Brain-Derived Steroids and Behaviors
Summary and Keywords
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.
The central nervous system (CNS), once considered simply a target of endocrine factors, is now known as a rich source of multiple hormones. These include, but are not limited to, peptidergic hormones of many sizes and several small secreted molecules such as steroids. The synthesis of the latter was once considered the domain of endocrine organs such as the ovaries, the testes, the thyroid, and the adrenal glands. For the past four decades or so, however, the understanding of steroidogenic tissues has broadened considerably and now irrevocably includes several limbic and non-limbic areas of the CNS across multiple organisms from every vertebrate class. Neurosteroidogenesis also involved many cell types, including neurons and glial cells, and appears to be constitutive and inducible in several species. In comparison, appreciation of the behavioral significance of neural steroidogenesis has lagged somewhat. Nonetheless, emerging evidence, bolstered by relatively novel model organisms and burgeoning approaches, seems to reveal a pluripotent and extensive influence of neurosteroidognesis on behavior.
Primary evidence supporting the “formation or accumulation (or both)” of steroids in the brain independent of the circulation was reported by Corpéchot, Robel, Axelson, Sjövall, and Baulieu (1981). Specifically, this study showed the presence of dehydroeipandrosterone sulfate (DHEAS) in rat brain at levels that (a) exceeded those in plasma, (b) were uncorrelated with circulating titers, (c) were unaffected by peripheral administration of adrenal steroids, and (d) were unaltered by removal of the adrenals and gonads, but (e) were dramatically responsive to stressors in adrenalectomized animals (Corpéchot et al., 1981). Taken together, these data strongly suggested the synthesis of steroids de novo via the expression of one or more steroidogenic enzymes in neural tissue. The product(s) of this expression were termed neurosteroids by the same group and set the stage for the discovery of many other neurosteroids in the CNS of multiple species across every class of vertebrates. This article highlights some of these findings.
Steroids are synthesized from cholesterol by successive enzymatic conversions in a steroidogenic pathway that is remarkably well conserved across vertebrate species. Briefly and in general, this steroidogenic pathway is initiated by P450 side chain cleavage (CYP11A1) and progresses through serial conversions, forming groups of progestins, androgens, and estrogenic products. More specifically, the formation of progestins like pregnenolone and progesterone precede the synthesis of multiple androgens including testosterone, androstenedione, and DHEA, which subsequently can be converted to the estrogens estradiol-17β and estrone (see Figure 1).
Over the past several decades, accumulating evidence has supported the idea that several of these steroid products can be synthesized within the brain itself (Schumacher et al., 2015; Porcu et al., 2016; Rahmani, Ghasemi, Dargahi, Ahmadiani, & Haeri, 2016; De Nicola et al., 2017; Diotel et al., 2018; Giatti, Garcia-Segura, Barreto, & Melcangi, 2018). While there is a smattering of evidence in some vertebrates for the expression of many, if not all of the enzymes depicted in Figure 1, this article focuses on reliable expression of a subset of these enzymes in vertebrates. This small subset of neurosteroids is known to affect specific behaviors via expression in neural cells. More specifically, the article highlights the following: neuroprogesterone and its role in the LH surge in rats, neural androgen synthesis and aggression in birds and mammals, neuroestrogens and the regulation of auditory communication and associated social behaviors in songbirds, and neuroestrogens and spatial memory in songbirds and mice.
Neuroprogestins and the Regulation of the Luteinizing Hormone Surge
The synthesis of progesterone from pregnenolone is catalyzed by the mitochondrial and cytosolic enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD; Cherradi, Chambaz, & Defaye, 1995; see Payne & Hales, 2004). While this enzyme has been extensively studied in the vertebrate gonad, placenta, and adrenal gland (Miller, 1988), its presence and activity in the CNS has also been documented in many species (Mellon, Griffin, & Compagnone, 2001). More specifically, 3β-HSD activity was first described in homogenates of discrete areas of the rat and primate brain (Robel et al., 1987). A few years later, in vitro studies using primary dissociated cultures of the developing nervous system supported these studies and showed the robust conversion of pregnenolone to progesterone in mixed cultures as well as purified glial cell cultures (Jung-Testas, Hu, Baulieu, & Robel, 1989; Jung-Testas, Renoir, Bugnard, Greene, & Baulieu, 1992). Further support of this idea was provided using in situ hybridization and immunocytochemical studies, which revealed the expression of specific isoforms of the 3β-HSD enzyme in the brains of rats (Guennoun, Fiddes, Gouézou, Lombès, & Baulieu, 1995). Indeed, this enzyme has been documented in the CNS of multiple species including teleost fish, amphibians, and birds (Mathieu et al., 2001; Vanson, Arnold, & Schlinger, 1996; Mensah-Nyagan et al., 1999; Takase, Ukena, Yamazaki, Kominami, & Tsutsui, 1999; Beaujean et al., 1999; Tsutsui & Yamazaki, 1995; Usui, Yamazaki, Kominami, & Tsutsui, 1995). Taken together, these studies strongly suggested that the vertebrate CNS was indeed capable of synthesizing progesterone de novo.
