December 2016 – Vol 18 – No. 4

The regulation and dysregulation of behavior is highly context-dependent. Context includes developmental stage, physiologic state, antecedent history, genetic background, and sex. This issue of Dialogues in Clinical Neuroscience explores this last contextual factor—sex—a particularly timely topic, given the recent mandate by the National Institutes of Health that researchers applying for NIH grants must explain how they will account for sex as a biological variable (SABV) in vertebrate animal and human studies.

In the State of the art article (p 361), Margaret McCarthy provides a wonderful review of sex differences in brain and behavior, revealing in the clearest and most interesting terms both the complexity and potential importance of sex differences. She argues—very persuasively—throughout this paper that the progressive unraveling of the molecular determinants of sex differences in brain and behavior serves to continually preclude simple, reductionist conclusions about the way in which sex and sex steroids influence susceptibility (or resistance) to behavioral disorders.

Janine Clayton’s Commentary (p 357) is a series of “minireviews” of the relevance of sex for several common neurologic illnesses. This interesting format clearly accomplishes one of the author’s goals, namely making the case that sex is an important determinant of variance. Dr Clayton raises multiple questions for further study, as well as arguing that failure to consider sex in research will adversely impact efforts to advance knowledge and improve public health.

In the first Basic research paper, Jordan Marrocco and Bruce McEwen (p 373) present a scholarly review of sex differences in brain structure and steroid signaling. From epigenetic impact on development to dendritic spine physiology to clinical implications, McEwen and his coauthor map out—often in a region-specific fashion—the determinants and consequences of sex differences in the brain. This comprehensive review provides the perfect foundation for readers to understand and appreciate the scope and importance of sex differences for cognitive function and behavior. What are the mechanisms by which observed sex differences in stress reactivity occur? Rita Valentino and Deborah Bangasser (p 385) answer this question in another Basic research paper by summarizing three levels of sex differences that may impact stress signaling in the locus coeruleus (LC)—LC dendritic morphology, corticotrophin-releasing factor (CRF) receptor coupling to its G protein, and CRF receptor internalization  and interaction with beta-arrestin 2. Both structural and functional sex differences may lead to exaggerated stress signaling in females compared with males, thus providing a potential, clinically meaningful contribution to sex differences in psychopathology in the form of increased risk of depression, anxiety, and even Alzheimer’s disease.

In the first Translational research paper, Jill Becker (p 395) addresses the mechanisms which lead to a more rapid escalation from casual drug taking to addiction. She summarizes the work with rodents on the influence of estradiol on the dopamine response in the nucleus accumbens and the lateral striatum, and proposes that these two neural subsystems underlie sex differences in addition. In the same section, Teniel Ramikie and Kerry Ressler (p 403) describe the potential role of the PACAPergic system in the sex-related risk for PTSD in particular and the fear and stress responses in general. The PACAP system is correlated with the likelihood of diagnosis and severity of PTSD, but only in women, complementing similar findings in animal stress models. This paper is a wonderful example of how gene-environment interactions can help us understand sex differences in susceptibility to psychiatric illness. In another interesting Basic research paper, Jamie Morford and Franck Mauvais- Jarvis (p 415) focus on sexual dimorphism and metabolic regulation. With a special focus on testosterone, the article summarizes how this hormone acts on the CNS to promote metabolic homeostasis.

In the Clinical research section, Jill Goldstein and colleagues (p 425) address the interesting interaction between depressive disorder and comorbid chronic diseases such as obesity/metabolic syndrome (MetS). They argue that prenatal maternal stress occurring during the sexual differentiation of the fetal brain has a sex-dependent effect on brain development, especially in those regions responsible for the regulation of mood, stress and metabolic function. Gender differences in dementia have not been discussed very clearly in the recent literature, and this topic is nicely summarized by Jessica Podcasy and Neill Epperson (p 437). They convincingly show that females have a greater risk for developing Alzheimer disease and that males have a greater risk of vascular dementia. They argue that taking gender into account as a biological variable in dementia research promises to boost our understanding of the pathophysiology and treatment of dementia and related conditions. A fundamental question underlying treatment with antidepressants concerns the sexual dimorphic reaction to these substances. We know that females respond better to serotonergic antidepressants and that postmenopausal females have a diminished response to antidepressants. In a Pharmacological aspects paper, Neal Cutler and colleagues (p 447) nicely summarize the lines of evidence in the literature, helping make sense of the sex effects of antidepressant treatment.

Prenatal insults, such as maternal stress, are associated with an increased neurodevelopmental disease risk, particularly impacting males. In the Brief report, Tracy Bale (p 459) discusses the potential critical involvement of the placenta in producing sex-specific responses to maternal insults in pregnancy that impact neurodevelopment and ultimately disease risk. Remarkably, she has identified sex differences in the expression of an X-linked gene, OGT, which drives neurodevelopmental programming and produces a malespecific stress phenotype in mice, while appearing to protect the female placentas (and the developing brain) from changing gestational environments.

David Rubinow, MD; Peter Falkai, MD, PhD