Sexual dimorphisms in the brain

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Processes Affected by Sex Steroids Sex steroid hormones lead to sexual differentiation of behavior by affecting a wide variety of cellular mechanisms within the nervous system (Cooke et al., 1998). Processes that have been shown to be modulated by sex steroid hormones include neurogenesis (Gurney and Konishi, 1979; Jacobson and Gorski, 1981), cell migration (Sengelaub and Arnold, 1986), growth of the neuronal soma (Breedlove and Arnold, 1981), dendritic growth, differentiation and synapse formation (Frankfurt et al., 1990; Goldman and Nottebohm, 1983; Gomez and Newman, 1991; Gould, Woolley, and McEwen, 1990; Juraska, 1991; Raisman and Field, 1973; Woolley and McEwen, 1992), synapse elimination (Leedy, Beattie, and Bres-nahan, 1987), neuronal atrophy and apoptosis (Davis, Shryne, and Gorski, 1996; McEwen, 1996; Woolley, Gould, and McEwen, 1990), neuropeptide expression (De Vries, 1990; Malsbury and McKay, 1994), the expression of neurotransmitter receptors (Levesque, Gag-non, and Di Paolo, 1989; McEwen, 1991; Turner and Weaver, 1985), and neuronal excitability (Teyler et al., 1980; Wong and Moss, 1992).

Examples of Sexually Dimorphic Brain Regions and Behaviors In mammalian species numerous sex differences in brain structure and function have now been documented. Sexual dimorphic brain areas include a number of regions of the hypothalamus, including the medial preoptic area and the ventromedial hypothalamus, the vomeronasal system, amygdala, bed nucleus of the stria terminalis, hippocampus, striatum, cerebellum, and various regions of the cerebral cortex. Behaviors showing documented sex differences include behaviors associated with reproduction (mating and maternal behaviors), aggression, activity, and various cognitive functions including spatial cognition, verbal skills, and various aspects of learning and memory. Examples of sexually dimorphic brain regions and behaviors in nonmammalian species have also proven to be very important for learning about basic mechanisms governing the establishment and maintenance of sexual dimorphisms, including bird and frog song systems. It is beyond the scope of this chapter to review all of these areas and behaviors. Here, we review areas and behaviors that demonstrate especially useful examples of general principles regarding sexual dimorphisms, or are particularly relevant to the topic of developmental cognitive neuroscience.

The medial preoptic area and sexual behaviors One of the first reports of a sexual dimorphism in a brain structure was by Raisman and Field (1973), who examined the rat medial preoptic area (mPOA; a brain area that plays an important role in the regulation of sexual behaviors) by electron microscopy and found that females had more dendritic spine synapses and fewer axosomatic synapses than males. Moreover, they showed that the synapse structure was modulated by the presence of androgen in the neonatal period. Previous reports had shown that the mPOA plays a role in male copulatory behavior in the rat, that implantation of testosterone into the mPOA of castrated males would restore mating behavior, and that similar implants in females would induce male-like mounting and copulatory behaviors (Madeira and Lieberman, 1995). Thus, this was the first report of a structural difference in the brain induced by a gonadal steroid hormone, one that may underlie a known behavioral effect of that hormone.

