2007 |
Schwarz, Jaclyn Marie |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Estradiol and Glutamate in the Developing Hypothalamus @ University of Maryland Baltimore
[unreadable] DESCRIPTION (provided by applicant): Male and female brains exhibit fundamental morphological differences thought to underlie sex differences in physiology and behavior. Development of the male rodent brain includes the completion of two distinct processes: masculinization and defeminization. In the rodent, estradiol initiates both processes during a restricted sensitive period. During development and adulthood, the medial basal hypothalamus (MBH) is a key target for estradiol. The MBH is important for female sex behavior and a possible site of defeminization in the male brain. Dendritic spines are the major sites of excitatory synapses. In the MBH, newborn males have more dendritic spines than females and treatment of females with testosterone, which is aromatized to estradiol, increases dendritic spines in this region to levels seen in males. Recent work has begun to investigate the mechanism of masculinization. However, little is known about the mechanism by which estradiol induces defeminization and establishes sexually dimorphic patterning in the MBH. Based on preliminary data and previous findings, we propose a novel role for glutamate release and the NMDA receptor in the process of defeminization of the brain and behavior. The goal of this proposal is to elucidate the mechanism by which estradiol induces defeminization of the rodent brain, to increase understanding of sex differences in brain development. Many neurological and psychiatric disorders including autism, affective disorder and schizophrenia exhibit a sex-biased prevalence and/or characteristics. These diseases are frequently disorders of neurochemicals or wiring. Understanding how sex effects normal brain development is necessary to understand how it may develop abnormally in psychiatric disorders. [unreadable] [unreadable] [unreadable]
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0.972 |
2010 — 2012 |
Schwarz, Jaclyn Marie |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Immune Function and Sex Differences in Morphine Analgesia and Reward
DESCRIPTION (provided by applicant): Opioid drugs, such as morphine, are widely prescribed for the treatment of moderate to severe pain. While morphine and other opioids are the most effective treatment of pain, they do not provide adequate pain relief for all. For others, treatment of pain with opioids can lead down a path of dependence and addiction. An individual's sex is one major factor in determining the effectiveness of opioids for the reduction of pain and the potential for abuse liability. In both the human and the rodent literature, it has been demonstrated that males experience greater analgesia than females after opioid administration. In contrast, the rewarding properties of morphine are much greater in females than in males. Searching for a common mechanism for such disparate effects of sex on morphine-induced analgesia and reward has been difficult. However, recent evidence indicates that a critical component of morphine effectiveness involves the direct activation of microglia in the brain via the innate immune system's pattern recognition receptor, toll-like receptor (TLR) 4. This morphine-induced activation of microglia in the brain initiates the release of pro-inflammatory cytokines that markedly increase opioid-induced reward, tolerance and dependence and simultaneously decrease opioid analgesia. We therefore hypothesize that morphine-induced activation of microglia is significantly greater in females compared to males, and this glial activation may be an underlying mechanism for the differential effects of sex on morphine-induced analgesia and reward. The major objectives of this proposal are three-fold;1) to understand basic sex differences in immune activation upon morphine treatment;2) to understand the potential role of morphine-induced glial activation in sex differences in morphine-induced analgesia and abuse liability;and 3) to establish the specific role of microglia and begin to determine potential mechanisms. PUBLIC HEALTH RELEVANCE: The sex of an individual is a major factor in determining the effectiveness of opioid analgesia. The results of this proposal will lend insight into the role that the immune system plays in the effectiveness of morphine, as well as the potential for drug abuse between the sexes. Understanding how drugs affect males and females differently is a first step in the quest for personalized medicine.
