Double duty for sex differences in the brain

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1 Behavioural Brain Research 92 (1998) Double duty for sex differences in the brain Geert J. De Vries *, Patricia A. Boyle Program in Neuroscience and Beha ior and Department of Psychology, Uni ersity of Massachusetts, Amherst, MA , USA Abstract Sex differences have been found in the anatomy of brains of a wide variety of vertebrates including humans. Common lore tells us that sex differences in the brain cause sex differences in behavior. This review entertains the possibility that sex differences in the brain may also do the exact opposite. Specifically, sex differences may allow males and females to display remarkably similar behaviors, despite major differences in their physiological and hormonal conditions. First, the difficulties in interpreting the relationship between structure and function will be illustrated by discussing the role of the sexually dimorphic medial preoptic area (MPOA) in male sexual behavior and parental behavior. Second, the sexually dimorphic vasopressin innervation of the brain will be presented as a system that appears to promote as well as prevent sex differences in behavior. Finally, basic and clinical aspects of sex differences in human brains will be discussed Elsevier Science B.V. All rights reserved. Keywords: Sexual dimorphism; Preoptic; Parental; Vasopressin; Amygdala 1. Introduction Historically, sex differences in the brain have been interpreted according to the views in vogue at the time of discovery. During the 19th-century anatomists regarded the lower average weight and more symmetrical anatomy of female brains as proof of the inferiority of the female intellect [36,78]. This type of thinking may have tainted research on sex differences in the brain by adding a political bent to an otherwise scientific endeavor. Nevertheless, research on sex differences resurged in the 1970s focusing on a politically less charged topic: the neural basis of reproductive behaviors and related functions [39,68]. Sex differences in structures involved in reproduction were typically associated with sex differences in the functions regulated by those structures. Consequently, such sex differences were believed to help solve the question of how brain structure contributes to brain * Corresponding author. Present address: Center for Neuroendocrine Studies, Tobin Hall, Box , University of Massachusetts, Amherst, MA , USA. Tel.: ; fax: ; devries@psych.umass.edu function. For example, sex differences in the medial preoptic area (MPOA), e.g. in the size of certain cell clusters, or the distribution of certain transmitters, have often been linked to sex differences in male sexual behavior. Sex differences in the ventromedial hypothalamic nucleus have been linked to sex differences in female sexual behavior and sex differences in the anteroventral portion of the periventricular nucleus have been linked to sex differences in the regulation of gonadotropic hormones [34]. These associations perpetuate the idea that sex differences in the brain generate sex differences in functions regulated by the brain. More recently, sex differences have been found in brain areas that are not clearly related to reproductive functions and behaviors. For example, several studies have reported sex differences in the corpus callosum [2,23,46], kindling speculation on a relationship between these differences and differences in cognitive abilities. Clearly, the notion that sex differences in structure cause sex differences in function has remained the prevailing viewpoint. The alternative possibility, that sex differences in brain structures may actually prevent sex differences in function, appears counterintuitive /98/$ Elsevier Science B.V. All rights reserved. PII S (97)

2 206 G.J. De Vries, P.A. Boyle / Beha ioural Brain Research 92 (1998) The relationship between structural and functional sex differences in the brain 2.1. Sex differences in brain structure It is difficult to assess whether a given sex difference produces or prevents sex differences in functions regulated by the brain, or does both simultaneously, simply because the structure-function relationship is only known superficially for most brain areas. In the spinal cord, a number of sex differences have been found in clusters of motor neurons that can be convincingly related to sex differences in function, because the size of these clusters correlates with the size of the sexually dimorphic muscle systems that they innervate [12,47]. From the hindbrain on up, however, it becomes progressively more difficult to determine exactly what differences in structure signify. Recent advances in tracing the descending pathways to motor neurons involved in specific components of male and female sexual behavior, mounting and lordosis, may lead to linking sexually dimorphic brain structures directly to sexually dimorphic behavior [62,84,85]. However, most known sex differences in the brain are not clearly connected to these descending pathways. One example is a condensation of cells found at the caudal aspect of the rat MPOA that is several times larger in males than in females, the sexually dimorphic nucleus of the MPOA (SDN) [39]. Similar differences have been found in the MPOA of other mammalian species, including humans [1,19,77,82]. Because the MPOA is essential for male sexual behavior, the conclusion that more tissue