Later studies by Gorski and colleagues (1978, 1980) identified a more striking sexual dimorphism in the mPOA. They showed a region of densely packed, darkly staining cells in the mPOA that was 2.5-5 times larger in the male rat than in the female rat—a region they designated as the sexually dimorphic nucleus of the medial preoptic area, or SDN-POA. In both male and female rats this region has the highest concentration of estradiol receptors in the brain (Herbison and Theodosis, 1992), and there is evidence that there are more estradiol receptors in the female than in the male (Brown, Naftolin, and MacLusky, 1992). This area also accumulates androgens to a greater degree in males than in females (Jacobson, Arnold, and Gorski, 1987). The SDN-POA is an excellent example of a nuclear region in which organizational influences of testosterone play a critical role and aromatization of testosterone to estradiol is an important intermediary step. Castration of males in the early neonatal period leads to a permanent decrease in the size of the SDN-POA, whereas treatment of female rats with testosterone in this same time period leads to a permanent increase in size of the SDN-POA (Gorski et al., 1978, 1980). Neonatal treatment with estrogen is even more effective than early androgen treatment in increasing the size of the nucleus, and neonatal treatment of males with an anties-trogen decreases the size of the SDN-POA (Dohler et al., 1984). In this nucleus there is evidence that either androgen or estrogen treatment increases neurogenesis in the early neonatal period (Jacobson and Gorski, 1981), and later prevents programmed cell death (Davis, Shryne, and Gorski, 1996). Despite the abundance of studies on the SDN-POA of the rat, and the profound sexual dimorphism of this nucleus, there is relatively little information about the role of the SDN-POA in mediating behavior. Lesions of the nucleus have been reported to have few behavioral effects (Arendash and Gorski, 1983). Nevertheless, the mPOAhas been shown to have significant sexual dimorphism in a wide variety of species (Ayoub, Greenough, andjuraska, 1983; Com-mins and Yahr, 1985; Hines et al., 1985; Tobet, Zahniser, and Baum, 1986), including humans (Allen et al., 1989; LeVay, 1991; Swaab and Fliers, 1985); thus, there remains a great deal of interest in the possible function of this brain area in mediating sexually dimorphic behaviors.

Other key areas involved in mediating sexual behavior in the rodent are the VMN, the vomeronasal system, and the bed nucleus of the stria terminalis (Cooke et al., 1998). In many cases, these brain areas show sexual dimorphisms in structure. And in many cases gonadal hormones have both organizational and activational activities.

The bird song system Three years after Raisman and Field's report of subtle structural sexual dimorphisms in synapse structure in the mPOA of the rat, Nottebohm and Arnold (1976) published a landmark report showing a much more robust sexual dimorphism in brain structure in songbirds. They found that the nuclei in the vocal control areas of male songbirds (canaries and zebra finches; species in which the male sings but the female does not) were five to six times the size of these same areas in their female counterparts. Later studies showed that species in which both the male and female sing exhibit no sexual dimorphism in these brain areas (Brenowitz, Arnold, and Levin, 1985). Since that time a great deal of research on the bird song system has been performed and there is excellent evidence linking structural differences between sexes with sexual dimorphism of singing behavior (Bottjer and Arnold, 1997).

In zebra finches, both organizational and activational affects of testosterone are apparent, and testosterone works through aromatization to estrogen. When treated with estrogens early in life and then given testosterone or estrogen steroids as adults, female zebra finches will sing in adulthood (Gurney and Konishi, 1979). In the neonatal time period, estrogen treatment increases neuronal number (Gurney and Konishi, 1979). Surprisingly, in zebra finches the converse experiment— castrating males or treating them with anti-estrogens— has not been effective either in preventing structural differentiation of male-like nuclei in vocal control areas or in preventing singing, leading to the proposal that male songbirds may also have a steroid-independent genetic mechanism regulating development of the nuclei in the vocal control areas (Arnold, 1996, 1997).

The neural systems underlying song production in the canary differ from those in the zebra finch in that organizational effects of androgens remain apparent into adulthood. Female canaries treated with androgens in adulthood show structural changes in the nuclei of the vocal control areas, specifically increased dendritic growth, eventually resulting in song production (DeVoogd and Nottebohm, 1981; Goldman and Not-tebohm, 1983). This is a good example of steroid hormones in adulthood causing long-term organizational effects in the brain.

Midbrain dopaminergic systems and motor activity The striatum is part of the midbrain system that plays a critical role in sensorimotor integration. The striatum receives input fibers from the motor and associated cortical areas, as well as from the substantia nigra. The nigrostriatal projection is dopaminergic, containing more than 90% of the dopamine neurons in the brain. When dopamine activity in this pathway is increased, animals display increased motor activity to sensory stimuli, whereas when dopaminergic activity in this pathway is decreased, animals become hyporesponsive to sensory input (Becker, 1991).

