Margaret M. McCarthy
University of Maryland, Baltimore
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Physiological Reviews | 2008
Margaret M. McCarthy
Estradiol is the most potent and ubiquitous member of a class of steroid hormones called estrogens. Fetuses and newborns are exposed to estradiol derived from their mother, their own gonads, and synthesized locally in their brains. Receptors for estradiol are nuclear transcription factors that regulate gene expression but also have actions at the membrane, including activation of signal transduction pathways. The developing brain expresses high levels of receptors for estradiol. The actions of estradiol on developing brain are generally permanent and range from establishment of sex differences to pervasive trophic and neuroprotective effects. Cellular end points mediated by estradiol include the following: 1) apoptosis, with estradiol preventing it in some regions but promoting it in others; 2) synaptogenesis, again estradiol promotes in some regions and inhibits in others; and 3) morphometry of neurons and astrocytes. Estradiol also impacts cellular physiology by modulating calcium handling, immediate-early-gene expression, and kinase activity. The specific mechanisms of estradiol action permanently impacting the brain are regionally specific and often involve neuronal/glial cross-talk. The introduction of endocrine disrupting compounds into the environment that mimic or alter the actions of estradiol has generated considerable concern, and the developing brain is a particularly sensitive target. Prostaglandins, glutamate, GABA, granulin, and focal adhesion kinase are among the signaling molecules co-opted by estradiol to differentiate male from female brains, but much remains to be learned. Only by understanding completely the mechanisms and impact of estradiol action on the developing brain can we also understand when these processes go awry.
Biological Psychiatry | 2010
Tracy L. Bale; Tallie Z. Baram; Alan S. Brown; Jill M. Goldstein; Thomas R. Insel; Margaret M. McCarthy; Charles B. Nemeroff; Teresa M. Reyes; Richard B. Simerly; Ezra Susser; Eric J. Nestler
For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Early theories about psychic conflict and toxic parenting have been replaced by more recent formulations of complex interactions of genes and environment. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. The mechanisms for these effects remain almost as much a mystery today as they were a century ago. Recent studies suggest that maternal diet can program offspring growth and metabolic pathways, altering lifelong susceptibility to diabetes and obesity. If maternal psychosocial experience has similar programming effects on the developing offspring, one might expect a comparable contribution to neurodevelopmental disorders, including affective disorders, schizophrenia, autism, and eating disorders. Due to their early onset, prevalence, and chronicity, some of these disorders, such as depression and schizophrenia, are among the highest causes of disability worldwide according to the World Health Organization 2002 report. Consideration of the early life programming and transcriptional regulation in adult exposures supports a critical need to understand epigenetic mechanisms as a critical determinant in disease predisposition. Incorporating the latest insight gained from clinical and epidemiological studies with potential epigenetic mechanisms from basic research, the following review summarizes findings from a workshop on Early Life Programming and Neurodevelopmental Disorders held at the University of Pennsylvania in 2009.
Nature Neuroscience | 2011
Margaret M. McCarthy; Arthur P. Arnold
In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.
The Journal of Neuroscience | 2009
Margaret M. McCarthy; Anthony P. Auger; Tracy L. Bale; Geert J. De Vries; Gregory A. Dunn; Nancy G. Forger; Elaine Murray; Bridget M. Nugent; Jaclyn M. Schwarz; Melinda E. Wilson
Epigenetic changes in the nervous system are emerging as a critical component of enduring effects induced by early life experience, hormonal exposure, trauma and injury, or learning and memory. Sex differences in the brain are largely determined by steroid hormone exposure during a perinatal sensitive period that alters subsequent hormonal and nonhormonal responses throughout the lifespan. Steroid receptors are members of a nuclear receptor transcription factor superfamily and recruit multiple proteins that possess enzymatic activity relevant to epigenetic changes such as acetylation and methylation. Thus steroid hormones are uniquely poised to exert epigenetic effects on the developing nervous system to dictate adult sex differences in brain and behavior. Sex differences in the methylation pattern in the promoter of estrogen and progesterone receptor genes are evident in newborns and persist in adults but with a different pattern. Changes in response to injury and in methyl-binding proteins and steroid receptor coregulatory proteins are also reported. Many steroid-induced epigenetic changes are opportunistic and restricted to a single lifespan, but new evidence suggests endocrine-disrupting compounds can exert multigenerational effects. Similarly, maternal diet also induces transgenerational effects, but the impact is sex specific. The study of epigenetics of sex differences is in its earliest stages, with needed advances in understanding of the hormonal regulation of enzymes controlling acetylation and methylation, coregulatory proteins, transient versus stable DNA methylation patterns, and sex differences across the epigenome to fully understand sex differences in brain and behavior.
