Gender and Brain Abnormalities in Schizophrenia

精神分裂症的性别和大脑异常

基本信息

批准号：
7691922
负责人：
JILL M GOLDSTEIN
金额：
$ 10.58万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-05 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7691922
关键词：
Adrenal Glands Adrenal hormone preparation Adult Adult Children Adverse effects Affect Affective Age-Years Amygdaloid structure Androgens Animals Anterior Anti-Inflammatory Agents Anti-inflammatory Appendix Arousal Aversive Stimulus Biological Assay Blood Boston Brain Brain Stem Brain region Cell Nucleus Cerebrum Clinical Communities Corticotropin Cytokine Receptors DSM-IV Data Development Disease Disruption Environment Estrogens Ethnic Origin Evaluation Exhibits Exposure to Family Female Fetal Development Foundations Functional Magnetic Resonance Imaging Functional disorder Funding Gender Glucocorticoid Receptor Glucocorticoids Gonadal Hormones Gonadal Steroid Hormones Grant Growth Factor Hippocampus (Brain)Hormonal Hormone Receptor Hormones Human Hydrocortisone Hypothalamic structure IL8 gene Inflammatory Knowledge Magnetic Resonance Imaging Measures Menopause Mothers National Institute of Mental Health Neurosecretory Systems New England Pathway interactions Patient currently pregnant Perinatal Perinatal Exposure Phase Pituitary Gland Pituitary-Adrenal System Pregnancy Prevention intervention Protocols documentation Psychotic Disorders Recruitment Activity Regulation Relative (related person)Risk Risk Factors Role Sampling Scanning Schizophrenia Serum Sex Characteristics Sexual Development Signal Transduction Site Specificity Stimulus Structure System TNF gene Testing Third Pregnancy Trimester Time Week Woman Work affective psychoses base biological adaptation to stress blood oxygen level dependent brain volume cingulate gyrus cohort cost efficient critical developmental period cytokine density fetal hypercortisolemia hypothalamic pituitary axis hypothalamic-pituitary-adrenal axis in utero interest locus ceruleus structure male maternal serum men paraventricular nucleus parity piriform cortex polypeptide programs receptor reproductive response sample fixation sex sexual dimorphism size theories

项目摘要

DESCRIPTION (provided by applicant): The P.I. has been investigating hypotheses regarding the role of one's sex in understanding schizophrenia (SCZ) for 20 years. This first resubmission, a competing continuation of MH56956 on sex differences in brain abnormalities in SCZ (ongoing since 1997), proposes to investigate potential mechanisms to explain sex differences in the brain in SCZ. Studies, including our own, have shown that high levels of maternal cytokines (IL-8 and TNF-a) during late fetal development (same time period as sexual differentiation of the brain), significantly increased the risk for SCZ, other psychoses and brain abnormalities associated with these disorders. Receptors for these cytokines have been located in hippocampus (HIPP), hypothalamus (HYPTH), amygdala (AMYG), and locus coeruleus, stress response circuitry involved in the hypothalamic- pituitary-adrenal (HPA) system and affective regulation, regions also found to be sexually dimorphic. Thus, we will test whether abnormalities in the maternal-fetal cytokine environment predict adult affective dysregulation and HPA dysfunction in SCZ and affective psychoses, with females being particularly affected. In MH56956 in which subjects are from a community sample followed from pregnancy through adulthood (New England Collaborative Perinatal Project), we identified 111 subjects with psychoses (63 nonaffective psychoses; 48 affective psychoses) matched to two normal controls per case. Using stored serum from their pregnant mothers (ascertained in the mid 1960's), we will assay cytokines IL-8 and TNF-a and relate to onset of psychoses and structural brain abnormalities in HIPP, HYPTH, AMYG and cortical regions implicated in the stress response circuitry, i.e. orbitofrental cortex and anterior cingulate gyrus (MRI data already collected in the current MH56956). 30 DSM-IV SCZ, 30 bipolar psychoses and 30 comparable normal controls, equally divided by sex, will be re-recruited and undergo functional MRI (fMRI) stimuli of aversive affective arousal and blood acquisition for neuroendocrine assessments to test our hypotheses relating an abnormal maternal-fetal cytokine environment with adult functional brain activity deficits in the stress response circuitry and HPA dysfunction. There are no studies that relate a fetal exposure to explaining adult sex differences in affective and HPA dysfunctions in SCZ, a clinical problem of high impact, with the potential for development of sex-specific anti-inflammatory interventions for prevention.

描述（由申请人提供）：P.I. 20 年来，我们一直在研究有关性别在理解精神分裂症 (SCZ) 中的作用的假设。第一次重新提交是 MH56956 关于 SCZ 大脑异常性别差异的竞争性延续（自 1997 年以来一直在进行），提议研究解释 SCZ 大脑性别差异的潜在机制。包括我们自己在内的研究表明，在胎儿发育后期（与大脑性别分化相同的时期）母体细胞因子（IL-8 和 TNF-a）水平较高，会显着增加 SCZ、其他精神病和脑部疾病的风险。与这些疾病相关的异常。这些细胞因子的受体位于海马 (HIPP)、下丘脑 (HYPTH)、杏仁核 (AMYG) 和蓝斑，应激反应回路参与下丘脑-垂体-肾上腺 (HPA) 系统和情感调节，还发现这些区域具有性别二态性。因此，我们将测试母胎细胞因子环境的异常是否可以预测成人情感失调和 SCZ 中的 HPA 功能障碍和情感精神病，其中女性尤其受到影响。在 MH56956 中，受试者来自从怀孕到成年的社区样本（新英格兰合作围产期项目），我们确定了 111 名患有精神病的受试者（63 名非情感性精神病；48 名情感性精神病），每个病例与两名正常对照相匹配。使用怀孕母亲储存的血清（在 1960 年代中期确定），我们将检测细胞因子 IL-8 和 TNF-a，并将其与精神病的发作以及与应激反应有关的 HIPP、HYPTH、AMYG 和皮质区域的结构性脑异常联系起来。电路，即眶额皮质和前扣带回（MRI 数据已在当前 MH56956 中收集）。将重新招募 30 名 DSM-IV SCZ、30 名双相情感障碍患者和 30 名可比较的正常对照，按性别平均分配，并接受厌恶情感唤醒的功能性 MRI (fMRI) 刺激和神经内分泌评估的血液采集，以检验我们与异常相关的假设母胎细胞因子环境与成人功能性脑活动缺陷的应激反应回路和 HPA 功能障碍。目前尚无研究将胎儿暴露与成人 SCZ 情感和 HPA 功能障碍的性别差异联系起来，SCZ 是一个影响很大的临床问题，具有开发性别特异性抗炎干预措施进行预防的潜力。