In females, estrogen and progesterone modulate the activity of this dopaminergic pathway (Becker, 1999). Female rats have been shown to have greater behavioral activity responses when the striatal dopamine system is stimulated on the evening of proestrous, when circulating estradiol levels are high, compared to the day of diestrous, when circulating estradiol levels are much lower (Becker and Cha, 1989). They also show increases in extracellular dopamine concentration within the striatum, amphetamine-stimulated striatal dopamine release, dopamine metabolism, and increased dopamine receptors on estrous compared to diestrous (Becker, 1990, 1999; Di Paolo, Falardeau, and Morisette, 1988; Levesque, Gagnon, and Di Paolo, 1989). With ovariectomy, stimulated activity is decreased (Camp, Becker, and Robinson, 1986), as well as stimulated strial dopamine release and dopamine receptor density (Becker and Ramirez, 1980; Levesque, Gagnon, and Di Paolo, 1989). Estradiol replacement can reverse these changes, although there are differences with acute versus more chronic estradiol treatment (Becker, 1999).

In male rats, estrogen does not affect striatal dopamine release; in addition, castration has littie effect on this system (Becker, 1999). Comparison of male and female rats shows that there is sexual dimorphism in striatal dopamine release and dopamine receptors. In castrated male rats, basal extracellular dopamine concentrations in the striatum are twice as high as in ovari-ectomized female rats (Xiao and Becker, 1994), and amphetamine-induced dopamine release is also higher in males (Becker and Ramirez, 1980). In addition, male rats have more dopamine D, receptors than do females (Hruska et al., 1982).

It seems likely that these sex differences in activity and ease of activation of the striatal dopamine system play important roles in governing behavior in various circumstances. Becker has postulated, based on studies administering estrogen directly into the striatum, that this system plays a role in pacing the rate of sexual encounters between male and female animals to optimize fertility (Becker, 1999; Xiao and Becker, 1997). One practical implication of these sex differences is that scientists need to be aware that sexual differences in activity may underlie sexual differences that are measured in animal's performances on a variety of laboratory tests, including tests of learning and memory.

The hippocampus and learning and memory Clinical studies showing that lesions of the hippocampus lead to severe memory damage indicate that this area of the brain can play a critical role in learning and memory, specifically with regard to deficits in the formation of new memories (anterograde amnesia; Milner, Teuber, and Corkin, 1968). The hippocampus is known to be influenced both by gonadal steroid hormones and by adrenal hormones, specifically glucocorticoids.

Microstructure within the hippocampus has also been shown to be influenced by early experience and rearing environment (Juraska, 1991). Thus, interactions between these two endocrine systems and experiences of an individual during development combine to result in long-term consequences for this brain area, both in structure and function.

