A role for circadian clock genes in hippocampal function?

生物钟基因在海马功能中的作用？

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7413754
• 关键词: Address; Behavior; Biology; Circadian Rhythms; Condition; Daily; Disease; Exhibits; Family member; Feedback; Functional disorder; Funding; Future; Gene Expression; Genes; Goals; Hippocampus (Brain); Human; Learning; Measures; Melatonin; Memory; Molecular; Motor output; Mus; Nature; Nervous system structure; Neurons; Numbers; Organism; Output; Patient Care; Patients; Pattern; Performance; Phase; Physiological; Population; Process; Proteins; Qualifying; Quality of life; Radial; Research; Role; Sensory; Sleep; Sleep Wake Cycle; Symptoms; Synaptic plasticity; System; Testing; Time; Upper arm; VIP gene; Variant; Vasoactive Intestinal Peptide; Work; awake; base; circadian pacemaker; conditioned fear; day; hippocampal pyramidal neuron; improved; interest; nervous system disorder; novel; suprachiasmatic nucleus

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学生物学的许多方面，包括感觉输入，中央处理和运动输出。我们对昼夜节律系统调节学习和记忆功能的输出的主张特别感兴趣。在我们自己的工作中，我们发现了昼夜节律差异的明确证据，并回忆了海马依赖的上下文恐惧条件。此外，我们发现在海马（HP）中测得的突触可塑性在昼夜节律时间尺度和褪黑激素上受到调节。最后，我们和其他人发现了证据，表明包括MPER1，MPER2，MBMAL1在内的时钟基因在HP中表达。这些时钟基因在HP中的功能尚不清楚，但是合理的假设是这些分子振荡可用于从SCN到海马特异性节奏输出的门信息。该提案的基础是几种可检验的假设：1）蛋白质和时钟基因的信息mper1，mper2和mbmal1将在保持在恒定条件下的小鼠的HP中以节奏表示； 2）这些基因在HP中的峰值表达将与SCN相同； 3）MPER2缺陷的小鼠将在HP和SCN中表现出基因表达中的晚期节律，而VIP缺陷小鼠将在SCN中表现出破坏的节奏，但在HP中不会表现出干扰。 4）MPER2，MCLOCK和VIP的丧失将影响恐惧调节和径向手臂迷宫中学习行为的回忆。在检验这些假设时，本提案将解决各种问题，包括SCN输出的基础机制以及某些类型学习的时间变化的生理基础。记录昼夜节律在学习控制中的角色可能对理解人类绩效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。许多患有精神病和神经系统疾病的患者在每日睡眠周期和醒来的症状中表现出障碍。这些患者在晚上睡觉很难入睡，白天保持清醒。这些患者的学习能力和记忆能力也表现出干扰。这些功能障碍并不是其疾病的因果关系，但这些症状对患者人群的生活质量以及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上核核（SCN）中神经元调节学习和记忆的时间模式的机制。然后，我们将使用此信息来改善患者的学习和记忆，并通过这种机制改善许多患者群体的生活质量。记录昼夜节律基因在学习控制中的角色可能对理解人类绩效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。这一研究是新颖的，有可能有助于我们对昼夜节律系统的输出的理解，从而调节神经系统中的其他区域，以及学习行为的时间组织的基础机制。这种研究线以前尚未资助，本质上是探索性的，因此以R21格式符合资格。

项目成果

Select cognitive deficits in vasoactive intestinal peptide deficient mice.

• DOI: 10.1186/1471-2202-9-63
• 发表时间: 2008-07-10
• 期刊: BMC NEUROSCIENCE
• 影响因子: 2.4
• 作者: Chaudhury, Dipesh;Loh, Dawn H.;Dragich, Joanna M.;Hagopian, Arkady;Colwell, Christopher S.
• 通讯作者: Colwell, Christopher S.