175, 197-198.
Hurd, Y.L., and O’Brien, C.P. (2018). Molecular Genetics and New Medication Strategies for Opioid Addiction. Am J Psychiatry 175, 935-942.
Michaelides, M., Miller, M.L., Egervari, G., Primeaux, S.D., Gomez, J.L., Ellis, R.J., Landry, J.A., Szutorisz, H., Hoffman, A.F., Lupica, C.R., et al. (2018). Striatal Rgs4 regulates feeding and susceptibility to diet-induced obesity. Mol Psychiatry.
Miller, M.L., Chadwick, B., Dickstein, D.L., Purushothaman, I., Egervari, G., Rahman, T., Tessereau, C., Hof, P.R., Roussos, P., Shen, L., et al. (2018a). Adolescent exposure to Δ (9)-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Mol Psychiatry.
Szutorisz, H., and Hurd, Y.L. (2018). High times for cannabis: Epigenetic imprint and its legacy on brain and behavior. Neurosci Biobehav Rev 85, 93-101.
Egervari, G., Ciccocioppo, R., Jentsch, J.D., and Hurd, Y.L. (2018a). Shaping vulnerability to addiction – the contribution of behavior, neural circuits and molecular mechanisms. Neurosci Biobehav Rev 85, 117-125.
Mazzone, C.M., Pati, D., Michaelides, M., DiBerto, J., Fox, J.H., Tipton, G., Anderson, C., Duffy, K., McKlveen, J.M., Hardaway, J.A., et al. (2018). Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Mol Psychiatry 23, 143-153.
Miller, M.L., Ren, Y., Szutorisz, H., Warren, N.A., Tessereau, C., Egervari, G., Mlodnicka, A., Kapoor, M., Chaarani, B., Morris, C.V., et al. (2018b). Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23, 1328-1335.
Fullard, J. F., M. E. Hauberg, J. Bendl, G. Egervari, M. D. Cirnaru, S. M. Reach, J. Motl, M. E. Ehrlich, Y. L. Hurd and P. Roussos (2018). An atlas of chromatin accessibility in the adult human brain. Genome Res 28(8): 1243-1252.
McKenzie, A. T., M. Wang, M. E. Hauberg, J. F. Fullard, A. Kozlenkov, A. Keenan, Y. L. Hurd, S. Dracheva, P. Casaccia, P. Roussos and B. Zhang (2018). Brain Cell Type Specific Gene Expression and Co-expression Network Architectures. Sci Rep 8(1): 8868.
Hurd, Y.L. (2017). Cannabidiol: Swinging the Marijuana Pendulum From ‘Weed’ to Medication to Treat the Opioid Epidemic. Trends Neurosci 40, 124-127.
Miller, M.L., and Hurd, Y.L. (2017). Testing the Gateway Hypothesis. Neuropsychopharmacology 42, 985-986.
Cheer, J.F., and Hurd, Y.L. (2017). A new dawn in cannabinoid neurobiology: The road from molecules to therapeutic discoveries. Neuropharmacology 124, 1-2.
Michaelides, M., Miller, M.L., DiNieri, J.A., Gomez, J.L., Schwartz, E., Egervari, G., Wang, G.J., Mobbs, C.V., Volkow, N.D., and Hurd, Y.L. (2017). Dopamine D2 Receptor Signaling in the Nucleus Accumbens Comprises a Metabolic-Cognitive Brain Interface Regulating Metabolic Components of Glucose Reinforcement. Neuropsychopharmacology 42, 2365-2376.
Egervari, G., Landry, J., Callens, J., Fullard, J.F., Roussos, P., Keller, E., and Hurd, Y.L. (2017). Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target. Biol Psychiatry 81, 585-594.
Bassir Nia, A., Medrano, B., Perkel, C., Galynker, I., and Hurd, Y.L. (2016). Psychiatric comorbidity associated with synthetic cannabinoid use compared to cannabis. J Psychopharmacol 30, 1321-1330.
Egervari, G., Jutras-Aswad, D., Landry, J., Miller, M.L., Anderson, S.A., Michaelides, M., Jacobs, M.M., Peter, C., Yiannoulos, G., Liu, X., et al. (2016). A Functional 3’UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits. Neuropsychopharmacology 41, 2512-2520.
Szutorisz, H., and Hurd, Y.L. (2016). Epigenetic Effects of Cannabis Exposure. Biol Psychiatry 79, 586-594.