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0.97 |
2014 — 2015 |
Schwarz, Jaclyn Marie |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Sex-Dependent Microglial Colonization and Vulnerability to a Neonatal Infection
DESCRIPTION (provided by applicant): Microglia are the resident immune cells of the brain. They are involved in many processes of brain development, the maintenance of the neural homeostasis, as well as the response to infection or injury, and repair. We have recently found a striking sex difference in the number of microglia in the developing rat brain. On postnatal day (P) 4 neonatal male rats have significantly more microglia than females in the hippocampus, cortex, and amygdala -- brain regions critical for emotion and cognition. At birth, P0, males have significantly elevated levels of two chemokines (chemotactic cytokines), CCL20 and CCL4, within the hippocampus and cortex than females. Given these data, the purpose of the present proposal is to test two interrelated hypotheses: (1) Neonatal testosterone increases the colonization of microglia in the developing male brain via the elevated expression of CCL20 and CCL4, and (2) Increased numbers of microglia within the developing male brain increases the vulnerability of males to the effects of a neonatal infection when compared to females. These data are consistent with epidemiological data that indicate males are more likely to be diagnosed with certain neurodevelopmental disorders that also have known or suspected immune etiologies, including autism, ADHD, schizophrenia, and cerebral palsy. Thus the proposed experiments will explore an important mental health issue from a novel perspective by identifying the interaction between microglial colonization of the developing brain in males and females, and the sex-dependent vulnerability of males to developmental/cognitive brain disorders.
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0.961 |
2016 — 2020 |
Schwarz, Jaclyn Marie |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Impact of Neonatal Infection On the Development of Hippocampal-Dependent Learning
? DESCRIPTION (provided by applicant): Developmental disorders are one of several disorders that interrupt normal development in childhood. These disorders may affect only one or several different areas of development, including language, motor, social and learning skills. Learning disabilities in particular are one of the most common forms of developmental disorders and are typically diagnosed early in children. Notably, learning disabilities and developmental disorders, in general, are more often diagnosed in boys than in girls and it is thought, at least in part, to e the result of immune activation during early brain development. Despite these theories, the underlying etiologies of many developmental disorders are not well understood, particularly in the context of peripheral immune function, microglial function, and sex. The purpose of the proposed experiments is two-fold. First, we will seek to understand normal hippocampal development of microglia and the developmental expression of synaptic plasticity molecules during the onset of hippocampal dependent contextual fear learning in juvenile male and female rats. Second, we will examine how activation of the developing immune system in males and females may result in subsequent delays in microglial development, the expression of synaptic plasticity molecules in the hippocampus, and developmental delays in hippocampal dependent learning in a sex-dependent manner. The results of these experiments will significantly increase our understanding of the interactions between intrinsic factors (such as sex) and environmental factors (such as immune activation) that perturb the normal development of brain and behavior from the juvenile period and into adulthood. In addition, these experiments will identify new molecular targets of neuronal and glial interactions that are likely disrupted throughout development as a result of early-life immune activation, providing potential targets for future therapeutic interventions.
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0.961 |
2017 — 2019 |
Schwarz, Jaclyn Marie |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Organization For the Study of Sex Differences Annual Meeting
PROJECT SUMMARY This application requests support for the 11th to the 13th Annual Meetings of the Organization for the Study of Sex Differences (OSSD). The 11th Annual Meeting of the OSSD will be held May 15 ? 18, 2017 at the Hyatt Regency Hotel in Montréal, Quebec, Canada. The 2018 meeting will be hosted by Georgia State University and held in Atlanta, GA. The 2019 meeting will be hosted by the University of Texas Health Science Center and will be held in Houston, TX. The mission of the OSSD is to enhance knowledge of the biological basis of sex/gender differences and the contribution of sex as a biological variable to health and disease by facilitating interdisciplinary communication and collaboration among scientists and clinicians from diverse scientific and professional backgrounds. The primary goal of the OSSD annual meeting is to provide a forum for scientists to explore aspects of sex differences research at the genetic, molecular, cellular, organ, and systems levels in humans and model systems. The annual meeting consists of one workshop, a Presidential Symposium, twelve parallel scientific sessions, a symposium highlighting the work of new investigators, and two poster sessions highlighting the work of new investigators and trainees. The title for the OSSD 2017 meeting is ?Sex Differences Across the Lifespan?, with a specific focus on aging and age-related diseases. Session topics for the 2017 meeting include: neurodegenerative diseases, pain, addiction, cardiovascular disease, kidney disease, metabolism, ophthalmological disease, stem cells, organ transplant and musculoskeletal disorders. These top-ranking proposals were selected out of 47 proposals based on scientific merit, relevance to the focus of the meeting on aging, relevance to the larger goals of the OSSD, a balance of basic and clinical speakers, and rotation of topics of interest across annual meetings. The size and format of this meeting (typically 220-250 participants) provides an excellent opportunity for networking opportunities and interactive discussions. Funds are requested to support registration fees for invited distinguished speakers, conference / travel support for junior investigators and trainees, and expenses related to room rental as well as necessary audio-visual equipment, associated technical support, and poster board rentals. The annual meeting program, including speaker and poster abstracts will be freely available on the OSSD website. We have partnered with McGill University and the University of Montréal to organize this event and will request support from the pharmaceutical and biotechnology industries, local businesses, private donors and foundations to help cover non-NIH costs.