The hippocampus is composed of three distinct regions, connected in a circuit—the dentate gyrus, which has granule neurons that send mossy fibers to the pyramidal neurons of the CA3 region of Ammon's horn, which in turn send collaterals to the pyramidal neurons in the CA1 region. In both males and females, cells in the CA1 region of the hippocampus contain ER (Loy, Gerlach, and McEwen, 1988; Simerly et al., 1990), while ER-P receptors are present in Ammon's horn and the dentate gyrus (Shughrue, Lane, and Merchen-thaler, 1997; Shughrue and Merchenthaler, 2000). Estradiol administration can alter the morphology of neurons in the CA1 region, increasing the number of spines and the amount of branching in apical dendrites and increasing the density of synapses in the hippocam-pal CA1 stratum radiatum, whereas the opposite changes occur with ovariectomy (Gould et al., 1990; Juraska, 1991; Woolley and McEwen, 1992). Progesterone administration initially potentiates the effects of estradiol on neurons in this brain region, but later triggers down-regulation of spines on CA1 neurons (Gould et al., 1990; Woolley and McEwen, 1993). Moreover, naturally occurring changes in estradiol and progesterone across the rat estrous cycle have been associated with changes in synaptic density and dendritic morphology in hippocampal CA1 neurons (Woolley and McEwen, 1992, 1993; Woolley et al., 1990). Estrogen effects on CA1 neurons appear to be mediated by an NMDA receptor-mediated mechanism, in that NMDA receptor antagonists block estrogen induction of spines and estrogen induces NMDA receptors in the CA1 region (Woolley and McEwen, 1994). In the adult rat, the effects of estradiol on the hippocampus are sexually dimorphic, with male rats showing fewer effects on hippocampal synapse formation when treated with estrogen (Lewis, McEwen, and Frankfurt, 1995). This appears to result from organizational effects of androgen (converted to estrogen) on the hippocampus, as treatment of neonatal male rats with an aromatase inhibitor can eliminate this sex difference in adulthood (Lewis, McEwen, and Frankfurt, 1995). Developmental changes in estrogen receptors (O'Keefe and Handa, 1990) and aromatase (MacLusky et al., 1987) have been reported in the hippocampus, and these developmental changes may play a critical role in sexual differentiation of this region of the brain.

There are also functional changes in hippocampal neurons associated with experimentally manipulated or naturally occurring fluctuations in estradiol and progesterone in the female rat. In general, there appears to be an increase in neuronal excitability in the hippocampus with elevated estradiol levels. EPSP duration is lengthened following estradiol administration, and population spike amplitude is elevated in response to estradiol (Teyler et al., 1980; Wong and Moss, 1992). Seizure threshold in the dorsal hippocampus is also lower following estrogen administration to ovariecto-mized female rats or on the day of proestrous in the naturally occurring estrous cycle (Buterbaugh and Hudson, 1991; Teresawa andTimiras, 1968). Long-term potentiation (LTP) in response to standardized stimulus trains has also been shown to be greater in the hippocampus of proestrous rats compared to other times in the estrous cycle (Warren et al., 1995).

Although estradiol receptors do not show sexual dimorphism in their distribution within the hippocampus, there is a sexual dimorphism in glucocorticoid receptors, with female rats having larger numbers of glucocorticoid receptors compared to males (Turner and Weaver, 1985). There is also an interaction between gonadal hormones and the glucocorticoid receptor system such that ovariectomy in females increases glucocorticoid receptors while castration in males has no effects on glucocorticoid receptors (Turner and Weaver, 1985).

Glucocorticoids have significant effects on hippocampal neuronal structure and function. In both the developing and adult rat, adrenalectomy leads to a decrease in size and dendritic arborization of neurons in the dentate gyrus, which can be prevented with adrenal steroid supplementation (Gould, Woolley, and McEwen, 1990; Woolley et al., 1991). In contrast, in the CA3 region of Ammon's horn high levels of glucocorticoids cause atrophy of pyramidal neurons (Woolley, Gould, and McEwen, 1990). Studies by Sapolsky (1990) show that glucocorticoids inhibit glucose uptake by pyramidal neurons, which precipitates atrophy and eventual cell death. These effects of glucocorticoids appear to play a role in the loss of CA3 neurons with aging, in that this loss can be prevented by adrenalectomy (Sapolsky, 1990). Glucocorticoids also lead to atrophy of CA3 neurons in conditions of chronic stress (McEwen, 1996).

In addition to plasticity induced by hormonal signals, environmental conditions during development also have a marked influence on morphology of neurons in the hippocampus, and there are clear sexual dimorphisms in the hippocampal responses to environmental stimuli (Juraska, 1991). For example, granule cells in the dentate gyrus of male rats raised in single cages show relatively few changes in their dendritic morphology as opposed to animals raised in a complex environment containing both toys and other rats. In contrast, these same hippocampal granule cells in female rats show a marked plasticity in response to rearing in a complex environment, with an increase in length of a specific population of dendrites. These sex differences appear to be regulated by organizational influences of testosterone in the neonatal period, in that neonatally castrated males show plasticity equivalent to females (Juraska, 1991).

