Sex differences in neurotransmitter systems.

Sex differences in behaviors and other centrally regulated processes have inspired research on structural differences in the brain that might underlie these functional differences. Structural sex differences have been found at almost every level in the brain (1-3). The manner in which such structural differences contribute to functional sex differences is only clear in some cases, notably in sex differences found in the spinal cord and lower brainstem, which contain motomeurons that innervate sexually dimorphic muscles. For example, rats have perineal muscles that are only present in males. These muscles contribute to erection, ejaculation and the deposition of a copulatory plug. They are innervated by motomeurons in the spinal dorsolateral nucleus and the nucleus of the bulbocavemosus, which contain about three times as many motomeurons in males as in females (4). It is more difficult to understand how structural sex differences at higher levels of the brain contribute to functional differences, even when such differences are found in areas implicated in sexually differentiated functions. For example, in songbirds, males typically sing, but females do not. This difference seems to be reflected in song control nuclei which, in males compared to females, are generally larger with more and bigger cells that have more extensive dendritic trees covered with more synapses (5). How most of the song nuclei contribute to song is, however, still largely unknown. Even less well understood are the well documented sex differences in the medial preoptic area (POA) of the rat in, for example, the size of nuclei, cell density, arborization and connectivity (6). Since the POA has been implicated in the regulation of male sexual behavior, it has been suggested that these differences might underlie sex differences in the regulation of male sociosexual behavior, but this suggestion has never been substantiated (6, 7). At least three factors make it difficult to relate structural sex differences in the brain to sexually dimorphic functions. First, sexually dimorphic structures are always found in areas implicated in more than one function. For example, the POA not only regulates male sociosexual behavior, but also female sexual behavior, gonadotropin release, body temperature, osmolarity of extracellular fluids, and sleep rhythms (8). Since many of these functions are sexually differentiated, it is hard to estimate the relative impact of the observed sex differences on each of these functions. Secondly, the connectivity of sexually dimorphic areas is often poorly documented. It is, therefore, often unknown which other brain areas might be influenced by a given sex difference. For example, the medial preoptic nucleus (MPN) of the rat may be one of the best studied sexually dimorphic areas in the brain, yet, many questions remain about its connections. Its central part, which is live times larger in males than in females, is still so small that it is almost impossible to limit tracer injections to that part (9, 10). Also, many questions remain as to the connections of the different neurotransmitter systems that either originate in, or innervate the MPN (11). Thirdly, not many of the reported structural sex differences are dramatically influenced by sex steroids in adulthood, although many of the sexually differentiated functions are so influenced (7). This makes it more difficult to identify which cellular systems in a sexually dimorphic area could contribute to functional sex differences. For example, the size of the central part of the MPN depends on the perinatal presence or absence of androgens, as does the tendency of a rat to display male sexual behavior. However, whereas the size of the central part is not notably influenced by castration in adulthood (6), male sexual behavior is strongly influenced. Studying the neurotransmitter systems that originate in, or innervate sexually dimorphic areas may help in relating structure to function, as many neurotransmitter systems are sensitive to sex steroid levels in adulthood. Neurochemical studies have revealed that, in certain areas, neurotransmitter synthesis, content and metabolism is sexually differentiated and under the influence of sex steroids in adulthood (12, 13). The results of such studies could, therefore, suggest which neurotransmitters might be involved in sexually dimorphic functions. However, since such studies often use homogenized brain tissue, they lack adequate anatomical resolution and, consequently, fail to close the gap between structure and function. This is rapidly changing, now neurotransmitter synthesis, content and receptors can be studied with histochemistry, immunocytochemistry, in situ hybridization and receptor autoradiography. These techniques have revealed sex steroid effects on neurotransmitter systems in development and adulthood that can be compared to similar effects of sex steroids on function regulated by the brain. Their anatomical