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Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain

Nature Reviews Neuroscience volume 18, pages 471–484 (2017)Cite this article

Subjects

Key Points

  • Many sex differences in the rodent brain are established during a sensitive period in early life.

  • Gonadal steroid hormones determine sex differences, but there is also a contribution of sex chromosome complement.

  • Epigenetic modifications in key brain regions both establish and maintain sex differences.

  • Neuroimmune and inflammatory signalling pathways are essential contributors to the masculinization of brain and behaviour.

  • Higher male vulnerability to neurodevelopmental disorders may have its origins in naturally occurring higher levels of inflammatory signalling molecules early in life.

Abstract

The study of sex differences in the brain is a topic of neuroscientific study that has broad reaching implications for culture, society and biomedical science. Recent research in rodent models has led to dramatic shifts in our views of the mechanisms underlying the sexual differentiation of the brain. These include the surprising discoveries of a role for immune cells and inflammatory mediators in brain masculinization and a role for epigenetic suppression in brain feminization. How and to what degree these findings will translate to human brain development will be questions of central importance in future research in this field.

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Figure 1: Early life programming of adult sex differences.
Figure 2: Sex chromosomes affect brain development directly and indirectly.
Figure 3: Neuroepigenetic and neuroinflammatory contributions to sex differences in the preoptic area.
Figure 4: Epigenetic sources of brain sex differences.

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Acknowledgements

M.M.M. is supported by US National Institutes of Health (NIH) grant R01MH052716-19, R01DA039062 and R01MH091424. K.M.L. is supported by NIH grants F32NS076327 and R21MH105826, and NARSAD Young Investigator Award 2382.

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Authors and Affiliations

  1. Department of Pharmacology and Program in Neuroscience, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, 21201, Maryland, USA

    Margaret M. McCarthy

  2. Department of Biomedical Sciences, University of Pennsylvania, University of Pennsylvania, 380 S. University Ave, Philadelphia, 19104, Pennsylvania, USA

    Bridget M. Nugent

  3. Department of Psychology and Program in Neuroscience, 1835 Neill Ave

    Kathryn M. Lenz

  4. Ohio State University, Columbus, 43210, Ohio, USA

    Kathryn M. Lenz

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  1. Margaret M. McCarthy
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Functional MRI

The detection of changes in regional brain activity through their effects on blood flow and blood oxygenation that in turn affect the brightness of magnetic resonance images.

Diffusion tensor imaging

An MRI technique that provides a three-dimensional image of water diffusion in the brain. As water diffuses more readily along the axis of myelinated nerve fibre tracts, this method can be used to obtain a non-invasive estimate of anatomical connectivity between brain areas.

Connectome

A comprehensive map of neural connections within the nervous system of an organism.

Steroid hormone

A signalling molecule that is synthesized from cholesterol and is released into the circulation from endocrine glands including the gonads and adrenals. It binds to nuclear transcription factor receptors and can directly and indirectly modify gene expression.

Early life programming

The phenomenon whereby events during development, such as stress, altered nutrition or endogenous hormone exposure, exert enduring influences on the nervous system in anticipation of the adult environment and experiences.

Critical period

A developmental window during which specific cellular events must occur or will be forever precluded. Sexual differentiation of the brain mediated by steroid hormones occurs during a perinatal critical period in the rodent and prenatally in humans.

Hormone response elements

Sequences of DNA in promoter regions that are recognized and bound to by steroid hormone receptors after binding of hormone, thereby promoting transcription.

Humoral signalling

Signalling molecules released into the blood stream that then act at a distance, such as steroid hormones.

Cytokine

Originally defined as an immune system protein that modifies biological responses; cytokines are now known to be released by most cells and are important in regulating intercellular communication, cell function and cell survival.

Immune surveillance

The hypothesized process by which the immune system constantly monitors the body for both invading pathogens and aberrant cell pathology, such as that seen in cancer.

Neuromodulators

Endogenous chemical substances that change the intrinsic properties of a neuron and the dynamics and strength of neurotransmission. Neuromodulators can modify neuronal responses to synaptic inputs on potentially long timescales.

Neurohormones

Steroid hormones that are further modified in the brain or synthesized de novo from cholesterol in the brain and are thus distinguished from those synthesized in the endocrine glands. Other neurohormones are peptides synthesized in the brain and released into the periphery such as oxytocin and vasopressin.

T cells

Lymphocytes produced by the thymus gland that actively participate in the immune response.

Mast cells

Multigranular cells that function as stores for several key inflammatory and/or pain mediators (including nerve growth factor, tumour necrosis factor, chemokines and histamine) and that originate in bone marrow but have a resident population in the brain.

Epigenetic marks

Modifications to the genome that do not change the nucleotide sequence but have an impact on gene regulation. Methylation groups added to cytosine nucleotides or histones on the chromatin, along with other chemical groups, are examples of epigenetic marks.

Chemokines

A subfamily of inflammatory molecules that were initially described as regulators of the chemotaxis of inflammatory cells but that also have important roles in other processes, such as cell growth and differentiation.

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McCarthy, M., Nugent, B. & Lenz, K. Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nat Rev Neurosci 18, 471–484 (2017). https://doi.org/10.1038/nrn.2017.61

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