RIG: Role of sustained GABA in light-induced phase shifts of the circadian pacemaker

哺乳动物的大脑包含一个生物钟，它产生的行为和生理节律接近24小时，但不完全是24小时。为了使生物体将这些内部产生的昼夜节律与24小时的环境同步，生物钟必须每天通过暴露在光线下进行调整。光调节生物钟的机制尚不完全清楚。该提案的中心目的是验证一个假设，即持续激活<s:1>氨基丁酸（GABA）受体介导光改变生物钟产生的日常节律的能力。利用仓鼠体内药理学方法，少量模拟或阻断GABA活性的药物将在几个小时内被递送到包含生物钟的大脑区域。这些药物对昼夜节律的影响将通过测量仓鼠的日常活动节律来确定。预计长期服用GABA类药物将以类似于光的方式改变仓鼠的日常活动节奏，并且服用阻断GABA活性的药物将阻止光改变生物钟产生的日常活动节奏的能力。这项研究的结果将为生物体同步或将其生物节律带入周期性环境的基本过程提供见解。这项研究对于理解轮班工作和跨大西洋旅行如何改变人类的生物节律（如时差）具有重要意义。此外，拟议的活动将在莫尔豪斯学院（莫尔豪斯学院是乔治亚州亚特兰大的一所历史悠久的黑人本科院校）举行，并有本科生参加，从而扩大了非裔美国男性在生物学领域的参与度。

The mammalian brain contains a biological clock that generates behavioral and physiological rhythms that are close to, but not exactly 24 hours. For organisms to synchronize these internally generated circadian rhythms to the 24-hour environment, the clock must be adjusted each day through exposure to light. The mechanism through which light is able to adjust the timing of the biological clock is not fully understood. The central aim of this proposal is to test the hypothesis that sustained activation of receptors for ã-aminobutyric acid (GABA) mediates the ability of light to shift the daily rhythms generated by the biological clock. Utilizing an in vivo pharmacological approach in hamsters, small quantities of drugs that either mimic or block GABA activity will be delivered over several hours to the region of the brain that contains the biological clock. The effect of these drugs on circadian rhythms will be determined by measuring the daily activity rhythms of hamsters given access to running wheels. It is expected that long-term administration of GABA-like drugs will shift the daily activity rhythms of hamsters in a manner similar to light, and that the administration of drugs that block the activity of GABA will prevent the ability of light to shift the daily activity rhythms generated by the biological clock. Results from this research will provide insight into a fundamental process by which organisms synchronize or entrain their biological rhythms to a cyclical environment. This research has important implications for understanding how shift work and trans-Atlantic travel alter biological rhythms in humans (e.g., jet lag). Furthermore, the proposed activities will take place at, and involve undergraduates from Morehouse College (a historically black undergraduate institution in Atlanta, Georgia), thus broadening the participation of African American males in biology.