Elsevier

Psychoneuroendocrinology

Volume 34, Supplement 1, December 2009, Pages S143-S161
Psychoneuroendocrinology

Review
Neurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions

https://doi.org/10.1016/j.psyneuen.2009.07.005Get rights and content

Summary

Hormones are trophic factors that integrate central and peripheral nervous system functions, and can influence social, cognitive, emotional and physical (SCEP) processes. Greater understanding of behavioral and neurobiological underpinnings of mental, cognitive, and/or physical changes with maturation is becoming increasingly important as the world's population ages. There are individual differences in how people age, but the factors that influence these differences are not well understood. Social supports are one factor that may influence the trajectory of age-related processes. The loss of close relationships, especially among older persons, is one of the greatest risk factors for mental and physical decline. Progesterone, secreted by the ovaries, or produced de novo in the brain, is readily converted centrally to 5α-pregnan-3α-ol-20-one (3α,5α-THP), and can influence SCEP, through rapid, non-classical steroid-mediated actions. Our hypothesis is that 3α,5α-THP is a key trophic factor in SCEP and development. Our research has demonstrated that 3α,5α-THP facilitates social and sexual behavior of rodents, which evokes further increases in 3α,5α-THP in midbrain and hippocampus, brain areas involved in SCEP. The role of 3α,5α-THP to influence social and/or sexual experience, and thereby SCEP, is discussed in this review. Further understanding of these neurobiological and/or behavioral factors may lead to findings that ultimately can promote health and prevent disease.

Introduction

Steroid hormones, such as progesterone (P), play a fundamental role in trophic actions that influence the development and function of the central nervous system (CNS) throughout the lifespan. In adult rodents, P facilitates social and sexual interactions. Progesterone influences the onset and duration of sexual behavior of rodents in part through its actions in the midbrain ventral tegmental area (VTA). To elucidate functionally relevant mechanisms of P, we have manipulated P's actions in the VTA of naturally, sexually receptive or ovariectomized (OVX), estrogen (E)-primed rodents, and examined changes in social and sexual (socio-sexual) behavior. Progesterone's actions in the VTA occur independent of traditional actions at cognate intracellular progestin receptors (PRs). Rather, P's actions in the VTA involve its conversion to 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), which is devoid of affinity for intracellular PRs and has actions via neurotransmitter substrates (Frye, 2001a, Frye, 2001b, Frye, 2007, Frye et al., 2006, Frye and Vongher, 1999). In addition to P and 3α,5α-THP facilitating mating, sex further increases levels of neurosteroids.

Mating has dynamic effects upon levels of 3α,5α-THP in the midbrain VTA. 3α,5α-THP is readily formed in the midbrain from ovarian P, and is also a neurosteroid that is rapidly produced de novo in the midbrain following mating (Frye, 2007). Mating induces neurosteroidogenesis of 3α,5α-THP in the midbrain, as well as the hippocampus, an important area of the brain for cognitive and emotional processes (Frye and Rhodes, 2006, Frye et al., 2006, Frye, 2007). We, and others, have demonstrated in separate lines of research that P and/or 3α,5α-THP can influence social, cognitive, emotional and physical (SCEP) performance (Engel and Grant, 2001, Frye, 2007, Frye, 2008, Herbison, 2001, Miczek et al., 2002, Pinna et al., 2008, Sherwin, 1999).

In young adulthood and/or middle age, alterations in 3α,5α-THP may play a fundamental role to enhance reproduction and social bonds, thereby influencing SCEP. Social relationships have a substantial effect on health. Grief and bereavement increases morbidity and mortality. The loss of close relationships, especially among older persons, is one of the greatest risk factors for mental and physical decline. However, the neurobiological and behavioral mechanisms underlying these effects are not well understood. A greater understanding of the neurobiological and behavioral factors associated with social responding is essential in order to elucidate interventions that will promote health and/or prevent disease among individuals. The neurobiological and behavioral mechanisms that underlie mating-induced neurosteroidogenesis, and the subsequent impact on social, cognitive, emotional and physical (SCEP) function among young and/or mid-aged rats is the subject of this review.

