Cognitive Modulation of Circadian Rhythms

描述(由申请人提供)：我们最近观察到，认知任务(特别是要求注意力的任务，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中恢复期间下降。此外，在主观休息阶段(即大鼠变得白天活跃)的日常训练中，稳定的昼夜活动模式被从根本上改变。由于这项任务的表现依赖于基础前脑-皮质胆碱能输入系统的完整性和活性，而且该系统在执行过程中的活动受自上而下的前额叶区域的控制，因此本研究的主要目的是确定允许认知相关胆碱能活动来调节昼夜节律的神经机制。尽管HPA轴和中枢注意机制相互作用，但自下而上和自上而下的唤醒机制对昼夜节律的影响似乎截然不同。我们假设，认知活动对昼夜节律的影响是通过激活基底前脑对SCN的胆碱能投射来调节的，而刺激HPA轴对认知节律的重组几乎没有帮助。特定目标1测试了这一假设，即在休息阶段，HPA介导的自下而上的唤醒不是吸引活动的充分或必要的。我们将通过检测皮质酮释放和ACh释放的变化来检验这一假设，这些变化是在白天携带到非光信号后，在完整或在肾上腺切除或基底前脑损伤后进行的。特定目标2检验了这样一种假设，即由注意力要求高的认知任务的表现引起的昼夜节律重组模式是渐进的、与学习相关的、并且是一天中特定时间的。特定目标3验证了这样的假设，即基底前脑的胆碱能传出到SCN是注意要求认知对昼夜牵引力的影响所必需的。这些实验的结果可能会增加我们对与倒班工作、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。此类疾病的潜在治疗方法可能包括操纵皮质胆碱能系统、控制昼夜节律缠绕。

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.