Within the CNS, the expression of 3β-HSD has been described in neurons and glia. More specifically, progesterone synthesis has been demonstrated in glial cell cultures (Jung-Testas et al., 1989) and in astrocytic cultures (Mellon & Deschepper, 1993). In addition, a considerable body of evidence strongly supports the expression of 3β-HSD in oligodendrocytes (Zwain & Yen, 1999; see Schumacher et al., 2012). In neurons, the rodent cerebellum appears to be rich in 3β-HSD expression where Purkinje neurons are a major site of progesterone synthesis, particularly in the developing brain (Ukena, Usui, Kohchi, & Tsutsui, 1998; Ukena, Kohchi, & Tsutsui, 1999; Compagnone & Mellon, 2000). However, many other brain areas contain neurons that express 3β-HSD including the olfactory bulb, cortex, hippocampus, and thalamus, among others (Guennon et al., 1995). Interestingly, progesterone synthesis appears to be highest in the neonatal mammalian hippocampus, with decreases in neural progesterone content at all other ages investigated (Ibanez et al., 2003).
It would be inaccurate, however, to consider the role of progesterone synthesis in the adult brain insignificant, as the role of hypothalamic 3β-HSD expression is a critical regulator of a fundamental aspect of mammalian reproductive neurophysiology—the surge in luteinizing hormone (LH). Briefly, it is well established that increases in circulating estradiol (E2), via a feed-forward mechanism, result in increased hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary LH release during proestrus. This, in turn, results in a rapid increase in plasma E2 and ovulation and precedes a return to the more normally observed inhibitory actions of circulating E2 on GnRH and gonadotropins. Importantly, central progesterone synthesis appears necessary (and critical) for E2-dependent increases in GnRH and LH. Specifically, ovariectomized and aderenalectomized rats treated centrally with the 3β-HSD inhibitor trilostane fail to show an E2-induced LH surge relative to control mice (Micevych et al., 2003; Micevych, Soma, & Sinchak, 2008). The hypothalamic cells responsible for this effect appear to be astrocytes, as hypothalamic astrocytes cultured from females, but not males, respond to E2 administration with increased 3β-HSD activity and progesterone synthesis (Micevych et al., 2007; Sinchak et al., 2003).
The influence of these changes on behavior is as yet unclear. Micevych et al. (2008) reported a decrease in proceptive but not receptive behaviors following inhibition of central progesterone synthesis by trilostane, suggesting that neural 3β-HSD activity can indeed influence some aspects of rodent sexual behavior. Taken together, these data strongly underscore the necessity for neuroprogesterone synthesis in the regulation of a critical aspect of mammalian neurophysiology and point to the broader involvement of neurosteroidogenesis in general as an important modulator of neural function.
Neural Synthesis of Androgens and the Regulation of Male Aggressive Behavior
The neural synthesis of progesterone clearly has physiological consequences. However, both circulating and central progesterone can also serve as precursors of other steroids that may be synthesized in neural tissue. Of these, the neural synthesis of androgens, specifically DHEA and its sulfated species (DHEA-S), has been most reliably demonstrated in the CNS of multiple vertebrates. Moreover, neural synthesis of androgens and estrogens from this steroid has been convincingly linked to the expression of aggression in multiple species, including birds and mammals.
As mentioned earlier (see “Introduction”), DHEA synthesis in the brain was first demonstrated almost 40 years ago and indeed was the first “neurosteroid” described (Corpechot, Robel, Axelson, Sjövall, & Baulieu, 1981). For many years, however, the functional significance of this neural androgen synthesis remained a mystery. However, the answer to this question was revealed via the study of seasonally breeding birds and mammals with interesting patterns of year-round territorial and aggressive behaviors.
More specifically, some photoperiodic birds such as song sparrows (Melospiza melodia) show dramatic cycles in circulating androgens with non-detectable levels of circulating testosterone (T) in the non-breeding season (Wingfield & Hahn, 1994; Soma, 2006). Despite low plasma T, however, males of this species show year-round territorial aggression, a behavior known to be strongly androgen-dependent (Wingfield, 1994). This apparent paradox was clarified with the observation that despite low T, the plasma (and therefore the CNS) contained high levels of DHEA at all times except during molting, a brief period where aggression is also low (Soma & Wingfield, 2001). These data suggested that the CNS not only had access to androgenic signals year-round, but that circulating DHEA could also serve as a readily available precursor of other neuroactive steroids associated with aggressive behavior, such as T and E2.