Section snippets

Significance

The understanding of mental, cognitive, and/or physical decline with aging is becoming increasingly important as the world's population ages. There are individual differences in how people age. For example, about 60% of aging individuals will experience some cognitive decline. Among these, about half will experience benign senescent forgetfulness, or mild cognitive impairment (MCI) associated with cell loss in the subiculum region of the hippocampus. Others will experience Alzheimer's Disease

Background

Hormones are pleiotropic and may have diverse actions that underlie their organizational and/or activational effects to influence normal cellular functions and/or behavioral processes. Emerging findings regarding the sources, mechanisms, and effects of steroids have challenged traditional dogma and revealed non-traditional actions of hormones to influence these processes. First, hormones are typically thought to be secreted from peripheral endocrine glands and get into circulation whereupon

Mating increases 3α,5α-THP in midbrain, cortex, hippocampus, and striatum

3α,5α-THP levels in the midbrain are particularly dynamic and increase with mating. Notably, following standard mating (10 min or 10 sexual contacts with a male in an aquarium), midbrain 3α,5α-THP levels are increased over those of non-mated naturally receptive or hormone-primed rodents (Frye, 2001a, Frye, 2001b; Fig. 5, top). In follow-up experiments, the effects of paced mating, in which proestrous rats are mated in a larger chamber wherein they can control the access to the male and thereby

Mating increases gene expression in the midbrain

We examined differences in gene expression in the midbrain of naturally receptive rats that underwent paced mating compared to naturally receptive rats that did not mate. Midbrain tissues were sent to two core microarray facilities for Affymetrix GeneChip Rat 230 2.0 arrays per Affymetrix protocol. First, among mated rats, genes that were upregulated in the midbrain were primarily related to those substrates that our past studies have elucidated as targets for P and/or 3α,5α-THP actions to

Parity enhances cognitive and anti-anxiety performance and 3α,5α-THP levels

One intriguing possibility that may underlie some of the common actions of 3α,5α-THP is its effects on neuroplasticity. For example, naked mole rats that are breeders have more favorable neural morphology than do non-breeders (Holmes et al., 2007). Given that 3α,5α-THP is elevated in brain during pregnancy and that 3α,5α-THP has demonstrated trophic effects, the extent to which 3α,5α-THP may influence behavior associated with parity is of interest. Parity enhances cognitive function and

Reproductive senescence influences social, cognitive, and affective performance

Social, cognitive and affective deficits can occur with aging in people and rodents. In females, these deficits may be initiated and/or coincide with the transition to reproductive senescence. Whether individual differences in the natural transition to reproductive senescence is associated with alterations in sexual, cognitive, and affective performance was investigated among age-matched, 12-month-old, Long-Evans female rats that were still reproductively competent, transitioning to

Conclusion

One factor that may have a profound influence on the trajectory of age-related processes are social supports. Loss of a social relationship can contribute to decline in mental, cognitive, and/or physical functioning. Given that hormones are mediating factors between the central and peripheral nervous system, and can influence social, affective, and cognitive processes, their role underlying neurobiological and/or behavioral mechanisms that influence aging, are of interest. The loss of close

Future directions

The effects, sites of action, and neural mechanisms of mating-relevant interactions for social, cognitive, and affective behavior are of interest. Levels of P and its metabolites and effects on metabolism enzymes need to be examined in different regions of the brain. 3α,5α-THP can delay progression of neurodegenerative processes (Brinton and Wang, 2006, Langmade et al., 2006, Mellon et al., 2008) perhaps in part through activation of metabolism enzymes, including those involved in conversion of

Role of funding sources

This research was supported by grants from The National Institutes of Health (MH06769801, MD003373, NS06323301A1) and National Science Foundation (03-16083).

Conflicts of interest

None declared.

Acknowledgements

The efforts of Dr. Alicia Walf, Jason Paris, and other members of my laboratory, present and past, are greatly appreciated. Danielle Osborne provided technical assistance in formatting the manuscript.

References (209)

  • N.A. Compagnone et al.

    Neurosteroids: biosynthesis and function of these novel neuromodulators

    Front. Neuroendocrinol.

    (2000)
  • A. Concas et al.

    Modulation of gamma-aminobutyric acid (GABA) receptors and the feeding response by neurosteroids in Hydra vulgaris

    Neuroscience

    (1998)
  • C.M. Contreras et al.

    Lateral septal neuronal firing rate increases during proestrus-estrus in the rat

    Physiol. Behav.

    (2000)
  • J.M. Deminière et al.

    Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers

    Brain Res.

    (1992)
  • G. Díaz-Véliz et al.

    Progesterone effects on the acquisition of conditioned avoidance responses an other motoric behaviors in intact and ovariectomized rats

    Psychoneuroendocrinology

    (1994)
  • R.C. Drugan et al.

    Environmentally induced changes in peripheral benzodiazepine receptors are stressor and tissue specific

    Pharmacol. Biochem. Behav.

    (1995)
  • D.L. Ebner et al.

    Ovarian hormones and retention of learned fear in rats

    Behav. Neural Biol.

    (1981)
  • W. Ellermeier et al.

    Gender differences in pain ratings and pupil reactions to painful pressure stimuli

    Pain

    (1995)
  • S.R. Engel et al.

    Neurosteroids and behavior

    Int. Rev. Neurobiol.

    (2001)
  • L. Fodor et al.