The Journal of Neuroscience | 2012
Margaret M. McCarthy; Arthur P. Arnold; Gregory F. Ball; Jeffrey D. Blaustein; Geert J. De Vries
### Introduction In 2001 the Institute of Medicine, a branch of the National Academy of Sciences in the U.S.A., concluded that many aspects of both normal and pathological brain functioning exhibit important yet poorly understood sex differences ([Wizemann and Pardu, 2001][1]). Ten years later, the
Physiology & Behavior | 1996
Margaret M. McCarthy; Christelle H Mcdonald; Phillip J. Brooks; David Goldman
The established role of oxytocin (OT) in facilitation of steroid-modulated reproductive and affiliative behaviors led to the speculation that it may have anxiolytic actions under certain hormonal conditions. NIH-Swiss mice were tested for responsiveness to OT in two behavioral tests of anxiety, the holeboard apparatus and elevated plus-maze. Dose-response assessment indicated that 3 mg/kg was the optimal dose for peripherally administered (IP) OT on the elevated plus-maze. There were no consistent effects at any dose on the holeboard apparatus. In ovariectomized mice pretreated with estradiol (E2), peripherally administered OT increased the number of entrances onto the open arms, as well as the amount of time on the open arms compared to other groups (ANOVA; p < 0.05). There was little to no effect of OT in ovariectomized animals not pretreated with E2. When OT was administered intracerebroventricularly (ICV), there was an increase in entrances and time on the open arms compared to that of females infused with arginine vasopressin (AVP). This increase was apparent in ovariectomized females, but was further enhanced in those pretreated with E2 (ANOVA; p < 0.05). In contrast, the combination of E2 pretreatment and ICV AVP decreased the number of entrances and time spent on the open arms of the elevated plus-maze compared to those receiving OT, suggesting an estrogen-modulated anxiogenic action of AVP. Analyses of [125]I-OVTA binding density indicated a significant increase in binding density in the lateral septum of E2-treated females compared to OIL-treated controls (ANOVA; p < 0.05). There was no effect of E2 treatment on [125]I-OVTA binding density in the amygdala or ventromedial nucleus of the hypothalamus. Taken together, these data indicate that OT exerts an anxiolytic action that is enhanced in the presence of circulating estrogen. This behavioral effect may be mediated by estrogen-induced increases in OT binding density in the lateral septum and may be important to the facilitation of social interactions.
Nature Neuroscience | 2004
Stuart K. Amateau; Margaret M. McCarthy
Adult male sexual behavior in mammals requires the neuronal organizing effects of gonadal steroids during a sensitive perinatal period. During development, estradiol differentiates the rat preoptic area (POA), an essential brain region in the male copulatory circuit. Here we report that increases in prostaglandin-E2 (PGE2), resulting from changes in cyclooxygenase-2 (COX-2) regulation induced by perinatal exposure to estradiol, are necessary and sufficient to organize the crucial neural substrate that mediates male sexual behavior. Briefly preventing prostaglandin synthesis in newborn males with the COX inhibitor indomethacin permanently downregulates markers of dendritic spines in the POA and severely impairs male sexual behavior. Developmental exposure to the COX inhibitor aspirin results in mild impairment of sexual behavior. Conversely, administration of PGE2 to newborn females masculinizes the POA and leads to male sex behavior in adults, thereby highlighting the pathway of steroid-independent brain masculinization. Our findings show that PGE2 functions as a downstream effector of estradiol to permanently masculinize the brain.
