Molecular mechanisms governing maintenance of neural identity

描述（由申请人提供）：精确的细胞身份对于维持通信神经元的连贯网络是必要的。在人类大脑中，神经网络是以一种良好控制的方式构建的，然后经过多次迭代的强化和调制，从而形成一个能够进行成人认知的系统。这种改进大部分发生在儿童和青少年时期，在与环境相互作用的背景下。在整个过程中，特定的细胞在网络中建立了独特的身份;它们的作用既取决于由早期发育程序定义的初始细胞类型，也取决于它们整合到整个神经系统中时发生的修饰。如果一个神经元不能保持其初始的、基本的特征，使自己适应周围的网络，那么它在系统中的作用就可能被破坏。这项研究旨在研究神经元在不断变化的环境中保持其身份的关键方面的分子手段。由于对细胞的多个未定义的输入可能难以控制，并且它们的影响可能难以跟踪，因此本研究使用了一个系统，其中刺激被很好地定义，并且细胞身份的标记很容易遵循。在线虫C.秀丽线虫检测一组确定的挥发性化学物质，并且可以通过一组特定的分子标记来识别。本研究的目的是确定和表征负责维持分化后AWCs的神经身份的分子，当神经元首次暴露于外部嗅觉刺激。具体而言，本研究的目的是：（1）确定核蛋白NSY-7的作用机制，该蛋白是AWC神经元在分化后保持其身份的一个方面所必需的;（2）表征nsy-7基因的表达和调节以便更好地理解其功能，以及（3）确定nsy-7与AWCs中负责感觉信号转导的分子途径之间的相互作用。对控制神经同一性维持的机制进行研究，可能有助于阐明某些精神疾病（如精神分裂症）所涉及的因素，这些精神疾病似乎部分受遗传控制，但首先在青春期或青春期之后表现出来。导致一个表面上正常的大脑在发育后期无法达到稳定状态的因素在很大程度上仍然没有得到确认，但是，一个表面上稳定的大脑偏离其正常状态的疾病是普遍存在的。因此，阐明通常控制这一现象的基因及其在治疗和预防精神疾病中的应用，将对公共卫生和社区产生广泛的益处。

DESCRIPTION (provided by applicant): Precise cellular identities are necessary to maintain a coherent network of communicating neurons. In the human brain, neural networks are constructed in a well-controlled manner and then subjected to multiple iterations of reinforcement and modulation, resulting in a system capable of adult cognition. Much of this refinement takes place during childhood and adolescence, in the context of interactions with the environment. Throughout this process, specific cells establish unique identities within the network; their roles are dependent both on the initial cell type, defined by an early developmental program, and on the modifications that occur as they become integrated into the nervous system as a whole. If a neuron cannot retain its initial, fundamental characteristics as it adapts itself to the network developing around it, its role in the system may be corrupted. This study aims to examine the molecular means by which a neuron maintains crucial aspects of its identity in a changing environment. Because multiple undefined inputs to a cell may be difficult to control and their effects may be difficult to track, this study makes use of a system in which stimuli are well defined, and markers of cell identity are easy to follow. The AWC olfactory neurons in the nematode C. elegans detect a defined set of volatile chemicals and can be identified by a specific set of molecular markers. The goal of this study is to identify and characterize molecules responsible for maintaining neural identity in the AWCs after differentiation, when the neurons are first exposed to external olfactory stimuli. Specifically, this study aims to: (1) determine the mechanism of action of the nuclear protein, NSY-7, which is required for one of the AWC neurons to retain aspects of its identity after differentiation; (2) characterize the expression and regulation of the nsy-7 gene in order to better understand its function, and (3) define interactions between nsy-7 and the molecular pathway responsible for sensory signal transduction in the AWCs. Examination of the mechanisms controlling maintenance of neural identity may serve to illuminate the factors involved in certain psychiatric disorders, such as schizophrenia, that appear to be partially under genetic control but that first manifest themselves at or after adolescence. The factors responsible for the failure of an apparently normal brain to attain stability late in development remain largely unidentified, but disorders in which an seemingly stable brain departs from its normal state are widespread. Elucidation of the genes that normally control this phenomenon, and their application in the treatment and prevention of psychiatric disease, would therefore be broadly beneficial to public health and to the community.