The formation of T from DHEA occurs via the expression of the aforementioned enzyme, 3β-HSD (see Mellon et al., 2001). T, in turn, can be enzymatically converted to E2 via the actions of aromatase (see Lephardt, 1996). Both these enzymes are expressed in the song sparrow brain and appear to be important in the regulation of aggression in the non-breeding season. More specifically, neural expression of 3β-HSD is highest during the non-breeding season (Pradhan et al., 2010). Perhaps more interestingly, aggressive encounters appear to rapidly and dramatically increase the activity of this enzyme in some brain areas (Pradhan et al., 2010), suggesting a strong correlation between aggressive behaviors and neural androgen synthesis. Androgens can be further converted into estrogens, also known modulators of vertebrate aggressive behavior. Indeed, brain aromatase and 5β-reductase change seasonally in the song sparrow brain (Soma, Schlinger, Wingfield, & Saldanha, 2003), suggesting that androgens can be modified within the brain itself and regulate behaviors in a seasonal manner. Finally, acute inhibition of aromatase decreases territorial aggression in this species, suggesting that the conversion of androgens to estrogens is an important aspect of aggression during the non-breeding season in song sparrows (Soma et al., 2000). Taken together, the data suggest that (a) the avian brain is sensitive to steroids, (b) these steroids can gain access to neural tissue from the periphery but can also be synthesized in the brain, despite being undetectable in plasma, (c) neurally derived androgens are associated with changes in avian aggressive behavior, and (d) this association can occur via the local synthesis of androgens and estrogens within discrete loci of the avian brain.
In mammals, the link between brain-derived steroids and aggression is suggested, but less unequivocally. In some species, such as the Siberian hamster (Phodopus sungorus) and deer mice (Peromyscus maniculatus), territorial aggression persists in the non-breeding season despite low undetectable levels of circulating androgens (Trainor, Martin, Greiwe, Kulhman, & Nelson, 2006; see Munley, Rendon, & Demas, 2018). Indeed, in Siberian hamster, circulating levels of DHEA do not appear to change or even increase following the onset of short photoperiods, suggesting that the brain continues to have a source of androgens (and androgenic precursors) during short days (Rendon, Amez, Proffitt, Bauserman, & Demas, 2017). This neural source of androgen may serve as a rich source of other androgens and even estrogens within circumscribed brain nuclei. While changes in the neural levels of these steroids remain to be demonstrated, one striking observation is that levels of estrogen receptor (ERα) increase in brain areas associated with aggression, but not in those associated with reproduction (Munley et al., 2018). Specifically, in the Siberian hamster brain, ERα increases in the lateral septum and bed nucleus of the stria terminals, but not in the preoptic area or the arcuate nucleus, suggesting that neural substrates for aggression may experience dramatic changes in local levels of E2 during the non-breeding season (Rendon et al., 2017). Similar changes have been reported in deer mice, where both ERα and ERβ appear to increase in the BnST in concord with increases in aggression during the non-breeding season (Trainor, Rowland, & Nelson, 2007).
Thus, in some birds and mammals, brain-derived androgens and estrogens, apparently synthesized from a peripheral androgenic precursor (DHEA), appear to be important modulators of aggressive behaviors during times of the year when gonadal steroids are low or completely unavailable. Emerging evidence strongly suggests that the suite of behaviors modulated by peripheral and centrally derived steroids has moved outside the realm of reproduction and aggression and now includes many more behaviors, including mood, balance, energy storage, and memory, among others.
Neural Estrogens, Learning, and Memory in Songbirds and Mice
The conversion of circulating hormone precursors to neurally active steroid hormones within circumscribed loci of the vertebrate brain has been known for decades. Over 35 years ago, Maclusky and Naftolin (1981) definitively described the presence of the enzyme aromatase in the rodent hypothalamus and the critical role of this synthesis of estrogens on the developing masculine brain. Around the same time, aromatization within hypothalamic circuits was shown as critical for the activation of male sexual behaviors (Schumacher & Balthazart, 1983, 1984). Together, these studies laid the foundation for what was to be an explosion of work describing the synthesis of estrogens in the brain and the importance of this central aromatization for non-reproductive behaviors, including learning and memory.
