Sex Differences in the Brain Get Down to the Molecular Level – the-scientist.com

Report on Sex-Based Disparities in Neuroscience and Alignment with Sustainable Development Goals

This report details the critical need for including both male and female subjects in neuroscience research to advance global health equity. It highlights how historical research biases have impeded progress towards key Sustainable Development Goals (SDGs), particularly SDG 3 (Good Health and Well-being), SDG 5 (Gender Equality), and SDG 10 (Reduced Inequalities). The findings underscore that inclusive research practices are essential for developing effective, targeted medical therapeutics for all.

Addressing Historical Research Bias to Promote Gender Equality (SDG 5)

The Problem of Male-Centric Research

A significant historical bias in preclinical biomedical research has seen the systematic exclusion of female animal subjects. This practice was based on the misconception that hormonal fluctuations during the estrus cycle would introduce excessive variability into experimental data. This exclusion represents a failure to uphold the principles of SDG 5 (Gender Equality) within the scientific process, leading to a knowledge gap that disproportionately affects the health outcomes of women.

Policy Shifts Towards Inclusive Science

Subsequent research has refuted the initial concerns, demonstrating that the estrus cycle does not lead to greater data variability in female mice. In response to this evidence and to address the research gap, policy changes have been implemented. A key development was the 2016 National Institutes of Health (NIH) mandate requiring the inclusion of female animals in preclinical research. This policy is a crucial step toward achieving SDG 10 (Reduced Inequalities) by ensuring that foundational biomedical knowledge is applicable to the entire population, thereby promoting more equitable health solutions.

The Impact of Inclusive Research on Good Health and Well-being (SDG 3)

Debunking Misconceptions about Brain Structure

Common misconceptions regarding dichotomous “male” and “female” brains are challenged by large-scale data. Analysis of structural MRI data from the UK Biobank reveals substantial overlap and mosaicism in brain structures, undermining simplistic views on sex-based differences. Correcting for total brain volume minimizes overall size differences. Specific findings include:

• No significant difference in hippocampus size based on sex.
• Slightly larger nucleus accumbens in females.
• Slightly larger amygdala in males.
• The vast majority of individual brains are a mosaic of larger and smaller areas, challenging the concept of a distinctly male or female brain.

These findings reinforce that progress toward SDG 3 requires a nuanced understanding that moves beyond outdated stereotypes.

Uncovering Molecular-Level Differences for Targeted Medicine

While macroscopic structural differences are minimal, significant sex-based distinctions exist at the molecular and synaptic levels. Research led by neuroendocrinologist Catherine Woolley at Northwestern University has identified “latent” sex differences, where processes appear identical on the surface but are driven by different underlying mechanisms. This is critical for achieving SDG 3, as these differences can determine the efficacy and safety of pharmacological interventions.

1. Estradiol’s Effect: Estradiol, a form of estrogen, increases synaptic strength in the hippocampus of both male and female mice.
2. Receptor-Specific Mechanisms: The effect is mediated by three different estrogen receptors. When activated individually, these receptors produce different effects not only between the sexes but also within the same sex.
3. Implications for Drug Development: A drug that selectively targets one of these receptors could have profoundly different, and potentially adverse, effects in males versus females. Understanding these latent differences is paramount for developing safe and effective therapeutics for everyone.

Acknowledging Hormonal Dynamics in Both Sexes

The argument for excluding females due to hormones is further weakened by evidence of significant hormonal fluctuations in males. A dense-sampling study conducted by Emily Jacobs at the University of California, Santa Barbara, on a single male subject over one month revealed daily fluctuations in testosterone and cortisol levels, which correlated with changes in the volumes of different brain regions. This demonstrates that hormonal dynamics are a feature of whole-organism physiology in both sexes and must be accounted for in all research to ensure robust and universally applicable results, in line with the ambitions of SDG 3.

A Call to Action for a More Equitable Future in Science

Educating for Change (SDG 4)

In a call to action for early-career neuroscientists, Dr. Woolley emphasized the responsibility of the next generation to change the status quo. By integrating both male and female subjects into standard research protocols, scientists can contribute to a more complete and accurate understanding of biology. This aligns with SDG 4 (Quality Education) by promoting an educational and research culture that values inclusivity and scientific rigor.

