Biological Sex as a Modulator of Neuronal Development and Function

摘要 生物性别是后生动物物种几乎普遍的特征，调节着动物的许多方面 发育和生理学。它也可以带来抵抗或易感性，许多 神经发育障碍、神经变性障碍和神经精神障碍。然而，在多大程度上， 生物性别影响神经系统的发育和功能，这一机制 发生，以及这些影响的功能后果，仍然在很大程度上未知。线虫C.优雅， 由于它的神经系统非常好地描述，强大的实验易处理性，以及保守的 遗传机制，为解决这些问题提供了极好的机会。C.两种线虫的成虫 性别共享一个由294个神经元组成的核心组;在此基础上，每种性别都有一个性别特异性的补充。 执行性别特异性行为的神经元。我们小组和其他人最近的研究发现， 生物性别对C. elegans神经系统远远超出了这些明显的神经解剖学 二态性我们发现，两性共有的神经元和回路不仅受到 这是生理上的性，但也是神经系统本身的性状态的结果，而不是 其他组织的信号。化学感觉功能是这种调节的重要目标，但多条线 有证据表明，性别对共享电路的影响不仅限于此。这些发现揭示了一种 C.以前不被重视的方面。elegans神经生物学and raises提出many许多interesting有趣new新questions问题， 特别是关于生理性别在感觉整合、行为状态和决策中的作用， 这些研究将解决。此外，最近的结果表明，在分子水平上，内部 生物性别的表征是令人惊讶的灵活性，使得单个神经元的性状态可以被 对发育和环境信号都有反应。我们将研究这一功能的意义 灵活性以及作为其基础的调控程序，其中涉及一种新的长非编码RNA， 可能是保守的细胞自主发育定时机制的一部分。这些研究将 为生物性别与发育和生理相互作用的方式提供了新的见解。 计划带来性别特异性的细胞，电路和行为特征。因此，他们将提供一个 重要的框架，了解这些鲜为人知的机制如何运作，在更复杂的 动物，包括人类。反过来，这将有助于深入了解人类的性别典型特征是如何影响 大脑可以赋予保护或对各种神经系统疾病的易感性。

ABSTRACT Biological sex, a nearly universal feature of metazoan species, modulates many aspects of animal development and physiology. It can also bring about resistance or susceptibility to numerous neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Nevertheless, the extent to which biological sex influences the development and function of the nervous system, the mechanisms by which this occurs, and the functional consequences of these effects, remain largely unknown. The nematode C. elegans, with its extraordinarily well characterized nervous system, powerful experimental tractability, and conserved genetic mechanisms, provides outstanding opportunities to address these questions. C. elegans adults of both sexes share a core group of 294 neurons; superimposed on this, each sex has a complement of sex-specific neurons that implement sex-specific behavior. Recent research from our group and others has found that the influence of biological sex on the C. elegans nervous system goes far beyond these overt neuroanatomical dimorphisms. We have found not only that neurons and circuits shared by both sexes are modulated by biological sex, but also that this is a consequence of the sexual state of the nervous system itself, rather than signals from other tissues. Chemosensory function is an important target of this modulation, but multiple lines of evidence indicate that the effects of sex on shared circuits are not limited to this. These findings reveal a previously unappreciated aspect of C. elegans neurobiology and raise many interesting new questions, particularly regarding the role of biological sex in sensory integration, behavioral state, and decision-making, that these studies will address. Further, recent results have indicated that, at a molecular level, the internal representation of biological sex is surprisingly flexible, such that the sexual state of individual neurons may be responsive to both developmental and environmental signals. We will study the functional significance of this flexibility as well as the regulatory programs that underlie it, which involve a novel long non-coding RNA that may be part of a conserved, cell-autonomous developmental timing mechanism. Together, these studies will provide new insight into the ways in which biological sex interacts with developmental and physiological programs to bring about sex-specific cellular, circuit, and behavioral features. As such, they will provide an important framework for understanding how these poorly understood mechanisms operate in more complex animals, including humans. In turn, this will help provide insight into how sex-typical features of the human brain could confer protection or susceptibility to a variety of nervous system disorders.