Numerous reports have indicated sex differences in the processes of learning and memory, particularly learning that involves the use of spatial abilities, a task believed to be strongly dependent on hippocampal function (O'Keefe, 1995). Using a variety of different learning paradigms, including passive avoidance learning, active avoidance learning, and complex maze learning (using the radial-arm maze, T-maze, and Morris water maze), differences have been shown in the performance of male versus female rats (Beatty, 1979; Becker, 1991). In complex maze learning, male rats generally have been found to learn more rapidly and with fewer errors compared to female rats. However, the issue of whether better performance by males results from differences in hippocampal function or from differences in activity, which appear to be governed by other brain systems (as discussed in the previous section; see Midbrain Dopaminergic Systems and Motor Activity), is not clear for some of these tasks. Beatty (1979) argued that females make more errors in many mazes simply because they are more active, and more active motions translate into a greater occurrence of errors. In an attempt to distinguish sex differences in learning from differences in activity, some investigators have focused on the rate of initial learning of a maze compared to that of later maze performance. In one such study, Einon (1980) showed that in a radial-arm maze males were more likely than females to use a successful strategy of visiting adjacent arms. Further studies with this paradigm have shown that males or neonatally androgenized females show faster acquisition of radialarm maze skill compared to females or neonatally castrated males, but that following skill acquisition the sex difference on this task disappears (Williams, Barnett, and Meek, 1990). It thus appears that there may be minor sex differences in the cognitive strategies that rats utilize to solve spatial learning paradigms, although both sexes show equal mastery of these tasks in the end. Further evidence that there are sex differences in hippocampal function comes from studies showing that bilateral hippocampal lesions in female rats lead to far greater impairment of function in the Morris water maze than do the same lesions in male rats (Therrien, 1982).

In humans, there are also reports of sex differences in spatial problem solving abilities, with males showing greater proficiency (Delgado and Prieto, 1996; Linn and Petersen, 1985; Witkin and Berry, 1975). But these differences are small in magnitude, and apparent only in terms of population statistics; there is considerable overlap in ability among individual males and females. It is also important to remember that spatial problem solving is a higher order cognitive task and that there is evidence that sexual dimorphism in this task reflects not only differences in hippocampal function but also functional differences within other regions of the cortex (De Courten-Myers, 1999; Kimura, 1987; Wis-niewski, 1998). There is a small amount of evidence that prenatal androgen exposure may affect spatial problem solving abilities. Resnick and colleagues (1986) reported that females with congenital adrenal hyperplasia (a syndrome involving increased exposure to adrenal androgens in prenatal development) had significantly enhanced performance on tests of spatial ability compared to their unaffected female relatives. However, the effects of sex steroids on this ability do not appear to follow the typical organizational and activational scheme. There is limited evidence that sex steroid hormone levels in adulthood may influence spatial problem solving abilities, with elevated levels of estradiol in females and testosterone in males being associated with lower, rather than higher, performance on tests of spatial ability. Several studies report that women perform worse on tests of spatial problem solving during the midpoint of the menstrual cycle, when estradiol levels are elevated, compared to other times during the menstrual cycle (Broverman etal., 1981; Hampson, 1990a,b; Hampson and Kimura, 1988; Komnenich et al., 1978; Wickham, 1958). Moreover, men with higher testosterone levels have been reported to perform worse on tests of spatial ability than their counterparts with lower testosterone levels (Gouchie and Kimura, 1991; Shute et al., 1983).