in the MPOA equates with a higher probability that an animal will show male sexual behavior almost forces itself on the observer. However, there is little to no evidence that the sexually dimorphic cell clusters in the MPOA are essential for male sexual behavior. For example, lesions in these cell clusters in rats or ferrets produce little to no decrements in male sexual behavior [5,17,83]. It is, therefore, impossible to point out if or how the size difference in the SDN contributes to the sex difference in male sexual behavior Inconsistencies in the correlation between morphological and functional sex differences The significance of sex differences in the size of cell clusters in the MPOA becomes even more ambiguous, considering that the MPOA has been implicated in many other functions that show no or very different sexual dimorphism. For example, the MPOA is also essential for parental behavior in males as well as females [65,71]. Although parental behavior shows sex differences, these differences do not correlate with sex differences in the MPOA as do sex differences in male sexual behavior. Typically, a virgin female does not show parental responsiveness toward pups. Parental responsiveness increases gradually during pregnancy and at about days before parturition, females show all aspects of maternal behavior. [14,55,70]. This increase appears to be caused by the rise in estrogen and prolactin levels in late pregnancy and by the sudden drop in progesterone levels after birth [13,72]. Like female rats, male rats are not naturally responsive to pups, but they can be induced to show parental behavior as juveniles if they are repeatedly exposed to pups. Unlike female rats, however, most male rats lose the ability to become parentally responsive even after exposure to pups that lasts long enough to induce parental responsiveness in virgin female rats [15,54]. The difference in parental responsiveness between males and females may be associated with sex differences in the MPOA. Considering the facilitating influence of the MPOA on parental behavior, the larger cell clusters in the MPOA in males than in females remain puzzling. Some comparative studies suggest that, rather than the direction of differences, the extent of the dimorphism of the MPOA correlates with the dimorphism in parental behavior. For example, the sex difference in the size of the MPOA is bigger in montane voles (Microtus montanus) than in prairie voles (Microtus ochrogaster) [74]. In montane voles, parental behavior appears to be sexually dimorphic: only females provide parental care. However, in prairie voles, apart from nursing, there are no major qualitative or quantitative differences in parental care between males and females [56]. In addition, in the California mouse, Peromyscus californicus, in which mothers and fathers take care of the young, the difference in the size of the MPOA is larger between virgin males and females than between fathers and mothers [40]. Gerbils, however, break this pattern. Although male and female gerbils provide parental care [6], the MPOA contains one of the most extremely sexually dimorphic cell clusters found in mammals, namely, the sexually dimorphic area, pars compacta. This structure is found in males, but not in females [19]. Like the SDN in rats and ferrets, the pars compacta is not essential for male sexual behavior, even though the adjacent medial and lateral sexually dimorphic areas are [92]. There are no studies that have tested the involvement of this cluster in parental behavior, however. The studies on the involvement of cell clusters in the MPOA in reproductive functions are difficult to compare between species, because it is often unclear whether sexually dimorphic clusters are homologous. In addition, it is not clear which specific components of the MPOA are involved in parental behavior. Structural dimorphism in brain areas that process accessory olfactory information can be more easily related to sex differences in parental behavior. In virgin female rats, pheromonal stimuli picked up by the

3 G.J. De Vries, P.A. Boyle / Beha ioural Brain Research 92 (1998) vomeronasal system appear to inhibit maternal behavior. When exposed to pups, virgin females with severed vomeronasal nerves start showing maternal behavior faster than females without such lesions [38]. The same is true for lesions of the olfactory and accessory olfactory bulbs, which receive vomeronasal input and for the bed nucleus of the accessory olfactory tract and the medial amygdaloid nucleus (MA), which receive input from the accessory olfactory bulbs [25,37,38]. These nuclei and the posteromedial division of the bed nucleus of the strict terminalis (BST), which also receives direct input from the accessory olfactory bulb, are all larger in males than in females [18,24,42,61]. In both sexes, lesions of these nuclei facilitate parental behavior [25,37,38,45,57]. Therefore, the larger size in males appears to correlate with a greater inhibition of parental responsiveness in males than in females. However, the opposite correlation found in sex differences in the size of cell clusters in the MPOA and the sex difference in parental behavior suggest that this correlation may be coincidental, especially because recent data suggest that the MPOA facilitates parental behavior in males [69]. Another source of confusion is that many of these sexually dimorphic areas have been implicated in functions other than male sexual behavior and parental behavior; for example, the regulation of autonomic processes, which does not show major sex differences [44,81]. 