Project 4 focuses on the ability of circadian genes in the ventral tegmental area (VTA)-nucleus accumbens(NAc) circuit to regulate mood and motivational state. This is related to the knowledge that abnormal moodand other symptoms in many patients with depression show prominent circadian oscillations. We havedemonstrated that NPAS2 (neuronal PAS domain protein 2), a transcription factor highly homologous toClock, regulates an animal's responsiveness to emotional stimuli, including their activity in animal models ofdepression. Interestingly, NPAS2 is not expressed in the suprachiasmatic nucleus (SCN), a hypothalamicregion important for circadian oscillations and their entrainment by environmental lighting. Rather, thehighest expression of NPAS2 is seen in the NAc. Our hypothesis is that NPAS2acting within the NAccontributes to circadian variations in mood, locomotor activity, and motivation. In parallel, we haveestablished a powerful influence of Clock itself on mood: mice lacking functional Clock protein exhibit astriking array of behavioral symptoms reminiscent of mania. This phenotype is reversed by lithium, and wehave growing evidence that Clock action in the VTA per se is an important mediator of this behavioralphenotype.The goal of the proposed studies is to carry out a systematic evaluation of the role played by NPAS2, Clock,and related circadian gene products expressed in the VTA and NAc in the regulation of mood andmotivation. This will be accomplished by use of mice with mutations in these various genes and of viralvectors that selectively manipulate the activity of the genes within the VTA-NAc. In addition, we will furtherestablish the regulation of circadian gene expression in the VTA and NAc in response to chronic exposure tostress and antidepressant treatments. As well, we will identify and characterize the target genes throughwhich NPAS2, Clock, and other circadian genes, acting as transcription factors, regulate the VTA-NAccircuit. We are also interested in cross talk between these circadian genes and CREB. CREB is known toregulate certain circadian genes in SCN, and we have found similar regulation in the VTA-NAc. Moreover,CREB, and circadian transcription factors, share some of the same target genes (e.g., cholecystokinin) inthese brain reward regions.
| Olausson, Peter; Kiraly, Drew D; Gourley, Shannon L et al. (2013) Persistent effects of prior chronic exposure to corticosterone on reward-related learning and motivation in rodents. Psychopharmacology (Berl) 225:569-77 |
| Warren, Brandon L; Vialou, Vincent F; Iñiguez, Sergio D et al. (2013) Neurobiological sequelae of witnessing stressful events in adult mice. Biol Psychiatry 73:7-14 |
| Nestler, Eric J (2013) Treating the brain deep down: Brain surgery for anorexia nervosa? Nat Med 19:678-9 |
| Quinn, Jennifer J; Pittenger, Christopher; Lee, Anni S et al. (2013) Striatum-dependent habits are insensitive to both increases and decreases in reinforcer value in mice. Eur J Neurosci 37:1012-21 |
| Golden, Sam A; Christoffel, Daniel J; Heshmati, Mitra et al. (2013) Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med 19:337-44 |
| Lobo, Mary Kay; Nestler, Eric J; Covington 3rd, Herbert E (2012) Potential utility of optogenetics in the study of depression. Biol Psychiatry 71:1068-74 |
| Tamminga, Carol A; Southcott, Sarah; Sacco, Carolyn et al. (2012) Glutamate dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. Schizophr Bull 38:927-35 |
| Li, Yun; Yui, Daishi; Luikart, Bryan W et al. (2012) Conditional ablation of brain-derived neurotrophic factor-TrkB signaling impairs striatal neuron development. Proc Natl Acad Sci U S A 109:15491-6 |
| Li, Yun; Li, Yanjiao; McKay, Renee M et al. (2012) Neurofibromin modulates adult hippocampal neurogenesis and behavioral effects of antidepressants. J Neurosci 32:3529-39 |
| Gourley, Shannon L; Swanson, Andrew M; Jacobs, Andrea M et al. (2012) Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding. Proc Natl Acad Sci U S A 109:20714-9 |
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