Cerebral cortical areas and higher cognitive functions We are still in the very early stages of understanding how sex differences in most higher cognitive functions and complex behaviors are linked to sex differences in the brain. In general, research in this area has suffered from inadequate delineation of the behaviors, the anatomical brain regions, and the functional neural systems that have been studied. Another confound in this area of investigation has been that many of these functions can be studied only in humans (e.g., studies of speech), such that invasive experiments are rarely possible and control of factors such as developmental experiences is much more difficult. With the advent of various neural imaging technologies, however, more information is becoming available concerning sexual dimorphisms in the brain, particularly in the cerebral cortex. Moreover, functional magnetic resonance imaging (MRI) is beginning to link differences in cognitive abilities with differences in specific anatomical regions and patterns of neural circuit activation.

Studies of sex differences in verbal abilities provide examples of the considerable difficulty in delineating the neuroanatomical substrates underlying a sexually dimorphic higher order behavior. A number of reports suggest that women perform better on some verbal tasks than do men (Hines, 1991; Hyde and Linn, 1988). There is limited evidence that this sexual dimorphism is related to sex steroid hormones. Several studies have reported that women's performance on verbal tasks is better when estradiol, or estradiol and progesterone, are elevated during the menstrual cycle than when circulating sex steroid hormone levels are very low (Hampson, 1990a,b; Silverman and Zimmer, 1975; Silverman, Zimmer, and Silverman, 1974; Wickham, 1958). It is important to note that such changes in performance over the menstrual cycle are not seen with all verbal tasks. Rather, there appears to be specificity for the type of task that may be influenced by sex steroid hormones (Hampson, 1990a,b).

In most humans, the left side of the brain is primarily responsible for the control of speech (Springer and Deutch, 1998). However, there is evidence that there may be less hemispheric specialization in women than in men, and it is possible that this sexual dimorphism may underlie the differences between the sexes in verbal abilities. Compared to men, for example, women have been reported to have less perceptual asymmetry in dichotic listening tests (McGlone, 1980) and less asymmetry in the size of the cortex, which leads to naming errors in response to electrical stimulus tests performed during surgeries to map out areas of the cortex involved in speech (Mateer, Polen, and Ojemann, 1982). More recently, using functional MRI, men were shown to have left lateralized inferior frontal gyrus activation in phonological tasks, whereas women were shown to have more bilateral activation in this cortical region when they performed the same phonological tasks (Shaywitz et al., 1995). Unilateral damage to the brain has also been reported to have less devastating consequences for performance on tests of verbal abilities in women compared to men (Inglis et al., 1982; McGlone, 1978). Similarly, Lansdell (1961) found that surgical lesions to the left temporal cortex disrupted performance on a verbal proverb test in men, but not in women. Evidence for organizational effects of prenatal sex steroid hormones on the degree of lateralization of verbal skills was provided by a study by Hines (1982), which found that women whose mothers took diethylstilbesterol (a potent estrogenic compound) in pregnancy to prevent miscarriage had greater lateralization than their nonexposed sisters.

There are also reports of sex differences in the size of cortical regions involved in speech (figure 5.4). Wada and colleagues (1975) reported that the planum temporale (a flat region of the temporal lobe in a language-associated area) is asymmetric, being larger on the left than the right side of the brain, but that this asymmetry was less marked in women than in men. This finding was confirmed in two recent studies (Kulynych et al., 1994; Witelson and Kigar, 1992). More recently, Witel-son, Glezer, and Kigar (1995) have reported that women have a greater density of neurons in this cortical region compared to men. In contrast, however, Rabi-nowicz and colleagues (1999) have found that, compared to females, males have thicker cortex, higher neuronal densities, and more neurons in the left temporal sites involved with language function. In other studies, females have been reported to have larger proportional volumes of gray matter in the dorsolateral prefrontal cortex and superior temporal gyrus compared with males (Schlaepfer et al., 1995), as well as cortex associated with the cingulate sulcus (Paus et al., 1996), and proportionately larger Wernicke and Broca areas (Harasty et al., 1997). At the microscopic level,

Figure 5.4 Sex differences in the proportional cortical volumes in language-related areas of the brain. Data are presented as percentages of brain hemisphere volume occupied by each region. Asterisks indicate a significant differences (P < 0.05) between males and females in the regional volume. (Adapted from Harasty, J., K. L. Double, G. M. Halliday, J. J. Kril, and D. A. McRitchie, 1997. Language-associated cortical regions are proportionally larger in the female brain. Arch. Neurol. 54:171-176.)