Szutorisz, H., Egervari, G., Sperry, J., Carter, J.M., and Hurd, Y.L. (2016). Cross-generational THC exposure alters the developmental sensitivity of ventral and dorsal striatal gene expression in male and female offspring. Neurotoxicol Teratol 58, 107-114.
Watson, C.T., Szutorisz, H., Garg, P., Martin, Q., Landry, J.A., Sharp, A.J., and Hurd, Y.L. (2015). Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure. Neuropsychopharmacology 40, 2993-3005.
Parsons, L.H., and Hurd, Y.L. (2015). Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci 16, 579-594.
Manini, A.F., Yiannoulos, G., Bergamaschi, M.M., Hernandez, S., Olmedo, R., Barnes, A.J., Winkel, G., Sinha, R., Jutras-Aswad, D., Huestis, M.A., et al. (2015). Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med 9, 204-210.
Hurd, Y.L., Yoon, M., Manini, A.F., Hernandez, S., Olmedo, R., Ostman, M., and Jutras-Aswad, D. (2015). Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage. Neurotherapeutics 12, 807-815.
Michaelides, M., and Hurd, Y.L. (2015). DREAMM: a biobehavioral imaging methodology for dynamic in vivo whole-brain mapping of cell type-specific functional networks. Neuropsychopharmacology 40, 239-240.
Xu, J., Lu, Z., Xu, M., Pan, L., Deng, Y., Xie, X., Liu, H., Ding, S., Hurd, Y.L., Pasternak, G.W., et al. (2014). A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the mu opioid receptor gene OPRM1 via hnRNPH interactions. J Neurosci 34, 11048-11066.
Alpar, A., Tortoriello, G., Calvigioni, D., Niphakis, M.J., Milenkovic, I., Bakker, J., Cameron, G.A., Hanics, J., Morris, C.V., Fuzik, J., et al. (2014). Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nat Commun 5, 4421.
Maze, I., Chaudhury, D., Dietz, D.M., Von Schimmelmann, M., Kennedy, P.J., Lobo, M.K., Sillivan, S.E., Miller, M.L., Bagot, R.C., Sun, H., et al. (2014). G9a influences neuronal subtype specification in striatum. Nat Neurosci 17, 533-539.
Szutorisz, H., DiNieri, J.A., Sweet, E., Egervari, G., Michaelides, M., Carter, J.M., Ren, Y., Miller, M.L., Blitzer, R.D., and Hurd, Y.L. (2014). Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation. Neuropsychopharmacology 39, 1315-1323.
Tortoriello, G., Morris, C.V., Alpar, A., Fuzik, J., Shirran, S.L., Calvigioni, D., Keimpema, E., Botting, C.H., Reinecke, K., Herdegen, T., et al. (2014). Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J 33, 668-685.
Trampush, J.W., Jacobs, M.M., Hurd, Y.L., Newcorn, J.H., and Halperin, J.M. (2014). Moderator effects of working memory on the stability of ADHD symptoms by dopamine receptor gene polymorphisms during development. Dev Sci 17, 584-595.
Kozlenkov, A., Roussos, P., Timashpolsky, A., Barbu, M., Rudchenko, S., Bibikova, M., Klotzle, B., Byne, W., Lyddon, R., Di Narzo, A.F., et al. (2014). Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites. Nucleic Acids Res 42, 109-127.
Mitchell, A.C., Bharadwaj, R., Whittle, C., Krueger, W., Mirnics, K., Hurd, Y., Rasmussen, T., and Akbarian, S. (2014). The genome in three dimensions: a new frontier in human brain research. Biol Psychiatry 75, 961-969.
Hurd, Y.L., Michaelides, M., Miller, M.L., and Jutras-Aswad, D. (2014). Trajectory of adolescent cannabis use on addiction vulnerability. Neuropharmacology 76 Pt B, 416-424.
Michaelides, M., Anderson, S.A., Ananth, M., Smirnov, D., Thanos, P.K., Neumaier, J.F., Wang, G.J., Volkow, N.D., and Hurd, Y.L. (2013). Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks. J Clin Invest 123, 5342-5350.
Anderson, S.A., Michaelides, M., Zarnegar, P., Ren, Y., Fagergren, P., Thanos, P.K., Wang, G.J., Bannon, M., Neumaier, J.F., Keller, E., et al. (2013). Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression. J Clin Invest 123, 5334-5341.
