Biological Sex as a Modulator of Neuronal Development and Function

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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.