Papers by Jaclyn M Schwarz
Brain, Behavior, and Immunity, 2014
Hormones and Behavior, 2008
Normal development of the male rat brain involves two distinct processes, masculinization and def... more Normal development of the male rat brain involves two distinct processes, masculinization and defeminization, that occur during a critical period of brain sexual differentiation. Masculinization allows for the capacity to express male sex behavior in adulthood, and defeminization eliminates or suppresses the capacity to express female sex behavior in adulthood. Despite being separate processes, both masculinization and defeminization are induced by neonatal estradiol exposure. Though the mechanisms underlying estradiolmediated masculinization of behavior during development have been identified, the mechanisms underlying defeminization are still unknown. We sought to determine whether neonatal activation of glutamate NMDA receptors is a necessary component of estradiol-induced defeminization of behavior. We report here that antagonizing glutamate receptors during the critical period of sexual differentiation blocks estradiol-induced defeminization but not masculinization of behavior in adulthood. However, enhancing NMDA receptor activation during the same critical period mimics estradiol to permanently induce both defeminization and masculinization of sexual behavior.
Hormones and Behavior, 2009
The hormonal regulation of sexual behavior has been the topic of study for over 50 years and yet ... more The hormonal regulation of sexual behavior has been the topic of study for over 50 years and yet controversies persist regarding the importance of early versus late events and the identity of the critical neural and cellular substrates. We have taken a mechanistic approach toward the masculinizing actions of the gonadal steroid estradiol, as a means to understand how organization of the neuroarchitechture during a perinatal sensitive period exerts enduring influences on adult behavior. We have identified important roles for prostaglandins, FAK and paxillin, PI3 kinase and glutamate, and determined that cell-to-cell signaling is a critical component of the early organizational events. We have further determined that the mechanisms mediating different components of sexual behavior are distinct and regionally specific. The multitude of mechanisms by which the steroid estradiol, exerts divergent effects on the developing nervous system provides for a multitude of phenotypes which can vary significantly both within and between the sexes.
Journal of Neurochemistry, 2008
Hormone exposure, including testosterone and its metabolite estradiol, induces a myriad of effect... more Hormone exposure, including testosterone and its metabolite estradiol, induces a myriad of effects during a critical period of brain development that are necessary for brain sexual differentiation. Nuclear volume, neuronal morphology and astrocyte complexity are examples of the wide range of effects by which testosterone and estradiol can induce permanent changes in the function of neurons for the purpose of reproduction in adulthood. This review will examine the multitude of mechanisms by which steroid hormones induce these permanent changes in brain structure and function. Elucidating how steroids alter brain development sheds light on how individual variation in neuronal phenotype is established during a critical period. The brain is a target organ for gonadal steroids. In adulthood, hormone exposure is responsible for inducing many of the functions necessary for sexual receptivity and reproduction. In adult males, testosterone is necessary for spermatogenesis in the gonads as well as sexual behavior, which involves both motivation to seek a mating partner (appetitive behavior) and motor components (consummatory behavior). In adult females, fluctuating levels of estradiol and progesterone induce follicular development and ovulation in the gonads, but are also essential for appropriately timing behavioral sexual receptivity within the limited time window for fertilization. Establishing the myriad functions for steroid hormones in the adult brain remains an active research goal, but equally important and substantially less investigated are the effects of gonadal steroids on the developing brain. The immature brain is highly sensitive to the same hormones produced in adulthood and this hormone exposure during development is necessary to express many of the functions in adulthood described above. The goal of this review is to elucidate the current understanding of how steroids act on the developing brain to permanently organize neuroarchitectural sex differences that then mediate adult sex differences in physiology and behavior.