Karatsoreos, I.N., Thaler, J.P., Borgland, S.L., Champagne, F.A., Hurd, Y.L., and Hill, M.N. (2013). Food for thought: hormonal, experiential, and neural influences on feeding and obesity. J Neurosci 33, 17610-17616.
Chadwick, B., Miller, M.L., and Hurd, Y.L. (2013). Cannabis Use during Adolescent Development: Susceptibility to Psychiatric Illness. Front Psychiatry 4, 129.
Lobo, M.K., Zaman, S., Damez-Werno, D.M., Koo, J.W., Bagot, R.C., DiNieri, J.A., Nugent, A., Finkel, E., Chaudhury, D., Chandra, R., et al. (2013). ΔFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli. J Neurosci 33, 18381-18395.
Keimpema, E., Alpar, A., Howell, F., Malenczyk, K., Hobbs, C., Hurd, Y.L., Watanabe, M., Sakimura, K., Kano, M., Doherty, P., et al. (2013). Diacylglycerol lipase alpha manipulation reveals developmental roles for intercellular endocannabinoid signaling. Sci Rep 3, 2093.
Sillivan, S.E., Whittard, J.D., Jacobs, M.M., Ren, Y., Mazloom, A.R., Caputi, F.F., Horvath, M., Keller, E., Ma’ayan, A., Pan, Y.X., et al. (2013). ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers. Biol Psychiatry 74, 511-519.
Manini, A.F., Jacobs, M.M., Vlahov, D., and Hurd, Y.L. (2013b). Opioid receptor polymorphism A118G associated with clinical severity in a drug overdose population. J Med Toxicol 9, 148-154.
Bergamaschi, M.M., Barnes, A., Queiroz, R.H., Hurd, Y.L., and Huestis, M.A. (2013). Impact of enzymatic and alkaline hydrolysis on CBD concentration in urine. Anal Bioanal Chem 405, 4679-4689.
Manini, A., Jacobs, M., Vlahov, D., and Hurd, Y. (2013a). On the role of genetic testing for personalized drug overdose management. J Med Toxicol 9, 294-295.
Jacobs, M.M., Okvist, A., Horvath, M., Keller, E., Bannon, M.J., Morgello, S., and Hurd, Y.L. (2013). Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels. Mol Psychiatry 18, 1205-1210.
Tomasiewicz, H.C., Jacobs, M.M., Wilkinson, M.B., Wilson, S.P., Nestler, E.J., and Hurd, Y.L. (2012). Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability. Biol Psychiatry 72, 803-810.
Jutras-Aswad, D., Jacobs, M.M., Yiannoulos, G., Roussos, P., Bitsios, P., Nomura, Y., Liu, X., and Hurd, Y.L. (2012). Cannabis-dependence risk relates to synergism between neuroticism and proenkephalin SNPs associated with amygdala gene expression: case-control study. PLoS One 7, e39243.
Dinieri, J.A., and Hurd, Y.L. (2012). Rat models of prenatal and adolescent cannabis exposure. Methods Mol Biol 829, 231-242.
DiNieri, J.A., Wang, X., Szutorisz, H., Spano, S.M., Kaur, J., Casaccia, P., Dow-Edwards, D., and Hurd, Y.L. (2011). Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring. Biol Psychiatry 70, 763-769.
Okvist, A., Fagergren, P., Whittard, J., Garcia-Osta, A., Drakenberg, K., Horvath, M.C., Schmidt, C.J., Keller, E., Bannon, M.J., and Hurd, Y.L. (2011). Dysregulated postsynaptic density and endocytic zone in the amygdala of human heroin and cocaine abusers. Biol Psychiatry 69, 245-252.
Morris, C.V., DiNieri, J.A., Szutorisz, H., and Hurd, Y.L. (2011). Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment. Eur J Neurosci 34, 1574-1583.
Meet the Team
Joseph Landry, BS, MS
Project Coordinator I
Teddy Uzamere, BA
Anissa Bara, PhD
Randy Ellis, BS
Ehsan Moazen-Zadeh, M.D., M.Sc.
