Neural Mechanisms of Diurnality: Role of the Intergeniculate Leaflet

描述（由申请人提供）：昼夜节律是生理和行为的日常波动，调节着日常生活的许多重要方面。尽管在阐明负责视交叉上核（SCN）主时钟和多个SCN外振荡器工作的分子机制方面取得了巨大进展，但大多数关于哺乳动物的工作都是使用传统的实验室物种，它们是夜间活动的。在像我们人类这样的物种中，支持昼夜活动概况的机制知之甚少。许多患有神经系统疾病的人，如阿尔茨海默病（AD）、帕金森病（PD）和其他与痴呆相关的神经系统疾病，都表现出昼夜节律障碍。具体来说，这些患者中的许多人表现出夜间活动水平增加，睡眠和体温节律异常，对光的掩蔽反应中断。支持昼夜活动和物种特异性遮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和其他神经病理学的这些功能中断的病因。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，视网膜受体间束小叶（IGL）是一个

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.