2002 Ph.D., Experimental Psychology, University of Kentucky
2000 M.S., Experimental Psychology, University of Kentucky
1996 B.S., Psychology, Texas A&M University
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 addition, 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.
Environmental enrichment produces protective phenotypes for addiction- and depression-related behavior in rats
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’s 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 (Green et al., 2002; Green et al., 2010), despite being more sensitive to the rewarding effects of the drug (as measured by conditioned place preference). Specific to depression-related behavior, EC rats show less depression-related behavior 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 (when allowed social contact). Our current research is focused on the molecular mechanisms underlying the protective addiction and depression phenotypes.
An inoculation stress hypothesis of environmental enrichment
Our environmental enrichment research led us to the surprising conclusion that enriched rats, despite the fact they co-exist in groups without violence or overcrowding, display many signs of being chronically stressed. For example, enriched rats have enlarged adrenal glands, blunted corticosterone release after a stressor, accumulation of the transcription factor deltaFosB in the nucleus accumbens, and blunted immediate-early gene induction in the nucleus accumbens. We arrived at an inoculation stress hypothesis, whereby environmental enrichment produces extremely mild daily stressors that inoculate EC rats against subsequent over stressors, including restraint stress, to produce the protective depression phenotype. Further, this inoculation stress decreases transcriptional responses in the brain from drugs of abuse, leading to the protective addiction phenotype (Crofton et al., 2015).
A tonic-phasic model of deltaFosB action
The inoculation stress hypothesis highlights the importance of deltaFosB accumulation, an effect that correlates with decreased immediate-early gene induction. We hypothesized that deltaFosB accumulation to high tonic levels feeds back to blunt induction of immediate-early gene phasic induction, thus providing a mechanistic explanation for the inoculation stress hypothesis and the protective phenotype from environmental enrichment (manuscript in preparation). According to the tonic-phasic hypothesis, a viral vector overexpressing deltaFosB in the nucleus accumbens should produce a protective addiction phenotype, an effect opposite to what most people would predict. Indeed, overexpression of deltaFosB produced a protective addiction phenotype similar to environmental enrichment (Zhang et al., 2014). Furthermore, deltaFosB can bind cAMP response elements (i.e. CREB sites) in addition to its own AP-1 sites. Immediate early gene induction is dependent upon CREB activity, so we hypothesize the high tonic levels of mechanistic explanation for the attenuated immediate-early gene induction seen with repeated stress, exposure to drugs of abuse, and environmental enrichment.
Retinoic acid signaling: a novel mediator of cocaine-taking behavior
To continue the search for the molecular mechanisms underlying the environmental enrichment protective phenotypes, we conducted comprehensive proteomic (Fan et al., 2013a,b; Lichti et al., 2014) and transcriptomic (Zhang et al., 2016a; Zhang et al., 2016b) analyses of nucleus accumbens tissue from EC and IC rats self-administering cocaine or saline. These experiments provided several promising leads, with the most promising lead being retinoic acid signaling in the nucleus accumbens shell. Genes relating to retinoic acid synthesis and signaling have highly selective expression confined predominantly to the nucleus accumbens shell, and several of these genes are regulated at the mRNA level by environmental enrichment and/or cocaine. To provide causal evidence of the importance of retinoic acid signaling we designed and constructed a viral vector expressing an shRNA to knock down CYP26B1, the enzyme that degrades retinoic acid, with the net result being an increase in retinoic acid levels. When injected into the nucleus accumbens shell, this vector produced an IC-like susceptible phenotype in standard-housed rats. Knockdown of the retinoic acid binding protein Fabp5 produced a resilient phenotype (decreased drug-taking and –seeking behavior (manuscript in preparation). These results validate retinoic acid as an important mechanism for addiction-related behavior.
van der Vaart, A., Meng, X., Bowers, S., Batman, A., Aliev, F., Farris, S., Hill, J. S., Green, T. A., Dick, D., Wolstenholme, J., Miles, M. F. Glycogen Synthase Kinase 3 Beta Regulates Ethanol Consumption and is a Risk Factor for Alcohol Dependence. Neuropsychopharmacology 43(13): 2521-2531.
Scala F., Nenov, M. N., Crofton, E. J., Singh, A. K., Folorunso, O, Zhang, Y, Chesson, B. C., Wildburger, N. C., James, T. F., Alshammari, M. A., Alshammari, T. K., Elfrink, H., Grassi, C., Kasper, J. M., Smith, A. E., Hommel, J., Lichti, C., Rudra, J., D'Ascenzo, M., Green, T. A., Laezza, F. (2018) Environmental enrichment and social isolation mediate neuroplasticity of medium spiny neurons through the GSK3 pathway. Cell Reports 23(2):555-567. doi10.1016/j.celrep.2018.03.062.
Aceto, G., Re, A., Mattera, A., Leone, L., Colussi, C., Rinaudo, M., Scala, F., Gironi, Saviana, K., Barbati, A., Fusco, S., Green, T., Laezza, F., D’Ascenzo, M., Grassi, C. (2018) GSK3β Modulates Timing-Dependent Long-Term Depression Through Direct Phosphorylation of Kv4.2 Channels. Cerebral Cortex. 29:5 1851-65.
