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Since the early 1980s, evidence suggesting that the vertebrate brain is a rich source of steroid hormones has been decisive and extensive. This evidence includes data from many vertebrate species and describes almost every enzyme necessary for the conversion of cholesterol to androgens and estrogens. In contrast, the behavioral relevance of neurosteroidogenesis is more equivocal and mysterious. Nonetheless, the presence of a limited number of steroidogenic enzymes in the brain of a few species has clearly been linked to reliable behavioral phenotype.

Puberty onset marks the beginning of adolescence and an organism’s transition to adulthood. Across species, adolescence is a dynamic period of maturation for brain and behavior. Pubertal processes, including the increase in gonadal hormone production, or gonadarche, can influence a broad array of neural processes and circuits to ultimately shape adult behavior. Decades of research in rodent models have shown that gonadal hormones at puberty promote adult-typical patterns of behavior across social, affective, and cognitive realms. Importantly, hormonal activation of sex-specific patterns of adult behavior relies on sexual differentiation of the brain around the time of birth, mediated by testicular hormones in males – and lack thereof in females. While it was originally believed that gonadal hormones play a purely activational role at puberty, studies in the early 21st century provide examples where the timing and relative levels of gonadal hormones exert long-lasting, or organizational effects on brain and behavior. In this way, adolescent exposure to gonadal hormones can orchestrate brain and body changes in unison and in some cases tune how the brain responds to gonadal hormones in adulthood. Notably, many of the effects of puberty on behavior may occur indirectly by altering sensitivity to environmental events and an organism’s ability to respond to or learn from experience. These insights from the animal literature provide a framework for understanding how puberty may influence the maturation of complex behaviors and modify risk or resilience to mental health disorders during human adolescence. In sum, puberty interacts with genetics, early life organizational effects of gonadal hormones, experience, and learning processes to shape behavior in adulthood.

Sex differences in the brain are established by the differential gonadal steroid hormonal milieu experienced by developing male and female fetuses and newborns. Androgen production by the testis starts in males prior to birth resulting in a brief developmental window during which the brain is exposed to high levels of steroid. Androgens and aromatized estrogens program the developing brain toward masculinized physiology and behavior that is then manifest in adulthood. In rodents, the perinatal programming of sex-specific adult mating behavior provides a model system for exploring the mechanistic origins of brain sex differences. Microglia are resident in the brain and provide innate immunity. Previously considered restricted to response to injury, these cells are now thought to be major contributors to the sculpting of developing neural circuits. This role extends to being an important component of the sexual differentiation process and has opened the door for exploration into myriad other aspects of neuroimmunity and inflammation as possible determinants of sex differences. In humans, males are at greater risk for more frequent and/or more severe neuropsychiatric and neurological disorders of development, many of which include prenatal inflammation as an additional risk factor. Emerging clinical and preclinical evidence suggests male brains experience a higher inflammatory tone early in development, and this may have its origins in the maternal immune system. Collectively, these disparate observations coalesce into a coherent picture in which brain development diverges in males versus females due to a combination of gonadal steroid action and neuroinflammation, and the latter increases the risk to males of developmental disorders.

Understanding of the brain mechanisms regulating reproductive behaviors in female laboratory animals has been aided greatly by our knowledge of estrogen receptors in the brain. Hypothalamic neurons that express the gene for estrogen receptor-alpha regulate activity in the neural circuit for the simplest female reproductive response, lordosis behavior. In turn, many of the neurotransmitter inputs to the critical hypothalamic neurons have been studied using electrophysiological and neurochemical techniques. The upshot of all of these studies is that lordosis behavior presents the best understood set of mechanisms for any mammalian behavior.

Female reproduction is an interplay between the hypothalamus, pituitary, and ovaries. While the gonadotropin releasing hormone (GnRH) neuron in the hypothalamus regulates gonadal function through the pituitary, GnRH neuronal activity is also profoundly influenced by ovarian steroid hormones. GnRH is released from GnRH neurons in a pulsatile manner after integration of a diverse array of internal and external milieus. Since the discovery of the mammalian GnRH molecule, over a dozen GnRH forms have been identified in the animal kingdom, and large numbers of publications in various lab animal and human studies suggest that GnRH neurons are regulated by multiple neuromodulators in the brain, such as kisspeptin, neurokinin B, β-dynorphin, neuropeptide Y, GnIH, GABA, glutamate, and glial factors. A recent emerging concept is that steroids synthesized locally in the hypothalamus, namely, neuroestradiol and neuroprogesterone, also contribute to the regulation of GnRH neuronal activity, and hence female reproduction. Together with modulation by various inputs and ovarian steroid feedback, GnRH neurons are responsible for puberty, cyclic ovulation, and menopause.