    Nanomolar allopregnanolone potentiates rat cerebellar GABAA receptors

    Neurosci. Lett.

    (2005)
  • C.A. Frye

    The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents

    Brain Res. Rev.

    (2001)
  • C.A. Frye

    The role of neurosteroids and nongenomic effects of progestins in the ventral tegmental area in mediating sexual receptivity of rodents

    Horm. Behav.

    (2001)
  • C.A. Frye

    Progestins influence motivation, reward, conditioning, stress, and/or response to drugs of abuse

    Pharmacol. Biochem. Behav.

    (2007)
  • C.A. Frye et al.

    Estrous cycle and sex differences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3α,5α-THP

    Pharmacol. Biochem. Behav.

    (2000)
  • C.A. Frye et al.

    3α-Hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors

    Neuroscience

    (2006)
  • C.A. Frye et al.

    Changes in progesterone metabolites in the hippocampus can modulate open field and forced swim test behavior of proestrous rats

    Horm. Behav.

    (2002)
  • C.A. Frye et al.

    Hippocampal 3α,5α-THP may alter depressive behavior of pregnant and lactating rats

    Pharmacol. Biochem. Behav.

    (2004)
  • C.A. Frye et al.

    Effects of progesterone administration and APPswe + PSEN1Δe9 mutation for cognitive performance of mid-aged mice

    Neurobiol. Learn. Mem.

    (2008)
  • C.A. Frye et al.

    Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways

    Steroids

    (2008)
  • C.A. Frye et al.

    Progesterone enhances motor, anxiolytic, analgesic, and antidepressive behavior of wild-type mice, but not those deficient in type 1,5 alpha-reductase

    Brain Res.

    (2004)
  • C.A. Frye et al.

    Effect of prenatal stress and gonadal hormone condition on depressive behaviors of female and male rats

    Horm. Behav.

    (2003)
  • A.R. Genazzani et al.

    Clinical implications of circulating neurosteroids

    Int. Rev. Neurobiol.

    (2001)
  • S.S. Girdler et al.

    Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder

    Biol. Psychiatry

    (2001)
  • A. Guidotti et al.

    Can the antidysphoric and anxiolytic profiles of selective serotonin reuptake inhibitors be related to their ability to increase brain 3α,5α-tetrahydroprogesterone (allopregnanolone) availability?

    Biol. Psychiatry

    (1998)
  • E. Hampson

    Variations in sex-related cognitive abilities across the menstrual cycle

    Brain Cogn.

    (1990)
  • J. He et al.

    Progesterone and 3α,5α-THP reduce inflammatory cytokines after traumatic brain injury

    Exp. Neurol.

    (2004)
  • A.E. Herbison

    Physiological roles for the neurosteroid allopregnanolone in the modulation of brain function during pregnancy and parturition

    Prog. Brain Res.

    (2001)
  • M.B. Herd et al.

    Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors

    Pharmacol. Ther.

    (2007)
  • M. Holzbauer

    Physiological variations in the ovarian production of 5α-pregnane derivatives with sedative properties in the rat

    J. Steroid Biochem.

    (1975)
  • N.S. Jain et al.

    Reversal of caffeine-induced anxiety by neurosteroid 3-α-hydroxy-5-α-pregnane-20-one in rats

    Neuropharmacology

    (2005)
  • I.M. Johansson et al.

    Allopregnanolone inhibits learning in the Morris water maze

    Brain Res.

    (2002)
  • P. Kehoe et al.

    Central allopregnanolone is increased in rat pups in response to repeated, short episodes of neonatal isolation

    Brain Res. Dev. Brain Res.

    (2000)
  • C.K. Kellogg et al.

    Endogenous levels of 5 alpha-reduced progestins and androgens in fetal vs. adult rat brains

    Brain Res. Dev. Brain Res.

    (1999)
  • G. Altomare et al.

    Depression circumstantially related to the administration of finasteride for androgenetic alopecia

    J. Dermatol.

    (2002)
  • T. Bäckström et al.

    Pathogenesis in menstrual cycle-linked CNS disorders

    Ann. N. Y. Acad. Sci.

    (2003)
  • M.L. Barbaccia et al.

    Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress

    Neuroendocrinology

    (1996)
  • M.L. Barbaccia et al.

    The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations

    Br. J. Pharmacol.

    (1997)
  • E.E. Baulieu

    Steroid hormone receptors

    Expos. Annu. Biochim. Med.

    (1980)
  • D. Belelli et al.

    Neurosteroids: endogenous regulators of the GABA(A) receptor

    Nat. Rev. Neurosci.

    (2005)
  • L.F. Berkman

    Tracking social and biological experiences: the social etiology of cardiovascular disease

    Circulation

    (2005)
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