Research Interest
The focus of our research is to understand the neurobiology underlying individual differences and sex differences in depression and drug addiction. Another focus of our research is to examine epigenetic mechanisms underlying social behaviors. Below are some examples of ongoing/past studies:
Neurobiological basis of individual differences in behavioral sensitization to amphetamine
The overall aim of this work is to investigate the neurobiological basis of behavioral sensitization to amphetamine in the context of individual differences. We aim to understand the interplay between psychosocial stress and the development of behavioral sensitization to amphetamine in the context of individual differences using a model of novelty seeking behavior that distinguishes outbred rats on the basis of their high (High Responder, HR) or low (Low Responder, LR) locomotor activity in a novel environment. HR rats acquire AMPH and cocaine self-administration faster than LR rats (Kabbaj et al., 2001; Mantsch et al., 2001; Marinelli and White, 2000; Piazza et al., 1989; Piazza et al., 2000; Pierre and Vezina, 1997) and show a greater behavioral sensitization to amphetamine or cocaine after repeated administration of low doses (Hooks et al., 1992; Hooks et al., 1991a; Piazza et al., 1989; Pierre and Vezina, 1997). Behavioral and neural sensitization may have a potential role in the pathogenesis of affective disorders and drug abuse (Robinson and Berridge, 2000; White and Kalivas, 1998).
One possible mechanism by which stress enhances drug taking and behavioral sensitization to psychostimulants is through an interaction between glucocorticoids and dopamine. Our working hypothesis is that differences in stress- and dopamine- related genes play a role in HR and LR behavioral differences in sensitization to AMPH, as well as in the effect of psychosocial stress on behavioral sensitization to AMPH. To test these hypotheses, we will describe the neurobiological basis of behavioral sensitization to amphetamine as well as the neurobiological basis of the effect of psychosocial stress (and glucocorticoids) on behavioral sensitization to AMPH in the context of individual differences.
Epigenetics of social defeat:
Histone acetylation and methylation, as well as deacetylation and demythylation are epigenetic states that can produce activation or silencing of specific genes. These post-translational processes have been shown to occur in the brain and to affect gene expression. Our preliminary studies show that there exist basal differences in the overall degree of acetylation of H3K14 and H2b, but not H4, in rats that differ in response to novelty. Indeed, the high responders rats (HR) exhibit higher levels of acetylation of H3K14 and H2b when compared to low responders rats (LR). Interestingly, chronic social defeat, which is an established animal model of depression, induces a differential acetylation of H3K14 and H2b in HR and LR rats. Social defeat decreases the acetylation levels on H3K14 and H2b in HR rats and increases it in the LR rats. Social defeat however decreased the level of acetylation of H4 independently of HR and LR rats. Since HR and LR rats exhibit different emotional responses, with the HR rats more prone to depression-like phenomena, we hypothesize that the epigenetic states described for the H3K14 and H2b contribute to individual differences in response to novelty and to individual differences in response to chronic stress-induced psychopathology.
