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Substance use disorder (SUD) is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in SU is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and Npas2 mutant mice at different times of day. In the light (inactive) phase, cocaine self-administration, reinforcement, motivation and extinction responding were increased in all Npas2 mutants. Sex differences emerged during the dark (active) phase with Npas2 mutation increasing self-administration, extinction responding, and reinstatement only in females as well as reinforcement and motivation in males and females. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and Npas2 mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated in Npas2 mutant females, we measured cocaine-induced ΔFosB expression. Relative to WT, ΔFosB expression was increased in D11 neurons in the nucleus accumbens (NAc) core and dorsolateral (DLS) striatum in Npas2 mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in Npas2 mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day (TOD)-specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of Npas2 mutation in females. [ABSTRACT FROM AUTHOR]

Polymorphisms in circadian genes such as CLOCK convey risk for bipolar disorder. While studies have begun to elucidate the molecular mechanism whereby disruption of Clock alters cellular function within mesolimbic brain regions, little remains known about how these changes alter gross neural circuit function and generate mania-like behaviors in Clock-Δ19 mice. Here we show that the phasic entrainment of nucleus accumbens (NAC) low-gamma (30–55 Hz) oscillations to delta (1–4 Hz) oscillations is negatively correlated with the extent to which wild-type (WT) mice explore a novel environment. Clock-Δ19 mice, which display hyperactivity in the novel environment, exhibit profound deficits in low-gamma and NAC single-neuron phase coupling. We also demonstrate that NAC neurons in Clock-Δ19 mice display complex changes in dendritic morphology and reduced GluR1 expression compared to those observed in WT littermates. Chronic lithium treatment ameliorated several of these neurophysiological deficits and suppressed exploratory drive in the mutants. These results demonstrate that disruptions of Clock gene function are sufficient to promote alterations in NAC microcircuits, and raise the hypothesis that dysfunctional NAC phase signaling may contribute to the mania-like behavioral manifestations that result from diminished circadian gene function. [ABSTRACT FROM AUTHOR]

Morphine dependence is associated with long-term adaptive changes in the brain that involve gene expression. Different behavioral effects of morphine are mediated by different brain regions, for example, the locus ceruleus (LC), a noradrenergic nucleus, is implicated in physical dependence and withdrawal, whereas the ventral tegmental area (VTA), a dopaminergic nucleus, contributes to rewarding and locomotor responses to the drug. However, the global changes in gene expression that occur in these brain regions after morphine exposure and during withdrawal remain unknown. Using DNA microarray analysis in both mice and rats, we now characterize gene expression changes that occur in these brain regions with chronic morphine and antagonist-precipitated withdrawal. In the LC, numerous genes display common regulation between mouse and rat, including tyrosine hydroxylase, prodynorphin, and galanin. Furthermore, we identify clusters of genes that are regulated similarly by chronic morphine and by withdrawal, as well as clusters that show opposite regulation under these two conditions. Interestingly, most gene expression changes that occur in the VTA in response to chronic morphine are different from those seen in the LC, but the gene expression patterns in the two brain regions are very similar after withdrawal. In addition, we examined two genes (prodynorphin and FK506 binding protein 5) that are strongly regulated by chronic morphine or morphine withdrawal in the LC for their role in regulating withdrawal-associated behaviors. Inhibition of either protein profoundly affects withdrawal responses, demonstrating that the genes identified in this study have important functional roles in mediating opiate-induced behaviors. [ABSTRACT FROM AUTHOR]

Hearing in Drosophila depends on the transduction of antennal vibration into receptor potentials by ciliated sensory neurons in Johnston's organ, the antennal chordotonal organ. We previously found that a Drosophila protein in the vanilloid receptor subfamily (TRPV) channel subunit, Nanchung (NAN), is localized to the chordotonal cilia and required to generate sound-evoked potentials (Kim et al., 2003). Here, we show that the only other Drosophila TRPV protein is mutated in the behavioral mutant inactive (iav). The IAV protein forms a hypotonically activated channel when expressed in cultured cells; in flies, it is specifically expressed in the chordotonal neurons, localized to their cilia and required for hearing. IAV and NAN are each undetectable in cilia of mutants lacking the other protein, indicating that they both contribute to a heteromultimeric transduction channel in vivo. A functional green fluorescence protein-IAV fusion protein shows that the channel is restricted to the proximal cilium, constraining models for channel activation. [ABSTRACT FROM AUTHOR]