Cognitive Modulation of Circadian Rhythms

描述（由申请人提供）：我们最近观察到，认知任务（特别是需要注意力的任务，不涉及应激源或意外事件，不需要去甲肾上腺素能激活）的表现在从光周期的相移恢复期间下降。此外，在主观休息阶段（即，大鼠变得白天活跃）。由于这项任务的表现取决于基底前脑-皮质胆碱能输入系统的完整性和活性，并且由于在执行过程中该系统中的活动由自上而下的前额叶区域控制，因此所提出的研究的主要目标是确定允许认知相关胆碱能活动调节昼夜节律的神经元机制。虽然HPA轴和中央注意机制相互作用，自下而上和自上而下的唤醒机制对昼夜节律的影响似乎是完全不同的。我们假设，昼夜节律的认知活动的影响介导通过激活基底前脑胆碱能投射到SCN，而HPA轴的刺激有助于认知夹带的节奏的重组。具体目标1测试的假设，自下而上，HPA介导的唤醒是不充分或必要的夹带活动在休息阶段。我们将通过检查皮质酮释放和乙酰胆碱释放的变化，夹带到一个非光信号在白天，而完整的肾上腺切除术或基底前脑病变后，检验这一假设。具体目标2测试的假设，昼夜节律重组的模式引起的注意力要求的认知任务的性能是渐进的，学习相关的，一天中的特定时间。具体目标3测试的假设，基底前脑胆碱能传出SCN的注意力需求的认知昼夜节律夹带的影响是必要的。这些实验的结果可能会增加我们对轮班工作、阿尔茨海默病、抑郁症和双相情感障碍相关的昼夜节律变化的理解。这种疾病的潜在治疗可能包括操纵皮质胆碱能系统控制昼夜节律的夹带。

DESCRIPTION (provided by applicant): We recently observed that performance of a cognitive task (specifically an attention-demanding task, not involving stressors or unexpected events and not requiring noradrenergic activation), declined during recovery from a phase-shift of the light cycle. Furthermore, stable circadian activity patterns were radically altered by daily training on such a task during the subjective rest phase (i.e., rats became day active). As performance on this task depends upon the integrity and activity of the basal forebrain - cortical cholinergic input system, and as activity in this system during performance is controlled by top-down prefrontal regions, the main goal of the proposed research is to determine the neuronal mechanisms allowing cognition- associated cholinergic activity to modulate circadian rhythms. Although the HPA axis and central attention mechanisms interact, the impact of bottom-up and top-down arousal mechanisms on circadian rhythms appears to be quite different. We hypothesize that the effects of cognitive activity on circadian rhythms are mediated via activation of basal forebrain cholinergic projections to the SCN, while stimulation of the HPA axis contributes little to the reorganization of cognition-entrained rhythms. Specific Aim 1 tests the hypothesis that bottom-up, HPA-mediated arousal is not sufficient or necessary for entraining activity during the rest phase. We will test the hypothesis by examining changes in corticosterone release and ACh release following entrainment to a non-photic signal during the day, while intact or after adrenalectomy or basal forebrain lesions. Specific Aim 2 tests the hypothesis that the pattern of circadian re-organization caused by performance of an attention-demanding cognitive task is gradual, learning-related, and time-of-day specific. Specific Aim 3 tests the hypothesis that basal forebrain cholinergic efferents to the SCN are necessary for the effects of attention-demanding cognition on circadian entrainment. Results from these experiments may increase our understanding of circadian changes associated with shift work, Alzheimer's disease, depression and bipolar disorder. Potential treatments for such disorders may include manipulation of the cortical cholinergic system control of circadian entrainment.