UTMB - The University of Texas Medical Branch

Research Interests

There is almost unanimous agreement among scientists that complex psychiatric conditions such as addiction, depression and anxiety are a function of interactions between genes and environment. Exposure to environmental factors such as drugs of abuse or stress activate signaling cascades within neurons that in turn alter gene transcription in specific brain regions involved in addiction, depression and anxiety. These changes in gene transcription are typically homeostatic, leaving the person better adapted to the changing environment. However, in a minority of cases the drug or stress insult triggers maladaptive changes in brain chemistry, leading to psychiatric conditions such as addiction or depression.

In contrast to drugs and stress, positive environmental stimuli such as novelty, social contact and exercise produce a protective phenotype that can render some people resistant to addiction or depression, even after exposure to drugs of abuse or stress. We can model this effect in rats using the environmental enrichment paradigm. Rats at 21 days of age are assigned either to an isolated condition (IC), where they are single housed with no social contact or novelty, or an enriched condition (EC) where they are housed 12 per cage in large home cages with novel objects (children toys) and social contact with cohorts. After a month in these environmental conditions, EC rats exhibit protective phenotypes for addiction- and depression-like behavior. Regarding addiction-like behavior, EC rats do not self-administer intravenous cocaine or amphetamine as readily as IC rats, despite being more sensitive to the rewarding effects of the drug (as measured by conditioned place preference). Specific to depression-like behavior, EC rats show less signs of behavioral despair than IC rats in the Forced Swim Test and greater preference for natural rewards such as sucrose. Not surprisingly, EC rats also engage in social grooming more than IC rats.

Our current research is focused on the molecular mechanisms underlying the protective addiction and depression phenotype. We have already identified the transcription factor cAMP response-element binding protein (CREB) as one major mechanism in the EC phenotype. We have shown that we can reproduce the EC phenotype in normal pair-housed animals simply by blocking CREB function in the nucleus accumbens shell using novel viral vectors. However, CREB itself is only a transcription factor, meaning that it can only be a distal mechanism. Our future plans are to utilize well-established genomic expression profiling techniques in EC and IC rats to identify CREB target genes as proximal mechanisms mediating the EC phenotype. Once identified, additional viral vectors will be constructed to validate the role of these CREB target genes in mediating the protective EC phenotype. The overall goal of the project is to identify new mechanisms of resistance to addiction and depression to target for treatment as well as prevention of addiction and depression.

Biographical Information

My research career began as and undergraduate at Texas A&M University studying the brain mechanisms underlying the anorexic effects of psychostimulants. Realizing that my interests were shifting toward gaining an understanding of the neurobiology of psychostimulants and their propensity to support addictive behaviors, I joined the laboratory of Dr. Susan Schenk. There I gained expertise in intravenous self-administration models in rats as well as other animal models of compulsive behaviors. Seeking to augment my knowledge in behavioral neuropharmacology, I entered the Experimental Psychology graduate program at the University of Kentucky under the direction of Dr. Michael Bardo, who is recognized for his focus on reward seeking and inhibition as biologically-based constructs that drive vulnerability to compulsive drug-seeking.

My experiences in Dr. Bardo's laboratory enhanced my research repertoire to include new behavioral models and in vitro neuropharmacological techniques. I was also introduced to the concept that rearing under environmentally enriched conditions results in a phenotype that protects against compulsive drug use in the adult rat, a construct that is at the heart of my current research program. Toward the end of graduate school Dr. Bardo suggested I broaden my horizons further by focusing my postdoctoral research on molecular neuroscience. I reasoned that environmental enrichment is a superb model of gene/environment interactions, and that the enrichment phenotype must be a function of differential gene transcription. Thus, I joined Dr. Eric Nestler's laboratory in 2002 as a Postdoctoral Fellow to study transcription factors in the progression from drug use to addiction. I was successful in validating my assertion that enrichment effects are due to changes in gene transcription and identified the transcription factor CREB as a critical mediator of these effects.

In 2008 I began an Assistant Professorship working with Dr. Michael Miles at the Medical College of Virginia last year to focus on a genomic/bioinformatic project investigating alcoholism-related genes. My experience in Dr. Miles' laboratory taught me the intricacies of analyzing large data sets, and how to employ functional genomic approaches in a manner that best exploits the advantages of large data sets while at the same time minimizing artifact and false positives.

