Kabbaj Laboratory Mohamed Kabbaj, Ph.D. University of Bordeaux II, France Florida State University College of Medicine Dept. of Biomedical Sciences 1115 West Call Street Tallahassee, FL 32306-4300 Office: (850) 5495 Lab: (850) 644-4930 Dr. Kabbaj's Faculty Profile
Research Interests
The focus of our research is to understand the brain basis of emotional behavior. Simply put, we are asking: What is it in our brains that make us different from each other in the way we react emotionally? Why are some of us very prone to stress and others not? Why are some willing to take risks and try new adventures, while others are timid and fearful? Why are some prone to becoming addicted to harmful drugs (such as cocaine or heroin), while others readily avoid them? The basis of these differences is in our genes, in our brains, but also in our environment, the way we develop and the way we interact with others around us. We are using an excellent animal model for asking, and answering, these complex questions. We have made some discoveries on the brain basis of these differences in emotionality. Moreover, the work addresses questions of great importance to psychiatric disorders, including depression, and substance abuse. The following are some of the projects we are working on: 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.
Techniques used in Dr. Kabbaj’s Laboratory
Molecular In situ hybridization (single and double) Immunohistochemistry Radioimmunoassays Westerm Blot Northerm Blot Microarray RT-PCR and quantitative real time RT-PCR ChIP assays ChIP on chips Behavioral Locomotor activity Tests of anxiety (Light dark box, elevated plus maze, open field) Learned helplessness Tests for learning and memory Conditioned place preference Operant chambers of drug self-administration
Current Laboratory Members
Justin M. Farook, National University of Singapore, 2004 Post Doctoral Scholar, Biomedical sciences Hui Wang, Tianjin University, 1992 Laboratory assistant, Biomedical Sciences Fiona Smyth, FSU 2006 Graduate student, Biomedical Sciences Nicole Carrier, FSU 2007 Graduate Student, Biomedical Science Hui Wang, Tianjin University China 1992 Laboratory assistant Kelly Schwirian, FSU 2010 Undergraduate student Jake Jasinski, FSU 2012 Undergraduate student
Actual Funding
1 R21 MH081046-01A2 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 1 R01 DA019627-01 4/1/2005-/31/2010 NIDA/NIH Dopamine regulates drug and social reward interactions The overall aim of this application is to test the hypotheses that social bonding inhabits drug abuse and drugs of abuse inhibit social binding Role: Co-Principal Investigator
Selected References
Lu XY, Shieh KR, Kabbaj M, Barsh GS, Akil H and Watson S.J. (2002) Diurnal Rhythm of Agouti-Related Protein and Its Relation to Corticosterone and Food Intake. Endocrinology, 143 (10): 3905-3915. Kabbaj M , Yoshida S, Numachi Y , Sato M, Devine D.P and Matsuoka H (2003) Metamphetamine differentially regulates hippocampal glucocorticoids and mineralocorticoids receptors mRNA in Fischer and Lewis rats (2003). Molecular Brain Research, 117(1):8-14. C. Isgor; M. Cecchi; M. Kabbaj; H. Akil and S.J. (2003) Watson Estrogen Receptor B in the Paraventricular Nucleus of Hypothalamus Regulates the Neuroendocrine Response to Stress and is regulated by Corticosterone. Neurosciences: 121:837–845. Neal Jr CR, Weidemann G, Kabbaj M, Vazquez DM (2004) Effect of Neonatal Dexamethasone Exposure on Growth and Neurological Development in the Adult Rat. In press in Am J Physiol, Aug;287(2):R375-85 Isgor C, M Kabbaj*, S.J. Watson and H. Akil (2004) Delayed Effects of Chronic, Variable Stress During Peripubertal-Juvenile Period on Hippocampal Morphology, Cognitive and Stress Axis Functions in Rats. Hippocampus. 2004;14 (5):636-48. *Isgor and Kabbaj are first coauthors Kabbaj M (2004) Neurobiological bases of individual differences in emotional and stress responsiveness: high responders/low responders model. Arch Neurol. Jul; 61(7):1009-12. Review Kabbaj M, Evans S, Watson SJ, Akil H (2004) The search for the neurobiological basis of vulnerability to drug abuse: using microarrays to investigate the role of stress and individual differences. Neuropharmacology. 47 Suppl 1:111-22. Dietz D.M, Tapocik J, Gaval-Cruz M and Kabbaj M (2005) Dopamine transporter, but not tyrosine hydroxylase, may be implicated in determining individual differences in behavioral sensitization to amphetamine. Physiology and Behavior: 86(3):347-55. Kabbaj M (2006): Individual vulnerability to drug abuse: the high responders/low responders model. CDT-CNS Neurological Disorders special issue on the effects of Stress on brain function. Review. Volume 5, No.5. SM. Clinton, DM. Vázquez, M Kabbaj, MH Kabbaj, SJ. Watson, and H Akil (2007) Individual differences in novelty-seeking and emotional reactivity correlate with variation in maternal behavior. In press. Hormones and Behavior 51 (5): 655-64 M Kabbaj, S. Morley-Fletcher, M. Le Moal, PV. Piazza and S. Maccari (2007) Individual differences in the effects of chronic prazosin treatment on hippocampal mineralocorticoid and glucocorticoid receptors. European Journal of Neurosciences 25(11):3312-8 Dietz D and H. Wang and Kabbaj M (2007) Corticosterone fails to produce conditioned place preference or place aversion in rats. Behavioral Brain Research 181 (2): 287-291 Kabbaj M and C Isgor (2007) Effects of chronic environmental and social stimuli during adolescence on mesolimbic dopaminergic circuitry markers Neuroscience Letters 422: 7-12 Dietz, D.M., Dietz, K.C., Moore, S., Ouimet, C.C. and Kabbaj, M (2008) Repeated Social Defeat Stress Induced Sensitization to the Locomotor Activating Effects of d-amphetamine: Role of Individual Differences. Psychopharmacology, 198(1): 51-62. William Renthal, Arvind Kumar, Guanghua Xiao, Matthew Wilkinson, Herbert E. Covington, III, Ian Maze, Devanjan Sikder, Alfred J. Robison, Quincey LaPlant, David M. Dietz, Scott J. Russo, Vincent Vialou, Sumana Chakravarty, Thomas J. Kodadek, Ashley Stack, Mohamed Kabbaj and Eric J. Nestler (2009) Genome Wide Promoter Analysis of Histone Modifications induced by Cocaine; Neuron 62: 335-348.