Permanence of brain sex differences and structural plasticity of the adult brain

Abstract

Sex differences in brain structure have been widely recognized since the pioneering studies of Raisman and Field (1). For the most part, brain sex differences are thought to arise in perinatal development through the actions of testosterone secreted by the developing testes, and these sex differences are believed to persist in the absence of gonadal hormones in adult life, very much like the basic plan of the male and female reproductive tracts, which are also developmentally determined. As shown in Fig. 1, the basic plan of brain and body sex differences is the result of a cascade of events beginning with the role of the sex-determining genes in sexual differentiation and continuing with the actions of hormones in embryonic, neonatal, peripubertal, and adult life. The emphasis on early developmental programming of brain structural sex differences was reinforced over several decades by the long-standing view that the brain is not capable of significant structural changes in adulthood. However, this view is changing, and in this issue of the Proceedings, Cooke et al. (2) describe a brain sex difference controlled entirely by circulating androgens. The postereodorsal nucleus of the medial amygdala is larger in male rats and females, but castration of adult males causes the volume of the nucleus to decrease to female levels within 4 weeks, whereas testosterone treatment of adult females for 4 weeks enlarges volume of this nucleus to male levels. Not only is the volume of the anatomical nucleus affected, but the individual cell soma areas are also increased in size by androgen, irrespective of genetic sex of the animal. These interesting findings are not as heretical as they might have seemed a few years ago, and they should be interpreted in light of new evidence for the structural plasticity of the adult brain at different levels of neuroanatomical and functional analysis in relation to the actions of circulating androgens, estrogens, and glucocorticoids. Moreover, as the authors point out, the findings of this new study also raise interesting issues pertaining to the interpretation of sex differences found in the human brain.Adult Neuronal Plasticity in Sexually Dimorphic Systems. Hormone actions in the adult brain affect not only neurochemistry but also structure of nerve cells in meaningful ways, and this realization constitutes a paradigm shift in our thinking about the plasticity of the adult brain. The first recognition of this came from studies on some of the recognized sexually dimorphic systems of the brain, in which adults treated with hormones showed sex-specific morphological changes. For example, androgen actions in the adult spinal nucleus of the bulbocavernosus (SNB), which innervates the penis, regulate both size and functional connectivity of these motor neurons, even though a significant part of the size of this nucleus is determined by developmental events (3, 4). Moreover, estrogen actions in the ventromedial nucleus of the adult female hypothalamus induce new synapses (5-7), and these effects ...

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…Developmental origins of sex differences. The failure of estradiol to induce hippocampal spine formation and up-regulate transmission in the septo-hippocampal cholinergic projections in the male brain is dependent on the aromatization of testosterone and estradiol exposure in the neonatal period (Luine et al, 1986;McEwen, 1999;Mitsushima et al, 2009a). This is evidence that masculinization of the hippocampus occurs in much the same way as the hypothalamus, and predicts that responsiveness to estrogen will be suppressed in adulthood.…”

“…Relatively few studies have made direct comparisons of males and females, but in some tests of hippocampal spatial discrimination (the Morris watermaze), hormone treatment of gonadectomized mice revealed that estradiol selectively impaired performance in females but had no effect in males (Fugger et al, 1998). Several reports suggest that functional sex differences are related to organizational influences in early development (Roof, 1993a,b;McEwen, 1999;. For example, exposure to high levels of estradiol during development improves (masculinizes) spatial behavior in adult female rats to levels seen in normal males (Williams and Meck, 1991).…”

“…Structural, neurochemical, and electrophysiological correlates of learning and memory. Many studies report clear sex dimorphisms in hippocampal structure and morphology in several species (rodents, nonhuman primates, and humans) that are thought to be related to functional differences (Roof, 1993a,b;McEwen, 1999;Swaab et al, 2003;Romeo et al, 2004). In very simple terms, the hippocampal formation comprises the dentate gyrus, which receives the main hippocampal input from the entorhinal cortex; the flow of information proceeds to the CA3 region, then the CA1 region and subiculum, with the main outflow arising from the latter two regions.…”

Toward discovery science of human brain function

“…However, global variables such as these do not explain the regionally specific sex-related phenomenon noted in the present work. Hormonal effects (e.g., estrogen), operating both during brain development (40) and acutely (41), are known to have regional specificity (42), making them potential contributors to the differences observed. Given the discovery nature of the present work and the lack of prior coordination among centers, the specific sex differences that we observed should be interpreted with caution until replicated in an independent sample.…”

Commentary: The Ever-Changing Brain

“…Circulating hormones also play a significant role in structural remodeling of the undamaged adult brain, as exemplified by androgen induced synaptic remodeling of the spinal cord (Rand and Breedlove 1995), ovarian hormone-induced synapse turnover in hippocampus (Yankova et al 2001), and stress-induced remodeling of dendrites in hippocampus (Magarinos et al 1996). Even some sex specific changes in neuronal structure and connectivity may be the product of hormone actions in adult life, rather than solely due to early developmental influences (Cooke et al 1999;McEwen 1999).…”