A role for circadian clock genes in hippocampal function?

描述(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这一命题特别感兴趣。在我们自己的工作中，我们发现了明显的证据表明，在海马体依赖的上下文恐惧条件反射的习得和回忆中存在昼夜变化。此外，我们还发现，在海马区(HP)测量的突触可塑性是在昼夜节律的时间尺度上调节的，并受褪黑素的调节。最后，我们和其他人发现了包括mPer1、mPer2、mBMal1在内的时钟基因在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，这些分子振荡用于将信息从SCN传递到海马区特有的节律输出。提出这个建议的依据有几个可检验的假说：1)时钟基因mPer1、mPer2和mBMal1的蛋白质和信息在保持恒定条件的小鼠的HP中将有节奏地表达；2)这些基因在HP中的峰值表达将与SCN异相；3)mPer2缺陷小鼠在HP和SCN中的基因表达都呈现出阶段性高级节奏，而VIP缺陷小鼠将在SCN中表现出紊乱的节律；4)mPer2、mClock和VIP的丢失将影响在恐惧条件反射和放射臂迷宫中学习行为的回忆。在检验这些假说时，本提案将解决一系列问题，包括SCN输出的潜在机制以及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会对理解人类行为的时间组织有广泛的影响。最后，我们希望本提案所述研究取得的成果将为今后的机械化工作奠定基础。许多患有精神和神经障碍的患者表现出睡眠和醒来的日常周期紊乱，这是他们症状的一部分。这些患者晚上难以入睡，白天也很难保持清醒。这些患者还表现出学习和记忆能力的障碍。这些功能障碍不是疾病的原因，但这些症状对患者群体的生活质量和照顾患者的家庭成员有重大影响。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，我们将使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。记录生物钟基因在学习控制中的作用，可能对理解人类行为的时间组织有广泛的意义。最后，我们希望本提案所述研究取得的成果将为今后的机械化工作奠定基础。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其他区域以及学习行为的时间组织的潜在机制。这一系列研究以前没有得到过资助，是探索性的，因此符合R21格式的条件。

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.