Yuanqi Sun, MS
Clinical Research Coordinator
Micah Frier, BS
James Callens, BA, BS, MS
Senior Associate Researcher
Henrietta Szutorisz, PhD
Gregory Rompala, PhD
Jeremy Sherman, BA
MD, PhD Student
Philip Kamilar-Britt, BA
Clinical Research Coordinator
Christopher Kudrich, DHSc, PA-C
Lisa Daitch, BA
Anna Oprescu, MPH
Clinical Research Project Manager
Jacqueline-Marie Ferland, PhD
Tanni Rahman, BA
Lauren Noble, BA, MA
Clinical Research Coordinator
An-Li Wang, Ph.D
Diana Akpoyibo, BS
Funding & Awards
Cannabidiol in the Treatment of Opioid Use Disorder (NIH-Funded UG3 Project)
Cannabidiol is a non-intoxicating cannabinoid that has been suggested to reduce features relevant to opioid addiction. The current project will test a new CBD formulation that increases CBD’s bioavailability to assess the reduction of craving and anxiety associated with opioid addiction. Three studies will be conducted to investigate the effects of Cannabidiol (CBD) on opioid use disorder. The first study is an open cross-over design study in healthy individuals to confirm the safety and pharmacokinetic effects of CBD. The second is a randomized, double-blinded, placebo-controlled study of CBD, we will determine the pharmacokinetic and pharmacodynamic effects in participants with an opioid use disorder and obtain knowledge about the concentration range of CBD that reduces craving studied over a 4- to 8-week period (Study 2 and 3). The third phase of this project will study various CBD dose effects on opioid abstinent individuals not maintained on medication assisted therapy (but supported with behavioral therapy) (Study 2) as well as on those managed on opioid agonists (Study 3). Study participants will be evaluated for measures of craving, anxiety, depression, elements of cognitive function, and psychiatric history.
Neuroimaging and Cannabidiol for Heroin Use Disorder
This study will investigate the neurobiological effects of Cannabidiol (CBD) a non-intoxicating cannabinoid that is being investigated as a potential treatment for opioid addiction. The study will utilize neuroimaging techniques to determine the neural circuits and transmitters associated with the effects of CBD on craving and anxiety. This is a randomized, double-blinded placebo-controlled study in abstinent subjects with a heroin use disorder. The neuroimaging will be conducted in participants immediately following their first administration of CBD or placebo and one week after the last administration (3 daily doses). Study participation duration is 2 weeks and includes MRI imaging; CBD/placebo administration; MRI tasks such as the resting-state functional MRI; and questionnaire measuring craving, anxiety, depression, elements of cognitive function, and psychiatric history.
Molecular Neurobiology of Human Drug Abuse - R01DA015446
Opiate addiction is now a national epidemic marked by an increased incidence of abuse and overdose of heroin and elevated misuse of prescription opioids which also bears a high incidence of overdose death. Despite this growing opiate problem there remains a lack of knowledge about the molecular neuropathology of this human disorder. A fundamental core of our reverse translational research efforts has thus been to fill critical gaps of knowledge by direct investigation of the brains of human heroin abusers. Such efforts have identified the transcription factor ets-like kinase 1 (ELK1) as a central candidate in human heroin abusers. ELK1 disturbance was downstream of the mu opioid receptor (the pharmacological target of heroin metabolites and prescription opiates) and mitogen-activated protein kinase (MAPK) pathway and it was found by in silico analysis of microarray data to target the promoters of a large percentage of down-regulated genes in the nucleus accumbens (NAc) of heroin abusers. Surprisingly, very limited knowledge exist about ELK1 in relation to drug abuse, but this transcription factor has been implicated in other fields in cellular differentiation and synaptic plasticity that are highly relevant to the pathophysiology of addiction disorders. We hypothesize that heroin abuse leads to dysregulated ELK1-mediated transcriptional activity of target genes involved in the reorganization of striatal synapses and that modulate drug-seeking behaviors. We propose: (1) to determine ELK1-mediated transcriptional regulation in neurons within striatal and mesocorticolimbic brain regions of human heroin abusers by conducting ELK1 ChIP in combination with high throughput sequencing (ChIP-seq) on the nucleus accumbens, dorsal striatum and medial orbitofrontal cortex of heroin abusers. This data will also be integrated with transcriptome analysis to determine the relationship to gene expression. (2) To identify the epigenetic landscape across the ELK1 gene that contributes to its dysregulation in heroin abusers. (3) To investigate the causal role of ELK1 in structural plasticity and heroin seeking behavior by use of animal models. The multidisciplinary approach will expand significant insights about novel targets for treatment interventions and the dataset accrued by this body of work will be a unique and valuable resource to the field given the current lack of such human brain data.