3. Neurochemical analysis of sexually dimorphic brain areas 3.1. Sex differences in neurotransmitter systems To understand the function of sex differences in brain structure at the same level that the sex differences in the spinal cord are understood, the components that make up these structures and their connections must be identified. Although the complexity of the brain appears to prohibit this level of understanding, the identification of neurotransmitter systems in sexually dimorphic structures has helped in testing hypotheses as to the function of these sexually dimorphic systems. For example, sex differences in the distribution of cholecystokinin-producing and cholecystokinin-receptive cells in the hypothalamus have been linked to sex differences in lordosis behavior [67]; also, sex differences in the distribution of dopamine, substance P, enkephalin and dynorphin-roducing cells have been linked to sex differences in the regulation of gonadotropic hormones [76]. These and other differences that may be linked to sex differences in reproductive functions are reviewed extensively in Refs. [67,76,3,26,41]. The sex difference in the vasopressin projections from the BST and medial amygdaloid nucleus may serve as an example of the type of insight that studying sex differences in neurotransmitter systems can offer. The BST and medial amygdaloid nucleus contain many sex differences in cell density, synapse distribution, neurotransmitter receptor distribution and neurotransmitter content, which have been linked to sex differences in the control of reproductive functions [24,42,61,64]. Recent studies on the vasopressin projections of these nuclei in rats and voles, however, suggest that sex differences in the amygdala and BST do not necessarily cause sex differences in function Sex differences in asopressin inner ation of the brain Vasopressin cells are found in the amygdala in a band stretching from the dorsolateral aspect of the medial amygdaloid nucleus to the ventromedial aspect of the central nucleus of the amygdala. In the BST, vasopressin cells are found in the intermediate and lateral zone of the posteromedial division and the caudomedial aspect of the lateral division of the BST [16,28,86]. Males have two to three times as many cells in these areas as females [27,32,60,79,87,88]. Correspondingly, males have vasopressin-immunoreactive projections that are two to three times as dense as do females (Fig. 1) [27,30]. These projections innervate subcortical forebrain areas such as the lateral septum, lateral habenular nucleus, the ventral pallidum, midbrain areas such as the periaqueductal grey, the ventral segmental area, dorsal raphe and hindbrain areas such as the locus coeruleus [28]. These are all multimodal areas. Although most of the areas have been implicated in reproductive functions, they have also been implicated in a staggering number of other functions that show no or much less obvious sex differences [66]. The multimodal nature of the areas innervated by vasopressin fibers suggests that vasopressin fibers influence many functions at the same time. Indeed, vasopressin itself has been linked in a variety of functions and behaviors, ranging from learning and memory to reproductive behavior, and from thermoregulation to the regulation of blood pressure [20,33,35,52]. The vasopressin projections are remarkably responsive to gonadal steroids. After 1 week gonadectomy, BST and MA cells have lost most of their vasopressin mrna. It takes months, however, before all immunoreactivity is lost from BST and MA projections [29,28,31,58,59,87]. Although vasopressin expression in the BST and MA depends on gonadal hormones in both sexes, the sex difference in vasopressin expression does not disappear if males and females are given similar hormone treatment. Rather, the presence or absence of testosterone early in development determines the number of cells that produce vasopressin, as well as

4 208 G.J. De Vries, P.A. Boyle / Beha ioural Brain Research 92 (1998) Fig. 1. Microphotographs of the lateral septum (LS) of a female (left) and a male (right) stained immunocytochemically for the presence of vasopressin. Note the denser vasopressin immunoreactive fiber plexus in the male lateral septum. the amount of vasopressin mrna that each cell expresses [32,88] In ol ement of asopressin in sexually dimorphic functions At first glance, the sexually dimorphic character and steroid responsiveness of the vasopressin projections of the BST and MA suggest that these projections are involved in sexually dimorphic functions that respond dramatically, albeit gradually, to gonadectomy. Male sexual behavior fits this mold [21] exceptionally well, considering that male sexual behavior also depends on testosterone metabolises the same way that expression of vasopressin in the BST and amygdala does. Estradiol, which is an estrogenic metabolise of testosterone [63], partially restores vasopressin immunostaining in castrated male rats, while 5 -dihydrotestosterone, which is a non-aromatizable, androgenic metabolise of testosterone [53], does not restore vasopressin immunostaining. However, a combination of 5 -dihydrotestosterone and estradiol does enhance vasopressin immunostaining [31]. Similarly, estradiol but not 5 -dihydrotestosterone stimulates male sexual behavior in castrated rats. However, only when estradiol is given together with 5 -dihydrotestosterone does it fully restore male sexual behavior in castrated rats [9]. Vasopressin agonists can indeed reverse the decline in sexual behavior after castration [11]; however, injections of vasopressin into the lateral septum do not dramatically alter sexual behavior [50,51]. The sex differences in vasopressin fibers can be more easily linked with intermale aggression than with male sexual behavior. Like male sexual behavior, intermale aggression is not only sexually dimorphic, but it also declines gradually after castration [22]. Injections of vasopressin into the lateral septum and medial amygdala stimulate intermale aggression and counters its decline after castration [50,51]. Therefore, the higher density of vasopressin fibers in the lateral septum of males fits with higher levels of aggression found in male rats Role of asopressin in functions that are not clearly sexually dimorphic Contrary to the role of vasopressin in intermale aggression, the recent claim that vasopressin boosts social recognition memory fits poorly with the sex differences found in vasopressin projections. In rats, there are no strong sex differences in social recognition memory, nor does castration attenuate social recognition memory [10]. However, vasopressin fibers appear to play an extremely sexually dimorphic role in social recognition memory: vasopressin antagonists injected into the lateral septum block social recognition memory in males, but not in females [10], suggesting that endogenous vasopressin is essential for social recognition memory in males, but not in females. It is not intuitively clear why social recognition memory may have different neurochemical underpinnings in males and females. However, lateral septal cells must be sexually different in the way they are influenced by androgen levels because the lateral septum has a very high concentration of androgen receptor-containing cells [93] and androgen levels are higher in males than in females. Although the lateral septum may be a site where androgen influences steroid-responsive functions,

5 G.J. De Vries, P.A. Boyle / Beha ioural Brain Research 92 (1998) it is unclear what the impact of androgen receptors is on functions regulated by the septum that do not appear to be strongly influenced by gonadal steroids. It may be that the denser innervation of vasopressin in males may be used by the lateral septum to compensate for the differences induced by androgen actions on septal cells, thereby, preventing sex differences in functions regulated by the lateral septum such as social recognition memory Role of asopressin in parental beha ior Recently, we have studied bi-parental behavior, a case in which the need for such compensatory mechanisms appears more obvious. In most mammals, parental behavior is strictly shown by females. In some rodent species, however, males and females participate in parenting [49]. Without pregnancy and its associated hormonal changes, paternal behavior must be induced through different mechanisms than is maternal behavior. In addition, parental males and females face different physiological challenges, for example, males do not lactate. Therefore, neural circuits involved in parental behavior may be affected in a sex-specific manner. Such circuits may need to differ to guarantee a similar behavioral output between males and females. Comparative studies using animals with different reproductive strategies suggest that the sex differences in the vasopressin projections of the BST and amygdala may indeed promote similar parental behavior in males and females. In prairie voles (M. ochrogaster), sexually naive males show spontaneous parental responsiveness. Mating, however, considerably increases paternal responsiveness [8]. Perhaps not coincidentally, mating also changes the expression of vasopressin in the BST and amygdala projections. The density of the vasopressinir projections in prairie vole males decreases after mating, then increases gradually during the gesta- Fig. 2. Vasopressin-ir fiber density in the lateral septum of prairie and meadow voles that were either sexually naive (closed bars) or parental (open bars). Greek letters indicate significant differences among groups (ANOVA, P 0.001). Bars: means S.E.M. Fig. 3. Vasopressin mrna labeling in the bed nucleus of the strict terminalis in prairie voles (top panels) and meadow voles (bottom panels). In both species, males (left panels) show more labeled cells and more labeling per cell than females (right panels). Only in prairie vole males, however, does the vasopressin mrna labeling increase after mating. Bar=50 m. tion period only to decrease again after the birth of pups [8]. The initial drop in vasopressin-immunoreactive fiber density after pairing may reflect an increase in vasopressin release, because it coincides with higher levels of vasopressin messenger RNA in the BST [90]. Similar effects were absent in female prairie voles. They were also absent in male and female meadow voles (Microtus pennsyl anicus), in which only females provide parental care (Figs. 2 and 3) [7,90]. Injections of vasopressin into the lateral septum of naive male prairie voles provided further evidence that vasopressin plays a role in paternal behavior. These injections stimulated grooming, crouching over and nestling with pups, the most prominent paternal activities displayed by parental prairie voles. In addition, injections of a V1 a receptor antagonist blocked these behaviors (Fig. 4) [89]. The absence of changes in the