I joined the faculty of the Center for Addiction Research in the Pharmacology and Toxicology Department at UTMB in January of 2009. I am currently setting up an in vivo viral vector production facility and beginning work on my primary focus: studying the molecular determinants of behavior as it relates to addiction and depression.

Selected Publications

Russo, S. J., Wilkinson, M., Mazei-Robison, M., Dietz, D. M., Maze, I., Krishnan, V., Robison, B., Renthal, W., Graham, A., Birnbaum, S. G., Green, T. A., Lesselyong, A., Perotti, L. I., Bolanos, C. A., Kumar, A., Clark, M. S., Neumaier, J. F., Neve, R. L., Bhakar, A. L., Barker, P. A., Nestler, E. J. (2009) NFKappaB signaling regulates neuronal morphology and cocaine reward. J Neurosci (in press).

Winstanley, C. A., Bachtell, R. K., Theobald, D. E. H., Laali, S., Green, T. A., Kumar, A., Chakravarty, S., Self, D. W., Nestler, E. J. (2009) Increased impulsivity during withdrawal from cocaine self-administration: Role for FosB in the orbitofrontal cortex. Cerebral Cortex. 19(2):435-44.

Wallace, D. L., Han, M. H., Graham, D. L., Green, T. A., Vialou, V., Iniguez, S., Cao, J. L., Chakravarty, S., Kumar, A., Kirk, A., Krishnan, V., Neve, R. L., Cooper, D., Bolanos-Guzman, C. A., Barrot, M., McClung, C. A., Nestler, E. J. (2009) CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci 12(2):200-9.

Wallace, D. L., Vialou, V., Rios, L., Carle-Florence, T. L., Chakravarty, S., Kumar, A., Graham, D., Green, T. A., Kirk, A., Iniguez, S. D., Perotti, L. I., Barrot, M., DiLeone, R. J., Nestler, E. J., Bolanos, C. A. (2008) The influence of FosB in the nucleus accumbens on natural reward-related behavior. J Neurosci. 28(41): 10272-10277.

Green, T. A., Alibhai, I. N., Unterberg, S., Ghose, S., Tamminga, C. A., Neve, R. L., Nestler, E. J. (2008) Induction of activating transcription factor 2 (ATF2), ATF3 and ATF4 in the nucleus accumbens and effects on behavior related to addiction, anxiety and depression. J Neurosci. 28(9):2025-32.

Winstanley, C. A., LaPlant, Q., Theobald, D. E. H., Green, T. A., Bachtell, R. K., Perotti, L. I., DiLeone, R. J., Russo, S. J., Garth, W. J., Self, D. W., Nestler, E. J. (2007) FosB induction in the orbitofrontal cortex regulates cocaine-induced cognitive dysfunction J Neurosci 27(39): 10497-10507.

Green, T. A., Alibhai, I. N., Hommel, J. D., DiLeone, R. J., Kumar, A., Theobald, D. E., Neve, R. L., Nestler, E. J. (2006) Induction of ICER in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli. J. Neurosci. 26(32): 8235-42

Han, M., Bolanos, C. A., Green, T. A., Olson, V. G., Neve, R. L., Liu, R., Aghajanian, G. K., Nestler, E. J. (2006) Role of camp response element-binding protein (CREB) in the locus coeruleus: regulation of neuronal activity and opiate withdrawal behaviors. J. Neurosci. 26: 4624-9.

Dong, Y., Green, T., Saal, D., Marie, H., Neve, R., Nestler, E. J., Malenka, R. C. (2006) CREB modulates excitability of nucleus accumbens neurons. Nat. Neurosci. 9:475-7.

Green, T. A. and Nestler, E. J. (2006). Psychiatric applications of viral vectors. In: Kaplitt, M. G. and During, M. J. (eds). Gene Therapy in the Central Nervous System: from Bench to Bedside, p181-193. New York: Elsevier Science.

Krishnan, V., Han, M. H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., Ghose, S., Reister, R., Tannous, P., Green, T. A., Neve, R., Chakravarty, S., Kumar, A., Eisch, A. J., Self, D. W., Lee, F. S., Tamminga, C. A., Cooper, D. C., Gershenfeld, H. K., Nestler, E. J. (2007) Molecular mechanisms of resilience in brain reward regions. Cell 131(2): 391-404.

Green, T. A., Gehrke, B. J., Bardo, M. T. (2002). Environmental enrichment decreases intravenous amphetamine self-administration in rats: dose response functions for fixed- and progressive-ratio schedules. Psychopharmacology, 162(4): 373-378.