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0.961 |
2020 |
Schwarz, Jaclyn Marie |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Long-Term Impact of Prenatal Zikv Infection On Neurogenesis
Project Summary / Abstract Zika virus (ZIKV) infection in pregnant women has been linked to a number of neurological disorders and complications in the offspring. Emerging evidence suggests that ZIKV preferentially infects neural progenitor cells resulting in the arrest of the neural progenitor cell cycle and ultimately the death of neural progenitor cells in the developing brain [3-5]. As a result, at its most extreme, prenatal ZIKV infection can result in severe neurological disorders including microcephaly; however, scientists have postulated that microcephaly may only be the ?tip of the iceberg? with regards to the neurological and cognitive consequences that may be associated with prenatal ZIKV infection. The purpose of the current proposal is to examine the long-term consequences of prenatal ZIKV infection using a novel rodent model. Dr. Schwarz's lab has recently found that infection of pregnant female rats with ZIKV significantly impacts the developing fetal brain of the offspring. Specifically, prenatal ZIKV infection increases cell death and reduces hippocampal and cortical volumes in the neonatal brain of the offspring. Moreover, prenatal ZIKV infection results in detectable levels of ZIKV in the neonatal serum at 7 days post infection and in the juvenile serum at 25 days post infection, suggesting that it may take weeks, if not longer, before the virus is fully cleared by the rat's immune system. The unique goal of these experiments is to (1) determine the location and duration of ZIKV in the brain following prenatal infection, (2) determine whether prenatal ZIKV infection results in long-term deficits in neurogenesis or the survival of these newborn neurons in the juvenile and adult brain, and (3) determine whether prenatal ZIKV infection results in later-life deficits in hippocampal dependent learning. The data obtained in these experiments, will allow scientists and clinicians to better understand the potential negative impact of prenatal ZIKV infection on later-life neurogenesis, an important neural process that is essential for cognitive function.
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0.961 |
2020 — 2021 |
Schwarz, Jaclyn Marie |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Peripheral and Environmental Factors Affecting Postpartum Mood State
Project Summary / Abstract Nearly 70% of women experience some form of sadness, anhedonia and anxiety in the weeks following the birth of a child [1,2]. Most women eventually feel better in the weeks after birth, but approximately 10-20% of women may continue to experience postpartum depression (PPD). Suicide is one of the leading causes of death in new mothers, sadly indicating that doctors may be unable to diagnose or effectively treat PPD within the timeframe that it emerges [3,4]. The risk factors for PPD include maternal isolation, negative life events, and low socioeconomic status or employment, suggesting that when mothers don't have the resources and support that they need, they are at increased risk of developing postpartum mood disorders. Yet the exact mechanisms that precipitate these changes in mood postpartum are still unknown. It is well-known that the function of the immune and endocrine systems are significantly altered during pregnancy and postpartum [5]. There is also a dramatic change in the neuroimmune system during and just after pregnancy in female rats [6]. Female rats exhibit anhedonia, as measured by sucrose preference test, on the day of birth that is associated with an increase in Interleukin (IL)-6 expression in the brain on the day of birth [7,8]. The goal of the current experiments is to determine whether a relevant maternal stress, in the form of limited bedding and nesting, can precipitate persistent postpartum anhedonia associated with a significant change in immune molecules, stress hormones or pregnancy hormones. This proposal also seeks to determine significant changes in neural activity associated with postpartum anhedonia and deficits in maternal care. The hope is that future research models incorporate relevant environmental risk factors of PPD to better understand they impact the physiological, behavioral and neural state associated with negative postpartum mood.
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0.961 |