ReviewNeurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions
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.
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2021, Journal of Sexual MedicineCitation Excerpt :They play a role in in several important functions including mental health (depression, anxiety, stress), cognition (learning, memory), and nervous system plasticity.31-35 Both inhibitory and excitatory neurosteroids ultimately have antidepressant, anxiolytic, neuroprotective, neurogenic, and cognition-enhancing effects.36-37 5ARIs may induce cognitive and psychiatric side effects through decreased neurosteroid levels by preventing steroid hormones from metabolizing through reduction.