MAILMAN RESEARCH CENTER
Behavioral Genetics Laboratory
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This multidisciplinary, preclinical research program explores in animal models how genes affect complex motivated behaviors. We are particularly interested in how experiences such as drug exposure or stress affect gene expression within the mesolimbic system (ventral tegmental area, nucleus accumbens) and cortical structures (frontal cortex, amygdala), and in turn how these molecular adaptations lead to alterations in behavior.
In some cases, we mimic the effects of drug exposure or stress on gene expression through the use of engineered viral vectors, which allow us to transfer genes directly into select areas of rat brain. In other cases, we manipulate gene expression using genetically engineered mice. We use a variety of behavioral assays in rats and mice (place conditioning, rewarding brain stimulation, fear-potentiated startle, prepulse inhibition, forced swimming), each of which models various aspects of addiction or neuropsychiatric conditions such as depression, schizophrenia, and anxiety-related disorders.
Using viral-mediated gene transfer in rats, we recently discovered that activation of genes within key brain regions can trigger in rats symptoms of cocaine withdrawal and, more importantly, depression. Specifically, we found that activation of CREB (cAMP response element binding protein) in frontal portions of the brain caused signs of depression that normally occur only in response to stressful situations. Importantly, we also found that blocking CREB lessened the effects of stress, and made rats behave as if they were being treated with antidepressant drugs. By comparing differences in the genetic profiles of rats with activated or deactivated CREB, we uncovered evidence that the gene for dynorphin serves as a "switch" for some signs of depression.
The Behavioral Genetics Laboratory Staff
Viral-mediated gene transfer into the brain
Allison Knoll received her Ph.D. from the Harvard Medical School Program in Neuroscience....
The identification of this "switch" could lead to new strategies for treating depression. For example, in preliminary tests, chemical blockers of brain receptors for dynorphin (kappa opioid antagonists) appear to have strong antidepressant effects in animal models.
We plan to expand this research to include the study of other neuropsychiatric conditions such as attention deficit hyperactivity disorder, anxiety disorders, and bipolar disorder, each of which involves the same neuronal circuitry.
The Carlezon lab participates in translational research with clinical groups at McLean Hospital, including Dr. Bruce Cohen's Molecular Pharmacology Laboratory. The Carlezon lab is a component of a Conte Neuroscience Center Grant awarded to Dr. Eric J. Nestler in the Department of Psychiatry at Mt. Sinai School of Medicine. Funded by the National Institute of Mental Health (NIMH), this award supports collaborative research on mental health and includes scientists from numerous universities around the United States. The specific purpose of this grant is to study the molecular basis of mood regulation. We are also part of a consortium of Harvard neuroscientists that received a Collaborative Initiative Award (CIA) from the Howard Hughes Medical Institute (HHMI). Led by Dr. Catherine Dulac, the purpose of this award is to study how gene imprinting affects brain development and behavior within the context of psychiatric illness.
- Bill Carlezon, Ph.D. - Professor of Psychiatry and Neuroscience & Director, Behavioral Genetics Laboratory, Harvard Medical School
- Elena H. Chartoff, Ph.D. - Assistant Professor of Psychiatry, Harvard Medical School
- Edward G. Meloni, Ph.D. - Assistant Professor of Psychiatry, Harvard Medical School
- John W. Muschamp, Ph.D. - Instructor in Psychiatry, Harvard Medical School
- Angela Sparrow, Ph.D. - Postdoctoral Fellow (with Dr. Chartoff)
- Amy L. Mahan, Ph.D. - Postdoctoral Fellow
- David Potter, M.A. - Research Lab Manager
- Sara Onvani, M.A. - Research Associate
- Shayla Russell, B.Sc. - Research Assistant (with Dr. Chartoff)
- Kristen Finn, B.Sc. - Research Assistant
- Rachel Donahue, B.Sc. - Graduate Student, Harvard Medical School Program in Neuroscience
- Ashlee Van't Veer, B.A. - Graduate Student, Harvard Medical School Program in Neuroscience
- Fontini Savvides - Lab Administrator
- Howard Hughes Medical Institute (HHMI)
- National Institute on Drug Abuse (NIDA)
- National Institute of Mental Health (NIMH)
- National Alliance for Research on Schizophrenia and Depression (NARSAD)
- The Stanley Foundation
- Carlezon WA Jr, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ. (1998) Regulation of cocaine reward by CREB. Science 282: 2272-2275
- Pliakas AM, Carlson R, Neve RL, Konradi C, Nestler EJ, Carlezon WA Jr (2001) Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element binding protein expression in nucleus accumbens. Journal of Neuroscience 21:7397-7403
- Andersen SL, Arvanitogiannis A, Pliakas AM, LeBlanc C, Carlezon WA Jr (2002) Altered responsiveness to cocaine in rats exposed to methylphenidate during early development. Nature Neuroscience 5: 13-14
- Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz HC, Zhang Y, Stevens WC Jr., Jones RM, Portoghese PS, Carlezon WA Jr (2003) Antidepressant-like effects of kappa opioid receptor antagonists in the forced swim test in rats. Journal of Pharmacology and Experimental Therapeutics 305: 323-330
- Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends in Neurosciences 28: 436-445
- Carlezon WA Jr, Beguin C, DiNieri J, Baumann MH, Richards M, Todtenkopf MS, Rothman RB, Ma Z, Lee DY-L, Cohen BM (2006) Depressive-like effects of the kappa-opioid receptor agonist Salvinorin A on behavior and neurochemistry in rats. Journal of Pharmacology and Experimental Therapeutics 314: 440-447
- Chartoff EH, Mague SD, Barhight MF, Smith AM, Carlezon WA Jr (2006) Behavioral and molecular effects of dopamine D1 receptor stimulation during naloxone-precipitated morphine withdrawal. Journal of Neuroscience 26: 6450-6457
- Meloni EG, Gerety LP, Knoll AT, Cohen BM, Carlezon WA Jr (2006) Behavioral and anatomical interactions between dopamine and corticotropin-releasing factor (CRF) in the rat. Journal of Neuroscience 26: 3855-3863
- Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA Jr (2007) Anxiolytic-like effects of k-opioid receptor antagonists in behavioral models of unlearned and learned fear in rats. Journal of Pharmacology and Experimental Therapeutics 323: 838-845
- Chartoff EH, Potter D, Damez-Werno D, Cohen BM, Carlezon WA Jr (2008) Exposure to the selective kappa agonist salvinorin A modulates the behavioral and molecular effects of cocaine in rats. Neuropsychopharmacology 33: 2676-2687
- Carlezon WA Jr, Thomas M (2009) Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacology 56, Suppl 1: 122-132
- DiNieri JA, Nemeth C, Parsegian A, Carle T, Gurevich VV, Gurevich E, Neve RL, Nestler EJ, Carlezon WA Jr (2009) Altered sensitivity to rewarding and aversive drugs in mice with inducible disruption of CREB function within nucleus accumbens. Journal of Neuroscience 29; 1855-1859