Conclusion: Maximizing Medical Benefits Through Inclusivity

The systematic inclusion of both sexes in neuroscience research is not merely a matter of scientific best practice; it is a fundamental requirement for achieving global health equity. By revealing novel patterns of synaptic modulation and understanding sex-specific molecular mechanisms, science can strengthen and broaden opportunities for drug development. This inclusive approach is essential to fulfilling the promise of SDG 3 (Good Health and Well-being) and SDG 5 (Gender Equality), ensuring that the benefits of medical science are maximized for all people.

1. Which SDGs are addressed or connected to the issues highlighted in the article?

SDG 3: Good Health and Well-being

• The article directly connects the research on sex differences in the brain to medical applications. It states that understanding these differences is crucial for “ensuring that we maximize the benefits of science for medicine” and could “lead to the development of better-targeted drugs.” This aligns with the goal of promoting health and well-being for all.

SDG 5: Gender Equality

• The central theme of the article is the historical “bias in neuroscience research” where female animals were excluded. This represents a significant gender inequality in scientific practice. The article highlights the 2016 National Institutes of Health (NIH) policy that made “the inclusion of female animals in preclinical biomedical research a requirement,” which is a direct action towards achieving equality in this field.

SDG 9: Industry, Innovation, and Infrastructure

• The article discusses the need to improve scientific research methodologies. The call for neuroscientists to “change the status quo in neuroscience research” and to “get into the habit of using both female and male samples” is a call to enhance the quality and robustness of scientific research. This contributes to building a more resilient and inclusive scientific infrastructure and fostering innovation.

2. What specific targets under those SDGs can be identified based on the article’s content?

SDG 3: Good Health and Well-being

• Target 3.b: “Support the research and development of vaccines and medicines for the communicable and non-communicable diseases…” The article’s emphasis on how inclusive research will “strengthen and broaden opportunities for drug development and development of other therapeutics” directly supports the goal of advancing research and development for new medicines that are effective for the entire population, not just one sex.

SDG 5: Gender Equality

• Target 5.c: “Adopt and strengthen sound policies and enforceable legislation for the promotion of gender equality…” The article explicitly mentions a key policy action: “in 2016, the National Institutes of Health made the inclusion of female animals in preclinical biomedical research a requirement.” This is a clear example of a policy adopted to correct a gender bias and promote equality in scientific research.

SDG 9: Industry, Innovation, and Infrastructure

• Target 9.5: “Enhance scientific research, upgrade the technological capabilities of industrial sectors in all countries…and substantially increasing the number of research and development workers…” The article is a direct call to enhance scientific research practices. By advocating for the inclusion of both sexes in experiments, it aims to improve the quality and applicability of neuroscience research, which is a fundamental aspect of enhancing the overall scientific research framework.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

Indicators for SDG 3 and SDG 9

• Proportion of preclinical studies including female subjects: The article implies this indicator by contrasting the past, where researchers “overwhelmingly decided to use only male mice,” with the present NIH requirement for “the inclusion of female animals.” Measuring the percentage of studies that adhere to this inclusive standard would directly track progress in enhancing scientific research (Target 9.5) and supporting more effective drug development (Target 3.b).

Indicator for SDG 5

• Adoption of policies mandating inclusion of both sexes in research: The article explicitly points to the “National Institutes of Health” policy from 2016 as a key development. The existence and enforcement of such policies by funding bodies and research institutions serve as a direct indicator for measuring progress on Target 5.c, which focuses on adopting sound policies for gender equality.

Implied Indicator for SDG 3

• Number of new drugs developed with sex-specific considerations: The article suggests that a key benefit of this research shift is the “development of better-targeted drugs.” While not a current metric mentioned in the text, the future development of therapeutics that account for sex differences in molecular mechanisms would be a tangible indicator of success in maximizing the benefits of science for medicine.

4. Create a table with three columns titled ‘SDGs, Targets and Indicators’ to present the findings from analyzing the article.

Source: the-scientist.com