In the last two decades of the 20th century, key findings in the field of estrogen signaling completely changed our understanding of hormones: first, steroidogenesis was demonstrated in the CNS; second, a vast majority of cells in the nervous system were shown to have estrogen receptors; third, a second nuclear estrogen receptor (ERß) was cloned; and finally, “nuclear” receptors were shown to be present and functional in the cell membrane. Shortly thereafter, even more membrane estrogen receptors were discovered. Steroids (estrogens, in particular) began to be considered as neurotransmitters and their receptors were tethered to G protein-coupled receptor signaling cascades. In some parts of the brain, levels of steroids appeared to be independent of those found in the circulation and yet, circulating steroids had profound actions on the brain physiology. In this review, we discuss the interaction of peripheral and central estrogen action in the context of female reproduction—one of the best-studied aspects of steroid action. In addition to reviewing the evidence for steroidogenesis in the hypothalamus, we review membrane-localized nuclear receptors coupling to G protein-signaling cascades and the downstream physiological consequences for reproduction. We will also introduce newer work that demonstrates cell signaling for a common splice variant of estrogen receptor-α (ERα), and membrane action of neuroprogesterone in regulating estrogen positive feedback.

The blood-brain barrier (BBB) is a dynamic structural interface between the brain and periphery that plays a critical function in maintaining cerebral homeostasis. Over the past two decades, technological advances have improved our understanding of the neuroimmune and neuroendocrine mechanisms that regulate a healthy BBB. The combination of biological sex, sex steroids, age, coupled with innate and adaptive immune components orchestrates the crosstalk between the BBB and the periphery. Likewise, the BBB also serves as a nexus within the hypothalamic-pituitary-adrenal (HPA) and gut-brain-microbiota axes. Compromised BBB integrity permits the entry of bioactive molecules, immune cells, microbes, and other components that migrate into the brain parenchyma and compromise neuronal function. A paramount understanding of the mechanisms that determine the bidirectional crosstalk between the BBB and immune and endocrine pathways has become increasingly important for implementation of therapeutic strategies to treat a number of neurological disorders that are significantly impacted by the BBB. Examples of these disorders include multiple sclerosis, Alzheimer’s disease, stroke, epilepsy, and traumatic brain injury.

Animals produce communication signals to attract mates and deter rivals during their breeding season. The coincidence in timing results from the modulation of signaling behavior and neural activity by sex steroid hormones associated with reproduction. Adrenal steroids can influence signaling for aggressive interactions outside the breeding season. Androgenic and estrogenic hormones act on brain circuits that regulate the motivation to produce and respond to signals, the motor production of signals, and the sensory perception of signals. Signal perception, in turn, can stimulate gonadal development.

It is well established that testosterone from testicular origin plays a critical role in the activation of male sexual behavior in most, if not all, vertebrate species. These effects take place to a large extent in the preoptic area although other brain sites are obviously also implicated. In its target areas, testosterone is actively metabolized either into estrogenic and androgenic steroids that have specific behavioral effects or into inactive metabolites. These transformations either amplify the behavioral activity of testosterone or, alternatively, metabolism to an inactive compound dissipates any biological effect. Androgens and estrogens then bind to nuclear receptors that modulate the transcription of specific genes. This process is controlled by a variety of co-activators and co-repressors that, respectively, enhance or inhibit these transcriptional processes. In addition, recent work has shown that the production of estrogens by brain aromatase can be modulated within minutes by changes in neural activity and that these rapid changes in neuroestrogen production impact sexual behavior, in particular sexual motivation within the same time frame. Estrogens thus affect specific aspects of male sexual behavior in two different time frames via two types of mechanisms that are completely different. Multiple questions remain open concerning the cellular brain mechanisms that mediate testosterone action on male sexual behavior.