Crofton, E. J., Nenov, M. N., Zhang, Y., Scala, F., Page, S. A., McCue, D. L., Li, D., Hommel, J. D., Laezza, L., Green, T. A. (2017) Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell. Neuropharmacology 117: 49-60. PMC5386787
James, T. F., Nenov, M. N., Tapia, C., Lecchi, M., Koshy, S., Green, T. A., Laezza, F. Consequences of acute Nav1.1 exposure to deltamethrin. Neurotoxicology 60:150-160. PMC5447465
Zhang, Y., Kong, F., Crofton, E. J., Dragosljvich, S. N., Sinha, M., Li, D., Fan, X., Koshy, S., Hommel, J. D., Spratt, H. M., Luxon, B. A., Green, T. A. (2016) Transcriptomics of environmental enrichment reveals a role for retinoic acid signaling in addiction. Frontiers Mol Neurosci 9:119. PMC5110542
Zhang, Y., Crofton, E. J., Fan, X., Li, D., Kong, F., Sinha, M., Luxon, B. A., Spratt, H. M., Lichti, C. F., Green, T. A. (2016) Convergent transcriptomics and proteomics of environmental enrichment and cocaine identifies novel therapeutic strategies for addiction. Neuroscience 339:254-266. PMC5118094
James, T. F., Nenov, M. N., Wildburger, N. C., Lichti, C. F., Luisi, J., Vergara, F., Panova-Electronova, N. I., Nilsson, C. L., Rudra, J., Green, T. A., Labate, D., Laezza, F. (2015) The Nav1.2 channel is regulated by GSK3. BBA – General Subjects 1850:832-844. PMC4336163.
Crofton, E. J., Zhang, Y., Green, T. A. (2015) Inoculation stress hypothesis of environmental enrichment. Neuroscience and Biobehavioral Reviews 49: 19-31. PMC4305384.
Chen, J., Winston, J. H., Fu, Y., Guptarak, J., Jensen, K. L., Shi, X., Green, T. A., Sarna, S. K. (2015) Genesis of anxiety, depression and ongoing abdominal discomfort/pain in ulcerative colitis-like colon inflammation. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 308: R18-R27. PMC4281679.
Zhang, Y., Crofton, E. J., Li, D., Lobo, M. K., Fan, X., Nestler, E. J., Green, T. A. (2014) Overexpression of deltaFosB in nucleus accumbens mimics the protective addiction phenotype but not the protective depression phenotype of environmental enrichment. Frontiers in Behavioral Neuroscience 8:297. PMC4148937.
Lichti, C. F., Fan, F., English, R. D., Zhang, Y., Li, D., Kong, F., Sinha, M., Andersen, C. R., Spratt, H., Luxon, B. A. and Green, T. A. (2014) Environmental enrichment alters protein expression as well as the proteomic response to cocaine in rat nucleus accumbens. Frontiers in Behavioral Neuroscience 8:246. PMC4104784.
Benzon, C. R., Johnson, S. B., McCue, D. L., Li, D., Green, T. A., Hommel, J. D. (2014) Neuromedin U receptor 2 knockdown in the paraventricular nucleus modifies behavioral responses to obesogenic high-fat food and leads to increased body weight. Neurosci. 258: 270-9. PMC3898339.
Fan, X., Li, D., Zhang, Y., Green, T. A. (2013) Differential phosphoproteome regulation of nucleus accumbens in environmentally enriched and isolated rats in response to stress. PLoS ONE 8(11): e79893. PMC3838351.
Anastasio, N. C., Stutz, S. J., Fox, R. G., Sears, R. M., Emeson, R. B., DiLeone, R. J., O’Neil, R. T., Fink, L. H., Li, D., Green, T. A., Moeller, F. G., Cunningham, K. A. (2013) Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. Neuropsychopharmacology 39(2): 370-82. PMC3970795.
Fan, X., Li, D., Lichti, C. F., Green, T. A. (2013) Dynamic proteomics of nucleus accumbens in response to acute psychological stress in environmentally enriched and isolated rats. PLoS ONE 8(9): e73689. doi:10.1371/journal.pone.0073689. PMC3767735.
Shavkunov, A. S., Wildburger, N. C., Nenov, M. N., James, T. F., Buzhdygan, T. P., Panova-Elektronova, N. I., Green, T. A., Veselenak, R. L., Bourne, N., Laezza, F. (2013) The fibroblast growth factor (FGF14)/voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). Journal of Biological Chemistry 288:19370-19385. PMC3707642.
Pavlovsky, A. A., Boehning, D., Li, D., Zhang, Y., Fan, X., Green, T. A. (2013) Psychological stress, cocaine and natural reward each induce endoplasmic reticulum stress genes in rat brain. Neuroscience 246:160-169. PMC3691328.
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