Photic Entrainment of Circadian Behaviors

描述(申请人提供)：该项目将继续研究神经化学信号如何在下丘脑视交叉上核(SCN)内相互作用，以使行为的昼夜节律与昼夜周期同步。由于昼夜节律系统的紊乱与各种精神疾病有关，了解昼夜节律的神经生物学应该有助于开发这些紊乱的新治疗方法。至少有三种不同的SCN传入投射参与了昼夜节律的光携带。视网膜下丘脑束是视网膜的直接投射，对于携带光刺激是必要的，也是充分的。从中缝和膝间小叶到SCN的投射也影响光的夹带。此外，有证据表明，这些投射可能调节非光刺激的相移效应。这个项目的长期目标是通过定义光和非光信息如何传递到SCN和在SCN内处理来确定昼夜节律夹带的神经化学基础。在接下来的四年里，我们将测试工作假说，即在SCN内释放的GABA调节昼夜节律起搏器的能力，以适应昼夜节律周期的不同阶段的相移。更具体地说，我们认为在白天，GABA通过直接作用于时钟细胞来调节任何刺激(如NPY或5-羟色胺)所产生的相移。在夜间，GABA通过直接作用于时钟细胞来调节任何刺激(NPY或5-羟色胺)抑制光诱导的相移的能力。此外，我们还将测试GABA调节两个时钟基因(即PER1和PER2)的mRNA水平的假设，这两个基因被假设为调节昼夜节律的相移。现有证据表明，PER1和PER2的mRNA水平在白天被相移刺激降低，而在晚上被光增强。因此，我们认为白天或夜间释放的GABA会降低PER1和PER2的mRNA水平。

DESCRIPTION (provided by applicant): This project will continue to investigate how neurochemical signals interact within the suprachiasmatic nucleus of the hypothalamus (SCN) to synchronize circadian rhythms in behavior with the day-night cycle. Since disorders of the circadian timing system have been linked to a variety of mental illnesses, understanding the neurobiology of circadian rhythms should lead to the development of new treatments for these disorders. At least three different afferent projection of the SCN are involved in the photic entrainment of circadian rhythms. The retinohypothalamic tract is a direct projection from the retina that is necessary and sufficient for entrainment to photic stimuli. Projections from the raphe and the intergeniculate leaflet to the SCN also influence photic entrainment. In addition, there is evidence that these projections may mediate the phase shifting effects of nonphotic stimuli. The long-term goal of this project is to define the neurochemical basis of the entrainment of circadian rhythms by defining how photic and nonphotic information is communicated to and processed within the SCN. During the next four years we will test the working hypothesis that GABA released within the SCN modulates the capacity of the circadian pacemaker to phase shift at different phases of the circadian cycle. More specifically, we propose that during the day GABA mediates the phase shifts produced by any stimulus (e.g., NPY or 5-HT) by its direct actions on clock cells. During the night, GABA mediates the ability of any stimulus (NPY or 5-HT) to inhibit light-induced phase shifts by its direct action on clock cells. Further, we will also test the hypothesis that GABA regulates the mRNA levels of two clock genes (i.e., Per1 and Per2) that have been hypothesized to regulate phase shifts of circadian rhythms. Existing evidence indicates that Per1 and Per2 mRNA levels are reduced by phase shifting stimuli during the day and increased by light during the night. We therefore propose that GABA released during the day or during the night will reduce Per1 and Per2 mRNA levels.