Studies on songbird species have been particularly advantageous in understanding the role of centrally synthesized estrogens on aspects of learning. The fact that peripheral estrogens were involved in aspects of song learning was suggested some time ago (Marler, Peters, Ball, Dufty, & Wingfield, 1988). Shortly thereafter, observations that some species that learned song expressed very high levels of aromatase in discrete telencephalic loci and at least in one such species, the brain was the major source of neural and circulating E2, suggested the possibility that neural aromatization may play a role in aspects of song discrimination and learning (Schlinger & Arnold, 1991, 1992). The precise function of neural aromatization on singing behavior, however, appears to have less to do with singing behavior per se and more to do with song recognition and discrimination—critical components of the social aspects of singing.
Remage-Healey, Maidment, and Schlinger (2008) definitively demonstrated a role for centrally derived E2 in the social interactions of zebra finches (Taeniopygia guttata). More specifically, males who interacted with females demonstrated rapid increases in local levels of E2 in the caudiomedial nidopallium (NCM), part of the auditory forebrain in birds. The same researchers went on to show that E2 synthesized in the NCM strengthened auditory encoding in adult birds, demonstrating for the first time a direct link between auditory discrimination and neural steroidogenesis in any species (Remage-Healey, Coleman, Oyama, & Schlinger, 2010). It is apparent that this influence on encoding may have important effects on the underlying physiology of song learning. Patterns of auditory-evoked activity and sensory coding accuracy are higher in birds actively engaged in the process of song learning as opposed to juveniles who have passed this stage in the process (Vahaba, Macedo-Lima, & Remage-Healey, 2017). Further work is necessary to elucidate the precise role(s) of brain estrogens in this complex form of learning.
Songbirds and other animals demonstrate another form of complex memory function—the memory for location or spatial memory, and evidence strongly suggests a role for neural aromatization within extremely circumscribed neural loci in the regulation of this type of memory. More specifically, Oberlander, Schlinger, Clayton, and Saldanha (2004) first suggested that spatial memory may be affected by neural aromatization in adult male zebra finches as evidenced by the fact that castrated birds with peripheral implants of T or E2 showed evidence of strong spatial memory relative to those implanted with blanks or the non-aromatizable androgen, dihydrotestosterone (DHT). The idea that aromatization within the hippocampus (HP), a telencephalic locus critical for spatial memory function across vertebrates, may prove key in the observed E2-dependent memory function was strongly supported by the observation of extremely high expression of the aromatase enzyme within this part of the brain, particularly at synaptic loci (Saldanha, Popper, Micevych, & Schlinger, 1998; Saldanha et al., 2000; Peterson, Yarram, Schlinger, & Saldanha, 2005; Rohmann, Schlinger, & Saldanha, 2007). These observations taken together suggested an influence of HP-derived E2 on the synaptic substrates of spatial memory in songbirds.
Bailey, Ma, Soma, and Saldanha (2013) provided the first empirical support for this hypothesis. Specifically, adult male zebra finches in which HP aromatase was locally and discretely inhibited showed compromised spatial memory function relative to controls. Perhaps more surprisingly, spatial memory performance in birds with low levels of E2 in the HP was similar to that of birds that received chemical lesions of the HP (Bailey et al., 2013). Importantly, inhibition of HP aromatase resulted in lower levels of HP E2, but did not affect neural levels of E2 in the NCM or the hypothalamus. Taken together, these data strongly argued for the influence of local aromatization in the HP on spatial memory in this species. This same group replicated these findings in a later study and went on to show that the influence of aromatization in the HP was due to E2 provision and involved the action of E2 on the membrane form of the ER–GPER1 (Bailey et al., 2017).
Which precise stage of memory function is affected by HP aromatization remains to be understood. However, research in mice is beginning to suggest a role for HP aromatization on consolidation as opposed to encoding and retrieval. In adult ovariectomized mice, inhibition of HP aromatase just after exposure to the spatial memory task results in compromised memory function relative to controls (Tuscher et al., 2016). These data support the idea that HP aromatization may support the consolidation of memories encoded during early exposure to the spatial memory task. Importantly, there is some evidence supporting the idea that HP levels of E2 actually increase upon learning of a spatial memory task (Frick, Tuscher, Koss, Kim, & Taxier, 2018), supporting the idea that neural levels of steroidogenesis may modulate aspects of complex memory function and behavior in several animal models.
There is now compelling evidence supporting the fact that steroidal precursors can be biochemically converted to neuroactive steroids within the brain of several vertebrates. These include progestins, androgens, and estrogens. While the precise link between neurosteroidogenesis and behavioral phenotype is emerging and convincing, much more work needs to be done to understand the precise role of brain-derived steroids on the formal aspects of behavior and the vertebrate brain.
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