Potentiation of photic circadian clock phase shifts

描述（由申请人提供）：唤醒和睡眠剥夺可以通过多种方式调节昼夜节律。一个极其重要的效应是这些非光的、更高水平的输入对抗光的同步效应的能力，例如，如在非光刺激可以阻断光相移响应的研究中所示。我们最近发现，阻断非光神经肽Y（NPY）输入途径的视交叉上核（SCN）可以增强光相移，这表明该途径紧张性抑制光的作用，药物治疗可以释放这些抑制作用的动物。我们知道，非光输入的昼夜节律钟是由神经肽Y和β-肾上腺素能途径。值得注意的是，阻断NPY和多巴胺能输入两者甚至更大程度地增强光效应，使得5分钟的光脉冲能够诱导经处理的仓鼠的昼夜节律的7小时相移，相比之下，未经处理的仓鼠中的约1小时相移。这项拨款将建立在这些发现的基础上，即当觉醒相关的NPY和多巴胺能输入被阻断时，光诱导的相移大大增强。我们将测试这些假设。假设1：NPY Y 5和5-羟色胺5 HT 1A受体在整个主观夜晚的多个阶段调节光的相移效应。假设2：非输入输入不需要与光重合，但在光偏移后呈现时可以改变对光的响应。假设3：NPY和5 HT输入改变光诱导的per 1和per 2基因表达。NPY和5-羟色胺拮抗剂增强光对昼夜节律系统的影响，激动剂减弱光对昼夜节律系统的影响的能力，可能是临床研究中潜在有用的工具。在夹带障碍的情况下，例如延迟或提前睡眠相位综合征，在1个时间增强光的作用，同时在另一个相位阻断光的作用可能是纠正夹带相位的方法。如果在新的时区光线的重置效果得到加强，时差综合征的症状可能会缩短。轮班工作者可能会受益于在夜间阻挡光线的影响。在昼夜节律增强的患者中，癌症的进展较慢，这可能是由于更好的昼夜节律所带来的好处。

DESCRIPTION (provided by applicant): Arousal and sleep deprivation can regulate circadian rhythms in multiple ways. 1 extremely important effect is the ability of these non-photic, higher level inputs to antagonize the synchronizing effects of light, as shown, for example, in studies where non-photic stimuli can block photic phase shift responses. We recently discovered that blocking the non-photic neuropeptide Y (NPY) input pathway to the suprachiasmatic nuclei (SCN) can potentiate photic phase shifting, suggesting that this pathway tonically suppresses the effects of light, and pharmacological treatments can release the animal from these inhibitory effects. We know that non-photic inputs to the circadian clock are represented by both NPY and serotonergic pathways. Remarkably, blocking both NPY and serotonergic inputs potentiates photic effects to an even greater degree, such that a 5 minute light pulse is able to induce a 7 hour phase shift of circadian rhythms of a treated hamster, as compared to a circa-1 hour phase shift in an untreated hamster. This grant will build upon these findings of greatly potentiated light-induced phase shifts when the arousal-related NPY and serotonergic inputs are pharmacologically blocked. We will test these hypotheses. Hypothesis 1: NPY Y5 and serotonin 5HT1A receptors regulate the phase shifting effects of light at multiple phases throughout the subjective night. Hypothesis 2: Non-input inputs do not need to coincide with light, but can alter the response to light when presented after light offset. Hypothesis 3: NPY and 5HT inputs alter light-induction of per1 and per2 gene expression. The capability of NPY and serotonin antagonists to potentiate and agonists to attenuate the effects of light on the circadian system, could be a potentially useful tool in clinical research. In cases of entrainment disorders, such as delayed or advanced sleep phase syndrome, potentiating the effects of light at 1 time while blocking effects of light at another phase might be an approach to correct the phase of entrainment. Symptoms of jet lag might be shortened in duration if resetting effects of light in the new time zone are potentiated. Shift workers might benefit from blocking the effects of light at night. The progress of cancer is slower in patients with enhanced circadian rhythmicity, a benefit that might accrue from better circadian entrainment.