1

Introduction and Background¹

Accumulating evidence gathered over the past three decades has demonstrated a biological basis for differences between men and women with respect to clinical features and treatment responses to several neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. Dramatic sex differences have also been identified in the brain transcriptomes of individuals with multiple brain disorders, including depression, posttraumatic stress disorder, and autism. The brain transcriptome includes all of the messenger RNA as well as the non-protein-coding RNA molecules expressed in brain tissue and thus represents gene activity. To explore these sex-based transcriptomic differences further, the National Academies of Sciences, Engineering, and Medicine’s (the National Academies’) Forum on Neuroscience and Nervous System Disorders (Neuroscience Forum) hosted a workshop on September 23, 2020, titled Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence and Implications for Therapeutic Development. The workshop brought together a broad spectrum of stakeholders to share cutting-edge emerging evidence, discuss challenges, and identify future opportunities and potential directions.

This workshop explored the evolving understanding of sex differences in brain disorders, as reflected in previous reports and workshops convened

___________________

¹ The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They should not be construed as reflecting any group consensus.

by the National Academies. Two decades ago, an Institute of Medicine (IOM) report asked whether sex matters in explorations of the biological contributions to human health. In that report, Mary-Lou Pardue, chair of the IOM Committee on Understanding the Biology of Sex and Gender Differences answered, “Sex does matter. It matters in ways that we did not expect. Undoubtedly, it also matters in ways that we have not begun to imagine” (IOM, 2001).

Ten years after that report, the Neuroscience Forum hosted a workshop on Sex Differences and Implications for Translational Neuroscience Research (IOM, 2011). By then, understanding of sex differences at the biological level had advanced considerably. Yet, in the summary from the 2010 workshop, Vivian Pinn, then the director of the Office of Research on Women’s Health at the National Institutes of Health (NIH), noted that sex-specific research had been stymied by a limited focus on clinical studies. Molecular- and cellular-level research, she said, was essential to understanding sex differences in health.

Now, 10 years after the 2010 workshop and 20 years after the 2000 IOM report, recent advances in developing tools and technologies for molecular- and cellular-level research have fueled further advances and investigators are vigorously pursuing this research, said Rita Valentino, director of the Division of Neuroscience and Behavior at the National Institute on Drug Abuse.

The increased focus on sex differences has emerged in part as a result of a 2016 NIH mandate requiring that all NIH-funded research consider sex as a biological variable, said workshop chair Eric Nestler, Nash Family Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai. Nestler called this mandate “transformational.” For many years, his lab, like many others, had studied male rodents only, reasoning that including females would require twice or more as many animals and add too much complexity. In recent years, however, he and many other scientists have discovered striking sex differences across the spectrum of nervous system phenomena in both health and disease. Moreover, recent molecular approaches have revealed differences at the transcriptomic level between men and women with certain neurological or psychiatric disorders in human postmortem brains as well as between males and females in animal models of these disorders, said Nestler. The results of Nestler’s and other scientists’ studies suggest that some brain disorders in men and women, despite being similar with respect to behavioral presentations, may have dramatically different underlying biology.

WORKSHOP OBJECTIVES

The workshop was designed to explore emerging data about sex differences in the underlying biology of many different brain disorders with

a focus on transcriptomic evidence; to consider how this evidence may advance understanding of brain disorder pathophysiology; to examine potential opportunities for applying this knowledge in the development of improved sex-specific treatments; and to review obstacles that must be overcome to realize this potential (see Box 1-1). Nestler noted that studying the impact of sex in a binary way—male and female—excludes people who do not fall along the male/female binary, for example, transgender individuals, those who have transitioned sex, and intersex individuals. Although this area of research is extremely important, he said, it is difficult to study in animal models, and the lack of availability of human brain tissue from non-binary individuals makes human studies equally challenging.

Research presented at the workshop by individual participants is not a systematic review of the scientific landscape, but rather examples of emerging transcriptomic evidence for sex differences in brain disorders. Due to time restrictions, this 1-day workshop also did not include a robust discussion on other important issues such as a framework for approaching sex

differences in health and disease, or the merits and limitations of comparative studies apart from those in humans and mice, due to time restrictions.

ORGANIZATION OF THE PROCEEDINGS

The workshop was organized around several psychiatric and neurological disorders with evidence of biological differences according to sex. Chapter 2 focuses on stress- and reward-related disorders; Chapter 3 explores neurodevelopmental and neurodegenerative disorders. Chapter 4 transitions to a focus on policy implications and how federal agencies, industry, and nonprofit organizations can partner to leverage this new biology of sex differences to improve diagnostics and therapeutics for a range of brain disorders.