Hormones and Behavior, 2005
The preoptic area of the mammalian forebrain is a critical substrate for the development and main... more The preoptic area of the mammalian forebrain is a critical substrate for the development and maintenance of many sexually dimorphic behaviors relevant to reproduction. Normal development of the male rodent brain requires completion of two processes: (1) masculinization-induction of the male phenotype, and (2) defeminization-removal of the female phenotype. Both processes, although distinct, are largely directed by the same steroid, estradiol. Whether estradiol achieves both ends via the same or separate mechanisms has been unknown. Here, we report that prostaglandin-E 2 (PGE 2 ) acting downstream of estradiol, is necessary and sufficient to masculinize sexual behavior but does not affect defeminization of sexual behavior or maternal behavior. Moreover, the volume of the sexually dimorphic nucleus of the preoptic area predicts defeminization of sexual behavior, but not masculinization of sexual behavior. Another sexually dimorphic cellular endpoint regulated by estradiol, spinophilin protein expression in the mediobasal hypothalamus, was not affected by PGE 2 . Thus, PGE 2 is a key divergence point in the downstream actions of estradiol to simultaneously masculinize and defeminize sexual behavior. D Hormones and Behavior 48 512 -521 www.elsevier.com/locate/yhbeh YHBEH-02225; No. of pages: 10; 4C:
The Journal of Steroid Biochemistry and Molecular Biology, 2008
The sexual differentiation of reproductive physiology and behavior in the rodent brain is largely... more The sexual differentiation of reproductive physiology and behavior in the rodent brain is largely determined by estradiol aromatized from testicular androgens. The cellular mechanisms by which estradiol masculinizes the brain are beginning to emerge and revealing novel features of brain development that are highly region specific. In the preoptic area, the major site controlling male sexual behavior, estradiol increases the level of the COX-2 enzyme and its product, prostaglandin E2 which promotes dendritic spine synaptogenesis. In the ventromedial nucleus of the hypothalamus, the major site controlling female reproductive behavior, estradiol promotes glutamate release from synaptic terminals, activating NMDA receptors and the MAP Kinase pathway. In the arcuate nucleus, a major regulator of anterior pituitary function, estradiol increases GABA synthesis, altering the morphology of neighboring astrocytes and reducing formation of dendritic spines synapses. Glutamate, GABA and the importance of neuronal-astrocytic cross talk are emerging as common aspects of masculinization. Advances are also being made in the mechanistic basis of female brain development, although the challenges are far greater.
Endocrinology, 2007
Steroid-mediated sexual differentiation of the brain is a developmental process that permanently ... more Steroid-mediated sexual differentiation of the brain is a developmental process that permanently organizes the brain into a male or female phenotype. Previous studies in the rodent have examined the steroid-mediated mechanisms of male brain development. In an effort to identify molecules involved in female brain development, a high-throughput proteomics approach called PowerBlot was used to identify signaling proteins differentially regulated in the neonatal male and female rat hypothalamus during the critical period for brain sexual differentiation. Focal adhesion kinase (FAK) and paxillin, both members of the focal adhesion complex family of proteins, were significantly elevated in the newborn female compared with the male hypothalamus. Sex differences in these proteins were not detected in brain regions that are not subject to substantial organizational effects of steroids. Estro-gens, the aromatized products of testosterone in the male, can both masculinize and defeminize the male brain. Daily estradiol administration to neonatal females significantly reduced FAK and paxillin in the hypothalamus, and aromatase inhibition increased paxillin in males to levels comparable with females. Androgens also appear to modulate paxillin levels in combination with estrogen action. Across development, hypothalamic levels of FAK were significantly elevated in females compared with males on postnatal d 6. Synaptic circuits in the hypothalamus develop sex differences perinatally. Estradiol treatment of cultured hypothalamic neurons significantly enhanced axon branching (P < 0.01), consistent with the phenotype of FAK-deficient neurons. Together, these data implicate FAK and paxillin as regulators of sex differences in neuronal morphology. ) Abbreviations: ARC, Arcuate nucleus of the hypothalamus; CREB, cAMP response element-binding protein; DHT, dihydrotestosterone; E14, embryonic d 14; FAK, focal adhesion kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MBH, medial basal hypothalamus; mPOA, medial preoptic area; pCREB, phosphorylated CREB; PN0, postnatal d 0; TTBS, Tris-buffered saline with 0.1% Tween 20; VMN, ventromedial nucleus of the hypothalamus.
Neuron, 2008
The naturally occurring sex difference in dendritic spine number on hypothalamic neurons offers a... more The naturally occurring sex difference in dendritic spine number on hypothalamic neurons offers a unique opportunity to investigate mechanisms establishing synaptic patterning during perinatal sensitive periods. A major advantage of the model is the ability to treat neonatal females with estradiol to permanently induce the male phenotype. During the development of other systems, exuberant innervation is followed by activity-dependent pruning necessary for elimination of spurious synapses. In contrast, we demonstrate that estradiol-induced organization in the hypothalamus involves the induction of new synapses on dendritic spines. Activation of estrogen receptors by estradiol triggers a non-genomic activation of PI3 kinase that results in enhanced glutamate release from presynaptic neurons. Subsequent activation of ionotropic glutamate receptors activates MAP kinases inducing dendritic spine formation. These results reveal a trans-neuronal mechanism by which estradiol acts during a sensitive period to establish a profound and lasting sex difference in hypothalamic synaptic patterning.
