Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Jul 1;319(1):R60-R68.
doi: 10.1152/ajpregu.00357.2019. Epub 2020 Jun 3.

Sex-steroid-dependent plasticity of brain-stem autonomic circuits

Erica L Littlejohn  1 , Stephanie Fedorchak  1 , Carie R Boychuk  1
Affiliations
Review

Sex-steroid-dependent plasticity of brain-stem autonomic circuits

Erica L Littlejohn et al. Am J Physiol Regul Integr Comp Physiol. .

Abstract

In the central nervous system (CNS), nuclei of the brain stem play a critical role in the integration of peripheral sensory information and the regulation of autonomic output in mammalian physiology. The nucleus tractus solitarius of the brain stem acts as a relay center that receives peripheral sensory input from vagal afferents of the nodose ganglia, integrates information from within the brain stem and higher central centers, and then transmits autonomic efferent output through downstream premotor nuclei, such as the nucleus ambiguus, the dorsal motor nucleus of the vagus, and the rostral ventral lateral medulla. Although there is mounting evidence that sex and sex hormones modulate autonomic physiology at the level of the CNS, the mechanisms and neurocircuitry involved in producing these functional consequences are poorly understood. Of particular interest in this review is the role of estrogen, progesterone, and 5α-reductase-dependent neurosteroid metabolites of progesterone (e.g., allopregnanolone) in the modulation of neurotransmission within brain-stem autonomic neurocircuits. This review will discuss our understanding of the actions and mechanisms of estrogen, progesterone, and neurosteroids at the cellular level of brain-stem nuclei. Understanding the complex interaction between sex hormones and neural signaling plasticity of the autonomic nervous system is essential to elucidating the role of sex in overall physiology and disease.

Keywords: autonomic; estrogen; neurosteroid; progesterone; sex.

PubMed Disclaimer

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.
Fig. 1.
A flowchart summarizing the framework of different experimental approaches and models used to determine sex differences. To determine whether a sex difference is present and to differentiate between an activational or organizational sex difference, a series of questions must be asked. After determining an effect of interest, a logical first question is to ask whether the effect varies between males and females. If so, one should proceed to comparing gonadectomized males and females. If the difference in effect disappears after males and females are gonadectomized, then this suggests an activational sex difference exists for which the cause may then be probed by hormone supplementation. If the difference in effect remains regardless of gonadectomy (GDX), then this suggests an organizational difference that must be tested using a method such as four-core genotype. Alternatively, one might be interested in whether the estrous cycle affects the responses of females to a known measurement. In this case, females would first be examined across different stages of the menstrual/estrous cycle. It would then be necessary to conduct an experiment in which gonadectomized females received hormone supplementation to mimic the different estrous stages and determine which stage correlates with the effect. Finally, if there is no difference in effect between males and females whether intact or gonadectomized, then the conclusion can be made that there is no sex difference.
Fig. 2.
Fig. 2.
A schematic representation of the autonomic brain stem. Viscerosensory afferent neurons from vital organs, such as the heart, gastrointestinal system, pancreas, adrenal glands, kidneys, and blood vessels, synapse in the nucleus tractus solitarius (NTS). NTS neurons modulate descending autonomic output nuclei, like the dorsal motor nucleus of the vagus (DMV), nucleus ambiguus (NA), and the ventral lateral medulla (VLM). Although significant work must be done to determine the integrated nature of sex steroid modulation of autonomic signaling, all critical autonomic brain-stem regions express estrogen and progesterone receptors. Of recent interest is allopregnanolone, a metabolite of progesterone, which may be produced locally by the NTS. The extent of allopregnanolone’s role in modulating signals is unknown, but there is evidence that it is important in the regulation of GABAA receptor activity. Since GABAergic signaling is a key mechanism by which the NTS regulates DMV, rostral VLM (RVLM), and NA activity (and, in turn, peripheral organ system function), allopregnanolone could be a novel modulator of autonomic output. ALLO, allopregnanolone; AP, area postrema; CVLM, caudal VLM; DVC, dorsal vagal complex; ER, estrogen receptor; GPER, G protein-coupled estrogen receptor; IML, intermediolateral column; PR, progesterone receptor.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Abramian AM, Comenencia-Ortiz E, Modgil A, Vien TN, Nakamura Y, Moore YE, Maguire JL, Terunuma M, Davies PA, Moss SJ. Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors. Proc Natl Acad Sci USA 111: 7132–7137, 2014. doi:10.1073/pnas.1403285111. - DOI - PMC - PubMed
    1. Arnold AP, Chen X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol 30: 1–9, 2009. doi:10.1016/j.yfrne.2008.11.001. - DOI - PMC - PubMed
    1. Arnold AP, Gorski RA. Gonadal steroid induction of structural sex differences in the central nervous system. Annu Rev Neurosci 7: 413–442, 1984. doi:10.1146/annurev.ne.07.030184.002213. - DOI - PubMed
    1. Asarian L, Geary N. Estradiol enhances cholecystokinin-dependent lipid-induced satiation and activates estrogen receptor-α-expressing cells in the nucleus tractus solitarius of ovariectomized rats. Endocrinology 148: 5656–5666, 2007. doi:10.1210/en.2007-0341. - DOI - PubMed
    1. Ashley RL, Clay CM, Farmerie TA, Niswender GD, Nett TM. Cloning and characterization of an ovine intracellular seven transmembrane receptor for progesterone that mediates calcium mobilization. Endocrinology 147: 4151–4159, 2006. doi:10.1210/en.2006-0002. - DOI - PubMed

Publication types

Substances

LinkOut - more resources