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.