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MAILMAN RESEARCH CENTER

Behavioral Genetics Laboratory

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The Scientist (06/13/2007)
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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.

Behavioral Genetics Laboratory Staff

The Behavioral Genetics Laboratory Staff
(click to enlarge)

TMS Equipment

Viral-mediated gene transfer into the brain
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TMS Group

The BGL collaborated with the Brain Imaging Center for the oscillating magnetic field study
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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 and Dr. Perry Renshaw's Brain Imaging Center. Through a collaboration with the Brain Imaging Center, we use a custom-made transcranial magnetic stimulator (left) to examine if exposure to oscillating magnetic fields affects behavior in animal models of depression. The Carlezon lab is also a component of a Conte Neuroscience Center Grant awarded to Dr. Eric J. Nestler in the Department of Psychiatry at the University of Texas Southwestern Medical Center in Dallas, Texas. 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.

For additional information please visit the Carlezon Lab website on the Harvard Medical School Program in Neuroscience website.

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