Superior Planum Inferior Frontal

Temporal Temporale (Broca)

Figure 5.4 Sex differences in the proportional cortical volumes in language-related areas of the brain. Data are presented as percentages of brain hemisphere volume occupied by each region. Asterisks indicate a significant differences (P < 0.05) between males and females in the regional volume. (Adapted from Harasty, J., K. L. Double, G. M. Halliday, J. J. Kril, and D. A. McRitchie, 1997. Language-associated cortical regions are proportionally larger in the female brain. Arch. Neurol. 54:171-176.)

greater dendritic arborizations in Wernicke's area in females compared to males have been reported (Jacobs, Schall, and Scheibel, 1993).

A third sexual dimorphism that has been proposed to underlie the sexual dimorphism in verbal abilities is the size of the corpus callosum. The corpus callosum is a nerve fiber tract that connects the two cerebral hemispheres, allowing transfer of information between the hemispheres for complex cognitive processing, including language (Hines et al., 1992). In 1982, de Lacoste and Holloway hypothesized that the decrease in functional neural asymmetry in women was due to increased interhemispheric exchange via the corpus callosum. Since that time, sexually dimorphic structural asymmetries of the corpus callosum have been reported for its area, shape, and fiber composition (Wisniewski, 1998). However, the issue of whether there is a consistent sexual dimorphism of this fiber tract has been highly controversial. The splenium is the posterior portion of the corpus callosum that contains fibers projecting between the main auditory and visual cortical areas of the two hemispheres. In humans, a number of postmortem studies and MRI investigations provide support for the conclusion that females have a more bulbous splenium, although it is important to control for the overall corpus callosum shape, chronological age of the individuals, cerebral volume, and handedness when making such comparisons (Allen et al., 1991; Burke and Yeo, 1994; Johnson et al., 1996; Wisniewski, 1998). The isthmus of the corpus callosum connects the parietal and temporal lobes, and has been more consistently reported to have a larger area in women compared to men, although for such comparisons it is again important to control for the same factors as in studies of the splenium (Denenberg, Kertesz, and Cowell, 1991; Steinmetz et al., 1992; Witelson, 1989). Sexual dimorphism in the corpus callosum of several rodent species has also been reported (Wisniewski, 1998), and an important finding in these studies is that environmental rearing conditions can have modulatory effects on the sexual dimorphism of corpus callosum (Juraska and Kopcik, 1988). Another interesting finding of these latter studies is that there are sexual dimorphisms in the ultrastructure of the rat corpus callosum, with sex differences in the number and diameter of axons projecting across the corpus callosum (Juraska and Kopcik, 1988; Kopcik et al., 1992).

Despite the great interest in and numerous studies devoted to the neural underpinnings of sexual dimorphisms in verbal abilities, little information is available regarding the role of sex steroid hormones in mediating the development of these functional differences. Although some investigators using rodent models have shown that neonatal exposure to androgens can masculinize some sexually dimorphic neuroanatomical differences found in the cortex, such as cortical thickness (Lewis and Diamond, 1995), little is known about the effects of sex steroid hormones on the morphology of brain areas specifically involved in language processing or the size or shape of the corpus callosum. However, one principle is clear from studies in other parts of the brain, including the hypothalamus and the hippocampus: There is profound cellular and circuit specificity for the actions of sex steroid hormones. Thus, in making conclusions about the role of steroid hormones on cortical functions, it will be important to be very specific with regard to both function and neuroanatomical substrate.

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