Epigenetics of social bonding:
Social attachments are a vital part of healthy human behavior and an inability to form such attachments is regarded as a symptom of mental disorders such as schizophrenia and autism. Studying the mechanisms underlying social attachment requires an animal model that displays behaviors similar to that of human social attachment. Prairie voles (Microtus ochrogaster) have become an important model for the study of the neurobiology of social attachment. In the field, male and female prairie voles form long-term bonds and share a nest throughout the breeding season. Such a breeding pair typically remains together until one animal dies. For prairie voles, it has been demonstrated that 24 h of mating reliably results in partner preference formation, whereas 6 h of cohabitation in the absence of mating does not induce this behavior. Given that mating in prairie voles induces neuroadaptations that eventually lead to bonding, we are investigating whether mating induced social bonding has an underlying epigenetic basis
Sex differences in anxiety: role of EGR I
In this proposal we are investigating sex differences in social interaction (SI) behavior and we are examining the role of the immediate early gene zif268 in the medial prefrontal cortex (mPFC) in mediating these behaviors in male and female rats. Another focus of this study is to determine the upstream and downstream molecular targets of zif268 that are relevant to sex differences in SI. In our hands, male rats exhibit higher SI than female rats -regardless of their estrus cycle-. Interestingly, the basal expression of zif268 in the medial prefrontal cortex (mPFC) varied between the sexes in that males had higher levels of zif268 expression in this region when compared to females. Through the use of zif268 antisense oligodeoxynucleotides (zif268 ASO), we induced a temporary down-regulation of zif268 expression in the mPFC of male rats and compared their SI behavior to both control males and females infused with zif268 missense oligodeoxynucleotides (zif268 MSO). Upon doing this, we found that zif268 ASO males displayed significantly less SI (and therefore, were more anxious) than control males and, in fact, displayed levels of SI which were similar to control females. In essence, down-regulation of zif268 expression in the mPFC of male rats eliminated the sex differences previously found in anxiety-like behavior in the SI test. Our novel findings have led us to hypothesize that sexually-dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific in anxiety-like behavior in the SI test, which has a strong social component. We are exploring further the hypothesis that zif268 in the medial prefrontal cortex play a major role in determining sex differences in SI and determine the upstream and downstream targets of zif268 in the mPFC that play a major role in these sex differences in anxiety.
Testosterone and Depression
Testosterone has mood-enhancing properties and antidepressant effects in men. In fact, increased incidence of hypogonadism occurs in men with major depressive disorder (MDD), and testosterone replacement effectively improves mood. In rodents, testosterone has antidepressant effects in aged male mice and protective effects against the development of depression-like behaviors in rats. Our studies suggest a modulatory role for testosterone in the regulation of depressive disorders; and proposed molecular mechanisms and brain sites of its actions. For example, we have recently shown that testosterone antidepressant effects are lost if we enhance gene expression of a dominant negative form of ERK2 (an important molecule in the MAPK pathway) in the hippocampus (see attached figure).
Techniques used in Dr. Kabbaj’s Laboratory
Molecular
- In situ hybridization (single and double)
- Immunohistochemistry
- Radioimmunoassays
- Westerm Blot
- Microarray
- RT-PCR and quantitative real time RT-PCR
- ChIP assays
- ChIP on chips
- Chip-sequencing
Behavioral
- Locomotor activity/Sensitization
- Tests of anxiety (Light dark box, elevated plus maze, open field, Social Interaction)
- Tests for learning and memory
- Conditioned place preference
- Operant chambers of drug self-administration
Current Laboratory Members
Dr. Hussam, Jourdi, Niigata University 2002
Assistant Research Scientist, Biomedical Sciences
Dr. Florian Duclot, University of Montpellier 2 2009
Postdoctoral scholar, Biomedical Sciences
Nicole Carrier, FSU 2007
Graduate Student, Biomedical Science
Hui Wang, Tianjin University, 1992
Laboratory assistant, Biomedical Sciences
Corinne Bunn, FSU 2013
Undergraduate student, Biology
Megan Frugoli, FSU 2014
Undergraduate student, Biology
Ariel Beermann-Young, 2014
Undergraduate student, Psychology
Carl Youssef, 2012
Undergraduate student, Biology
Stefanie Stallard, 2013
Undergraduate student, Biology
Actual Funding
1 R01 MH087583-01A1 (Kabbaj) 9/1/2010-8/30/2015
NIMH/NIH
Sex differences in anxiety: role of zif268
The major aim of this application is to examine the role of zif268 in the prefrontal cortex in determining sex differences in anxiety in rats.
1 R21 MH081046-01A2 (Kabbaj) 4/1/2009-3/30/2011
NIMH/NIH
Epigenetics of social defeat
The overall aim of this application is to examine histone modifications following chronic social defeat in the context of individual differences
Role: Principal Investigator
1R21 MH083128-01A2 (Kabbaj) 12/1/2009-11/30/2011
NIMH/NIH
Epigenetics of Social Bonding
The major goal of this award is to investigate the role of histone modifications in social bonding in prairie voles