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.
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