6 210 G.J. De Vries, P.A. Boyle / Beha ioural Brain Research 92 (1998) Fig. 4. Time spent on paternal behavior by male prairie voles injected into the septum with saline followed by vasopressin (saline/avp) or a V1 a antagonist followed by vasopressin (antagonist/avp, t-test, P 0.05), and by voles injected twice with saline (saline/saline) or with a V1 a antagonist followed by saline (antagonist/saline, t-test, P 0.001). Bars: means S.E.M. vasopressin system in females suggests that the sex difference in the vasopressin innervation of the lateral septum may indeed function to allow males to show a similar behavioral response to pups as do females. The challenge is to figure out how vasopressin can prevent sex differences in some functions (for example, social recognition memory) while contributing to sex differences in others (for example, aggressive behavior). Similar challenges may present themselves in understanding sex differences in other systems that are involved in diverse functions, some sexually dimorphic, others not. The sex difference in cholecystokinin systems in the brain is one example. Those systems have been implicated in female sexual behavior but also in food intake, which does not show nearly as dramatic a sex difference as does female sexual behavior [73,91]. How one neurotransmitter system may play both roles at the same time can only be understood fully when certain conditions are met: one should know which neural systems are necessary for generating the functions that are sexually dimorphic; which are necessary for functions that are not; and where and how the functions of each system influences the functions of the other systems. Even though this is a Utopian goal, our current understanding still allows us to make inferences about the role of sex differences in human brains. 4. Sex differences in human brains That structural sex differences may promote as well as prevent sex differences in behavior and other functions regulated by the brain is probably true for human brains as well as for animal brains. Human brains show differences in several brain areas, including the corpus callosum, the anterior commissure, the size and shape of the left planum temporale, and in several clusters of neurons in the hypothalamus, and even in neurotransmitter systems [1,2,43,77,94]. Although researchers have tentatively suggested links between these differences and differences in function (for example, in language abilities and visuospatial insight for the corpus callosum and in sexual behavior and sexual orientation for the hypothalamic clusters), these sex differences may also prevent differences in functions regulated by the brain. The effects of stroke strongly support this possibility. Strokes affect language abilities differently in males than they do in females. Frontal lesions cause aphasias more frequently in females, whereas, the opposite is true for temporal lesions, which suggests that there are fundamental sex differences in the organization of cortical function [48]. Fundamental differences in the organization of cortical function were also evident in functional MRI scans obtained from males and females during specific language tasks. These tasks activated the left inferior frontal lobe in males and a more diffuse and bilateral group of areas in the same frontal region in females [75], even though males and females did not differ dramatically in their abilities to execute this task. If sex differences can indeed prevent or cause sex differences in brain-generated functions, the different organization of cortical function may have contributed to the absence of sex differences in these cases. Similarly, sex differences in the corpus callosum and anterior commissure may have caused sex differences in some functions, but the same sex differences may have prevented or minimized sex differences in other functions. Although some of the sex differences in brain organization may actually prevent sex differences in brain output, they may paradoxically contribute to differences seen in behavioral and neurological disorders. For example, the different cognitive deficits seen after stroke reflect different patterns of cortical organization

7 G.J. De Vries, P.A. Boyle / Beha ioural Brain Research 92 (1998) that originally may have served to prevent differences between males and females. In addition, if behavior has similar sex differences in its neurochemical underpinnings in humans as it has in rodents, such differences may contribute to the differences seen in the incidence and expression of behavioral disorders. For example, women are more afflicted by affective disorders than are men [4], whereas, males develop schizophrenia at an earlier age than do females [80]. If the symptoms of these behavioral disorders are indeed caused by the malfunctioning of specific neurotransmitter systems, sex differences in the neurochemical underpinnings of behavior will cause differences in the vulnerability for, and expression of, behavioral disorders. Acknowledgements Research of GJD that was presented in this review was funded by NSF grant IBN and NIMH grant MH References [1] Allen LS, Hines M, Shryne JE, Gorski RA. 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