A role for circadian clock genes in hippocampal function?

描述（由申请人提供）：昼夜节律系统调节生物体生物学的许多方面，包括感觉输入、中央处理和运动输出。我们对昼夜节律系统的输出调节学习和记忆功能的命题特别感兴趣。在我们自己的工作中，我们已经发现了海马体依赖性情境恐惧条件反射的获取和回忆的昼夜节律变化的明确证据。此外，我们还发现，在海马体中测量的突触可塑性（HP）受昼夜节律时间尺度和褪黑激素的调节。最后，我们和其他人发现了时钟基因包括mPer1， mPer2， mBmal1在HP中表达的证据。这些时钟基因在HP中的功能尚不清楚，但一个合理的假设是，这些分子振荡有助于将信息从SCN传送到海马特异性节律输出。几个可验证的假设构成了这一提议的基础：1)在恒定条件下，时钟基因mPer1、mPer2和mBmal1的蛋白和信息将在小鼠HP中有节奏地表达；2)这些基因在HP中的峰值表达将与SCN不同步；3) mPer2-缺陷小鼠在HP和SCN中均表现出阶段超前的基因表达节律，而vip -缺陷小鼠在SCN中表现出节律紊乱，而在HP中则没有；4) mPer2、mClock和VIP的缺失会影响恐惧条件反射和桡臂迷宫习得行为的回忆。在测试这些假设时，本提案将解决各种问题，包括SCN输出的潜在机制和某些类型学习中一天中时间变化的生理基础。记录昼夜节律系统在学习控制中的作用可能对理解人类表现的时间组织具有广泛的意义。最后，我们希望从本提案中描述的研究中获得的结果将为未来的机制工作奠定基础。许多精神和神经疾病患者的日常睡眠和觉醒周期紊乱是其症状的一部分。这些病人夜间难以入睡，白天难以保持清醒。这些患者还表现出学习和记忆能力的障碍。这些功能障碍并不是导致疾病的原因，但这些症状对患者的生活质量和照顾患者的家庭成员产生了重大影响。我们的长期目标是了解哺乳动物视交叉上核（SCN）中的神经元调节学习和记忆的时间模式的机制。然后，我们将利用这些信息来改善患者的学习和记忆，并通过这种机制改善一些患者群体的生活质量。记录生物钟基因在控制学习中的作用可能对理解人类表现的时间组织具有广泛的意义。最后，我们希望从本提案中描述的研究中获得的结果将为未来的机制工作奠定基础。这条研究路线是新颖的，有可能有助于我们理解昼夜节律系统的输出调节神经系统的其他区域，以及学习行为的时间组织机制。这方面的研究以前没有得到资助，本质上是探索性的，因此符合R21格式。

DESCRIPTION (provided by applicant): The circadian system regulates many aspects of an organism's biology including sensory input, central processing, and motor output. We are particularly interested in the proposition that outputs of the circadian system modulate learning and memory functions. In our own work, we have found clear evidence for circadian variation in acquisition and recall of hippocampal-dependent contextual fear conditioning. In addition, we have found that a synaptic plasticity measured in the hippocampus (HP) is regulated on a circadian time scale and by melatonin. Finally, we and others have found evidence that clock genes including mPer1, mPer2, mBmal1 are expressed in the HP. The function of these clock genes in the HP is not yet known but a reasonable assumption is that these molecular oscillations serve to gate information from the SCN to hippocampal-specific rhythmic outputs. Several testable hypotheses form the basis of this proposal: 1) protein and message of the clock genes mPer1, mPer2, and mBmal1 will be rhythmically expressed in the HP of mice kept in constant conditions; 2) The peak expression of these genes in the HP will be out of phase with the SCN; 3) mPer2- deficient mice will exhibit phase advanced rhythms in gene expression in both HP and SCN while the VIP-deficient mice will exhibit disrupted rhythms in the SCN but not in the HP; 4) the loss of mPer2, mClock, and VIP will impact the recall of learned behaviors in both fear conditioning and radial arm maze. In testing these hypotheses, the present proposal will address a variety of issues including the mechanisms underlying the output from the SCN and the physiological basis for time of day variation in certain types of learning. Documenting a role for the circadian system in the control of learning may have broad implications for understanding temporal organization of human performance. Finally, we hope that the results obtained from the studies described in the present proposal will lay groundwork for future mechanistic work. Many patients with psychiatric and neurological disorders exhibit disturbances in their daily cycle of sleep and wake as part of their symptoms. These patients have difficulty sleeping at night and staying awake during the day. These patients also exhibit disturbances in their ability to learn and remember. These dysfunctions are not a causal to their disorder yet these symptoms have a major impact on the quality of life of the patient population and on the family members who care for the patients. Our long-term goal is to understand the mechanisms by which neurons in the mammalian suprachiasmatic nucleus (SCN) regulate the temporal patterning of learning and memory. We would then use this information to improve the learning and memory of the patient and through this mechanism improve the quality of life for a number of patient groups. Documenting a role for the circadian clock genes in the control of learning may have broad implications for understanding temporal organization of human performance. Finally, we hope that the results obtained from the studies described in the present proposal will lay groundwork for future mechanistic work. This line of research is novel and has the potential to contribute to our understanding of both the output of circadian system regulates other regions in the nervous system as well the mechanisms underlying the temporal organization of learned behavior. This line of research has not been previously funded, is exploratory in nature, and thus qualifies under the R21 format.