Polyinosinic:polycytidylic acid (poly I:C), an agonist for TLR3, induces type-I interferons and o... more Polyinosinic:polycytidylic acid (poly I:C), an agonist for TLR3, induces type-I interferons and other inflammatory mediators such as TNF-alpha, IL-6 and to a lesser extent IL-1beta. Poly I:C induces sickness behaviour in mice and it is known that type-I interferons impact on behaviour and CNS function. Here we assess the role of type-I interferons in pI:C-induced sickness behaviour. Type-I interferon receptor 1 knockout (IFNAR1À/À) and WT C57BL/6 mice were challenged with pI:C (12 mg/kg i.p). IFNAR1À/Àanimals displayed reduced sickness behaviour compared to WT mice and only WT animals displayed a significant hypothermic response. All mice showed a reduction in weight 28 h post-challenge but full recovery was more rapid in IFNAR1À/Àmice. In addition to this, 3 h post-challenge, WT mice showed decreased activity in the open field with respect to IFNAR1À/À. As expected, the interferon responsive genes PKR and IRF7 were not induced by pI:C in IFNAR1À/Àmice. While IL-1beta and TNF-alpha responses to pI:C were equivalent in KO and WT in blood, hippocampus and hypothalamus, there was no synthesis of IL-6 in IFNAR1À/Àin either blood or brain. These results demonstrate a role for type-I interferons in the sickness behaviour response to pI:C and in the induction of IL-6 responses. Further investigations will examine whether the IL-6 deficiency seen in IFNAR1À/Àmice is responsible for the reduced pI:C-induced sickness behaviour.
Hormones and behavior, 2012
Q2 5 6 a b s t r a c t a r t i c l e i n f o 7 Microglia and astrocytes are the primary immune ce... more Q2 5 6 a b s t r a c t a r t i c l e i n f o 7 Microglia and astrocytes are the primary immune cells within the central nervous system. Microglia influence 24 processes including neural development, synaptic plasticity and cognition; while their activation and produc-25 tion of immune molecules can induce stereotyped sickness behaviors or pathologies including cognitive dys-26 function. Given their role in health and disease, we propose that glia may also be a critical link in 27 understanding the etiology of many neuropsychiatric disorders that present with a strong sex-bias in their 28 symptoms or prevalence. Specifically, males are more likely to be diagnosed with disorders that have distinct 29 developmental origins such as autism or schizophrenia. In contrast, females are more likely to be diagnosed 30 with disorders that present later in life, after the onset of adolescence, such as depression and anxiety disor-31 ders. In this review we will summarize the evidence suggesting that sex differences in the colonization and 32 function of glia within the normal developing brain may contribute to distinct windows of vulnerability be-33 tween males and females. We will also highlight the current gaps in our knowledge as well as the future di-34 rections and considerations of research aimed at understanding the link between neuroimmune function and 35 sex differences in mental health disorders. 36 39 40 41 42 65 cyte/macrophage lineage. Microglia also exert crucial physiological 66 functions in the healthy CNS. Astrocytes, the largest glial cell popula-67 tion within the brain, are also capable of synthesizing pro-68 inflammatory immune molecules at rest and during an insult or chal-69 lenge, and thus are similarly considered immunocompetent CNS cells.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 14, 2009
Epigenetic changes in the nervous system are emerging as a critical component of enduring effects... more 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...
Journal of Neuroimmune …, 2011
Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may ... more Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may account for these declines, microglial sensitization and/or dystrophy has emerged as a leading culprit in brain aging and dysfunction. However, glial activation is consistently observed in normal brain aging as well, independent of frank neuroinflammation or functional impairment. Such variability suggests the existence of additional vulnerability factors that can impact neuronal-glial interactions and thus overall brain and cognitive health. The goal of this review is to elucidate our working hypothesis that an individual's risk or resilience to neuroinflammatory disorders and poor cognitive aging may critically depend on their early life experience, which can change immune reactivity within the brain for the remainder of the lifespan. For instance, early-life infection in rats can profoundly disrupt memory function in young adulthood, as well as accelerate age-related cognitive decline, both of which are linked to enduring changes in glial function that occur in response to the initial infection. We discuss these findings within the context of the growing literature on the role of immune molecules and neuroimmune crosstalk in normal brain development. We highlight the intrinsic factors (e.g., chemokines, hormones) that regulate microglial development and their colonization of the embryonic and postnatal brain, and the capacity for disruption or "re-programming" of this crucial process by external events (e.g., stress, infection).
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Papers by Jaclyn M Schwarz