Frontiers in Neuroendocrinology | 2005
Margaret M. McCarthy; Anne T. M. Konkle
Brain sexual differentiation in mammals requires activity of gonadal hormones; organizational effects of these steroids on brain development occur early in life while activational ones in adulthood ensure appropriate and timely sex-specific behaviors. This traditional view has long served as a reliable model for sexual differentiation of reproductively relevant brain structures. Here, we take a fresh look at this model but refocused in the context of sexual differentiation of non-reproductive parameters and with an emphasis on the hippocampus, a telencephalic brain structure predominantly involved in cognition and stress regulation. We explore sex differences in morphology, neurochemistry, and hippocampal-dependent behaviors to propose a new prototype that can be used to explain and further investigate the effects of steroid hormones, those synthesized gonadally or intracerebrally, on hippocampal development and function. We also propose that a new vernacular be employed, one that distinguishes hormonally modulated responses from sex differences, and argue these are mechanistically and functionally distinct. Understanding when and how the sexes are different is as important as understanding when and how they are the same, at the biological, social, and cultural level.
The Journal of Neuroscience | 2013
Kathryn M. Lenz; Bridget M. Nugent; Rachana Haliyur; Margaret M. McCarthy
Brain sexual differentiation in rodents results from the perinatal testicular androgen surge. In the preoptic area (POA), estradiol aromatized from testosterone upregulates the production of the proinflammatory molecule, prostaglandin E2 (PGE2) to produce sex-specific brain development. PGE2 produces a two-fold greater density of dendritic spines in males than in females and masculinizes adult copulatory behavior. One neonatal dose of PGE2 masculinizes the POA and behavior, and simultaneous treatment with an inhibitor of additional prostaglandin synthesis prevents this masculinization, indicating a positive feedforward process that leads to sustained increases in PGE2. The mechanisms underlying this feedforward process were unknown. Microglia, the primary immunocompetent cells in the brain, are active neonatally, contribute to normal brain development, and both produce and respond to prostaglandins. We investigated whether there are sex differences in microglia in the POA and whether they influence developmental masculinization. Neonatal males had twice as many ameboid microglia as females and a more activated morphological profile, and both estradiol and PGE2 masculinized microglial number and morphology in females. Microglial inhibition during the critical period for sexual differentiation prevented sex differences in microglia, estradiol-induced masculinization of dendritic spine density, and adult copulatory behavior. Microglial inhibition also prevented the estradiol-induced upregulation of PGE2, indicating that microglia are essential to the feedforward process through which estradiol upregulates prostaglandin production. These studies demonstrate that immune cells in the brain interact with the nervous and endocrine systems during development, and are crucial for sexual differentiation of brain and behavior.
Endocrinology | 2011
Anne T. M. Konkle; Margaret M. McCarthy
The prevailing view of sexual differentiation of mammalian brain is that androgen synthesized in the fetal and neonatal testis and aromatized centrally during a perinatal sensitive period is the sole source of brain estradiol and the primary determinant of sex differences. Subregions of the diencephalon are among the most sexually dimorphic in the brain, and there are well-established sex differences in the amount of testosterone and estradiol measured in the hypothalamus and preoptic area during the perinatal period. We previously reported unexpectedly high estradiol in the hippocampus and cortex of both male and female newborn rat. This prompted a thorough investigation of the developmental profile of steroids in the rat brain using RIA to quantify the level of estradiol, testosterone, and dihydrotestosterone in discrete subregions of the brain from embryonic d 19 to adulthood. Plasma estradiol levels from individual animals were assessed when sufficient sample was available. A significant sex difference in hypothalamic testosterone prior to birth was consistent with previous findings. Postnatally, there was a distinct pattern of changing steroid concentrations in each brain region, and these were unrelated to circulating steroid. Removal of the gonads and adrenals at birth did not significantly reduce steroids in any brain region assayed 3 d later. Aromatase activity was detectable in all brain areas at birth, and the difference in activity level paralleled the observed regional differences in estradiol content. Based on these findings, we propose that steroidogenesis in the brain, independent of peripherally derived precursors, may play a critical role in mammalian brain development of both sexes, beyond the establishment of sex differences.