Molecular Neurobiology of Drug Addiction/Project 4 - P01DA008227
The objective of this project is to elucidate transcriptional and epigenetic mechanisms underlying glutamatergic dysregulation in mesocorticolimbic circuits in heroin abuse, a chronic relapsing disorder. Aberrant glutamatergic transmission in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) is central to drug-seeking behavior and addiction vulnerability. Our research focuses on studies of the human brain for which limited molecular insights are available. Preliminary data from microarray analysis already revealed distinct impairments of NAc glutamate-related gene expression in heroin abusers. The majority of these genes are upregulated, indicating that transcriptional change may be predominantly activation. Bioinformatic prediction of potential transcriptional regulators of these gene alterations identified DNA-binding factors SP1 and CREB1 as most likely regulators. SP1 and CREB1 are known to interact with various molecules involved in histone modification, such as histone acetyltransferases (e.g., Ncoa1, Ncoa3) that were also affected in the heroin population, which is mechanistically consistent with the observed predominance of upregulated glutamatergic genes. We will validate these findings using a comprehensive view of the genome by RNA-seq next-generation sequencing (Program Core) in the NAc of another subset of heroin abusers and control subjects, and will also examine the transcriptome in the mPFC, which provides glutamatergic innervation to the NAc. Specific glutamatergic disturbances will be assessed within discrete striatal output pathways using laser capture microdissection. To interrogate the molecular mechanisms by which glutamatergic aberrations are maintained, we will perform parallel studies in the rat heroin self-administration model in which viral-mediated gene manipulation strategies will be used to evaluate causal relationship of gene targets to heroin-seeking and intake. ChIP-Seq will be conducted (Program Core) to map genome-wide binding of a select number of target transcription factors, chromatin modifiers and histone marks in the NAc and mPFC. Overall, the novel research in this Project, which is fully integrative with the Core and other Projects of the PPG, will advance molecular knowledge about the pathophysiology of addiction disorders.
Neurodevelopmental Effects of Cannabis and its Epigenetic Regulation - R01DA030359
Emerging lines of evidence suggest that interactions between genes and the environment play a critical role in individual vulnerability to psychiatric disorders including drug addiction. The epigenome is influenced by environment and thus is a highly relevant biological candidate to maintain persistent aberrant neuronal processing as a result of developmental drug exposure. The developing brain may be particularly sensitive to epigenetic influences, given the dynamic neuroplasticity characteristic of this period. Marijuana (Cannabis sativa) is the illicit drug most commonly used by pregnant women and teenagers. Our studies of human fetuses with maternal cannabis use revealed selective alterations of striatal preproenkephalin (PENK) and dopamine receptor D2 gene expression (predominantly enriched in striatopallidal neurons), but not prodynorphin or dopamine D1 receptors (enriched in striatonigral neurons). Similar gene expression patterns were detected in the ventral striatum of rats exposed to -tetrahydrocannabinol (THC), the psychoactive component of cannabis, prenatally as well as during adolescence. Importantly, PENK and D2 gene expression impairments persisted into adulthood following either prenatal or adolescent THC exposure and the animals exhibited increased heroin self-administration and inhibitory control deficit, phenotypes predictive of drug addiction vulnerability. Epigenetic modifications are capable of maintaining modified gene expression states that can persist throughout development and it is an intriguing possibility that such mechanisms would underlie the long-term effects of cannabis exposure. In this project, we propose to study chromatin modification at specific regulatory regions of the PENK and D2 genes in the ventral striatum of adult rats with developmental THC exposure. The fact that PENK and D2 genes are preferentially expressed in subpopulations of stratial neurons that constitutes the striatopallidal pathway suggests a potential THC-sensitivity of genes aligned to this circuit. We set out to discover novel striatopallidal genes that are affected by developmental THC exposure and explore the epigenetic mechanisms that regulate their expression. Furthermore, we will investigate the causal relationship between THC-sensitive striatopallidal genes and addiction-related behaviors by use of gene manipulation in the ventral striatum. Overall, these studies will provide important mechanistic insights into the long-term impact of developmental THC exposure that would enable the development of targeted treatment interventions for addiction vulnerability and other related psychiatric disorders associated with developmental insults.