Neural Mechanisms of Diurnality: Role of the Intergeniculate Leaflet

描述(申请人提供)：昼夜节律是生理和行为的日常波动，调节日常生活的许多重要方面。虽然在阐明视交叉上核(SCN)主钟和多个SCN外振荡器的分子机制方面已经取得了巨大的进展，但大多数哺乳动物的工作都使用了传统的实验室物种，这些物种是夜间活动的。对于支持像我们这样的物种的昼夜活动的机制，我们知之甚少。许多患有阿尔茨海默病(AD)、帕金森病(PD)和其他与痴呆相关的神经系统疾病的人表现出昼夜节律紊乱。具体地说，这些患者中的许多人表现出夜间活动增加，睡眠和体温节律异常，以及对光的掩蔽反应中断。支持昼夜活动和物种特异性掩蔽反应的神经机制尚不清楚，因此限制了动物模型的使用，以了解伴随AD和其他神经病理的这些功能中断的原因。在这里，我们利用一种昼夜活动的哺乳动物模型--草鼠(Arvicanthis Niloticus)--来研究这个问题。我们有新的数据表明，视网膜膝间叶(IGL)是一种 对草鼠日常活动正常模式的显示至关重要的关键脑区。具体地说，具有IGL损害的白天草鼠逆转了它们的活动轮廓，使其成为夜间活动的动物，在相位逆转后，它们对急性光线的反应类似于夜间动物。我建议用昼夜草鼠来验证这样一个假设，即涉及IGL的大脑回路对昼夜行为和生理的表达至关重要，并在掩蔽对光的反应方面发挥重要作用。在这里，在目标I-1中，我们研究了IGL在多大程度上有助于协调昼夜节律行为和生理的许多方面，包括日常活动模式、睡眠、清醒、温度调节和压力。目的I-2将检验IGL及其下游结构在光的急性效应中起重要作用的假设。利用神经追踪和药理学操作，AIMS II和III更仔细地研究这些效应的中介机制(通过神经肽Y或脑啡肽)。总之，这项拟议的工作将有助于更好地理解昼夜更年期背后的神经机制，并对理解神经疾病(如阿尔茨海默病)具有重要意义，这些疾病涉及活动的昼夜节律模式中断和对光的异常反应。

DESCRIPTION (provided by applicant): Circadian rhythms are daily fluctuations in physiology and behavior that regulate many important aspects of daily life. Although there has been tremendous progress elucidating the molecular mechanisms responsible for the workings of the master clock of the suprachiasmatic nucleus (SCN) and those of multiple extra-SCN oscillators, most of the work with mammals has used traditional laboratory species, which are nocturnal. Little is known of the mechanisms that support a diurnal profile of activity in species like our own. Many humans with neurological disorders such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and other dementia related neurological disorders exhibit circadian rhythm dysfunction. Specifically, many of these patients exhibit increased levels of nocturnal activity, aberrant sleep and body temperature rhythms, and disrupted masking responses to light. The neural mechanisms that support diurnal activity and species specific masking responses are not yet known, thus limiting the use of animal models for understanding the etiologies of the disruptions in these functions that accompany AD and other neurological pathologies. Here, we take advantage of a diurnal mammalian model, the grass rat (Arvicanthis niloticus), to examine this issue. We have new data suggesting that the retinorecipient intergeniculate leaflet (IGL) is a key brain area critical for the display of normal patterns of daily activity in grass rats. Specifically, diurnal grass rats with IGL lesions reverse their activity profiles to become night-active, and after the phase reversal, they respond to acute presentations of light similarly to nocturnal animals. I propose to use diurnal grass rats to test the hypothesis that brain circuitry involving the IGL is critical for the expression of diurnal behavior and physiology, and plays an important role in masking responses to light. Here, in Aim I-1, we examine to what extent the IGL contributes to the coordination of many aspects of circadian behavior and physiology, including daily activity patterns, sleep, wakefulness, temperature regulation, and stress. Aim I-2 will test the hypothesis that the IGL, and structures downstream of the IGL, play an important role in the acute effects of light. Using neural tracing and pharmacological manipulations, Aims II and III look more closely at the mechanism by which these effects are mediated (via Neuropeptide Y or Enkephalin). Altogether, the proposed work will lead to an improved understanding of the neural mechanisms underlying diurnality, and has implications for the understanding of neurological disorders, such as Alzheimer's Disease, that involve disrupted circadian patterns of activity and aberrant responses to light.