A role for circadian clock genes in hippocampal function?

生物钟基因在海马功能中的作用？

基本信息

批准号：
7413754
负责人：
CHRISTOPHER SCOTT COLWELL
金额：
$ 18.82万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-30 至 2010-02-28
项目状态：
已结题

项目摘要

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.

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，我们发现了海马依赖性情境恐惧调节的习得和回忆的昼夜节律变化的明确证据。此外，我们发现海马体（HP）中测量的突触可塑性受到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包括 mPer1、mPer2、mBmal1 在内的时钟基因在 HP 中表达的证据。 HP 中这些时钟基因的功能尚不清楚，但合理的假设是这些分子振荡用于将信息从 SCN 传送到海马特定的节律输出。几个可检验的假设构成了该提议的基础：1）时钟基因 mPer1、mPer2 和 mBmal1 的蛋白质和信息将在恒定条件下的小鼠 HP 中有节律地表达； 2）这些基因在HP中的峰值表达会与SCN异相； 3) mPer2缺陷型小鼠在HP和SCN中的基因表达节律将呈现相位超前节律，而VIP缺陷型小鼠将在SCN中呈现节律紊乱，但在HP中则不会； 4) mPer2、mClock 和 VIP 的丢失将影响恐惧条件反射和径向臂迷宫中习得行为的回忆。在测试这些假设时，本提案将解决各种问题，包括 SCN 输出的机制以及某些学习类型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影响。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械工作奠定基础。许多患有精神和神经系统疾病的患者表现出日常睡眠和觉醒周期紊乱，这是其症状的一部分。这些患者晚上睡眠困难，白天保持清醒。这些患者的学习和记忆能力也出现障碍。这些功能障碍并不是其疾病的原因，但这些症状对患者群体的生活质量以及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，我们将利用这些信息来改善患者的学习和记忆，并通过这种机制提高许多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械工作奠定基础。这一研究方向是新颖的，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的机制。该研究方向以前没有获得过资助，本质上是探索性的，因此符合 R21 格式。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapid changes in the light/dark cycle disrupt memory of conditioned fear in mice.

光/暗周期的快速变化扰乱了小鼠条件性恐惧的记忆。

DOI：
发表时间：
2010
期刊：
影响因子：
3.7
作者：
Loh, Dawn H;Navarro, Juliana;Hagopian, Arkady;Wang, Louisa M;Deboer, Tom;Colwell, Christopher S
通讯作者：
Colwell, Christopher S

Select cognitive deficits in vasoactive intestinal peptide deficient mice.

选择血管活性肠肽缺乏小鼠的认知缺陷。