Potentiation of photic circadian clock phase shifts

描述(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。1极其重要的效应是这些非光学的、更高水平的输入对抗光的同步效应的能力，例如，在非光学刺激可以阻止光学相移反应的研究中所示。我们最近发现，阻断非光性神经肽Y(NPY)进入视交叉上核(SCN)的通路可以增强光相移，这表明这一通路可以强直地抑制光的影响，药物治疗可以解除这种抑制作用。我们知道，对生物钟的非光输入由NPY和5-羟色胺能通路代表。值得注意的是，阻断NPY和5-羟色胺能传入在更大程度上增强了光效应，以至于5分钟的光脉冲能够诱导接受治疗的仓鼠昼夜节律的7小时相移，而未治疗的仓鼠大约1小时的相移。这项资助将建立在这些发现的基础上，当唤醒相关的NPY和5-羟色胺能输入被药物阻断时，光诱导的相移大大增强。我们将检验这些假设。假设1：NPY Y5和5-羟色胺5-HT1a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一致，但在光偏移后呈现时可以改变对光的反应。假设3：NPY和5-羟色胺的输入改变光诱导的PER1和PER2基因的表达。NPY和5-羟色胺拮抗剂增强和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的有用工具。在夹带紊乱的情况下，如睡眠相延迟或晚期综合症，在1次加强光的影响，而在另一阶段阻止光的影响，可能是纠正夹带的阶段的一种方法。如果在新时区增强光线的重置效应，时差症状的持续时间可能会缩短。倒班工人可能会从夜间阻挡光线的影响中受益。在昼夜节律性增强的患者中，癌症进展较慢，这可能是更好的昼夜节律性带来的好处。

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.