PROJECT 2: HORMONES, MEMORY & SEX EFFECTS IN ILLNESS PROGRESSION IN SCHIZOPHRENIA

项目 2：荷尔蒙、记忆

• 批准号: 7279678
• 负责人: JILL M GOLDSTEIN
• 金额: $ 11.84万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279678
• 关键词: Adrenal Glands; Adrenal hormone preparation; Adult; Age; Androgen Receptor; Androgens; Animals; Anterior; Area; Autopsy; Blood; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cerebrum; Characteristics; Chronic; Clinical; Cognitive; Corticotropin; Development; Disruption; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Ethnic Origin; Etiology; Evaluation; Exhibits; Feedback; Female; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; GABA Receptor; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Gonadal Hormones; Gonadal Steroid Hormones; Gray unit of radiation dose; Growth Factor; Gur; High Risk Woman; Hippocampus (Brain); Hormonal; Hormone Receptor; Hormones; Human; Hydrocortisone; Hypothalamic structure; Image; Intervention; Investigation; Lasers; Life; Link; Literature; Localized; Long-Term Potentiation; Magnetic Resonance Imaging; Magnetism; Mediating; Memory; Menopause; Messenger RNA; Molecular Genetics; Neurodevelopmental Disorder; Neurons; Neurosecretory Systems; Neurotransmitters; Numbers; Onset of illness; Outcome; Parvalbumins; Patients; Performance; Phase; Phenotype; Physiology; Pituitary Gland; Prefrontal Cortex; Process; Production; Rate; Receptor Gene; Recruitment Activity; Relative (related person); Research Personnel; Rest; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Schizophrenia; Series; Severity of illness; Sex Characteristics; Sex Ratio; Signal Pathway; Signal Transduction; Synapses; Testing; Time; Tissues; Walkers; Woman; base; blood oxygen level dependent; cingulate gyrus; cohort; fetal; first episode schizophrenia; gamma-Aminobutyric Acid; genetic association; gray matter; high risk men; hippocampal pyramidal neuron; human study; human tissue; hypothalamic-pituitary-adrenal axis; insight; interest; male; men; novel; programs; research study; response; sex; size; white matter

Memory dysfunction and associated abnormalities in prefrontal-hippocampal (PFC-HIPP) circuitry are key vulnerabilities in schizophrenia (SZ). This CIDAR application focuses on the roles of gamma aminobutyric acid (GABA), glutamate (GLU) and brain-derived neurotrophic factor (BDNF) in explaining SZ illness progression, domains associated with memory dysfunction and PFC-HIPP circuitry. We have demonstrated significant sex differences in this circuitry and in memory dysfunction, with males exhibiting worse deficits and higher risk for severity and illness progression than females. Animal and human studies have identified in these brain regions, the co-localization of estrogen (ER-alpha & -beta) and androgen (AR) receptors and glucocorticoid receptors (GR) with GABA and BDNF, which in part regulate their development and ongoing physiology. This study will test a series of hypotheses to begin to explain the increased risk for illness progression in SZ men versus women. We predict that sex differences in memory dysfunction and illness progression will be, in part, explained by GR, ER & AR-associated signaling pathways in gene expression regulating neurotransmitters (GABA and GLU) and growth factors (such as BDNF) in HIPP and PFC. In the proposed study, we will characterize sex differences in the associations between deficits in brain activity in PFC-HIPP circuitry in response to a memory task conducted using functional magnetic resonance imaging, structural abnormalities in PFC-HIPP circuitry, and neuroendocrine dysfunction associated with these brain deficits in SZ compared with normal controls. Further, we will relate abnormalities in GABA genes, BDNF, ER, AR and GR genes to these sex differences in brain abnormalities and hormonal dysregulation and begin to validate associationsbetween GR, ER and AR mRNA, BDNF and GABA in HIPP and PFC in postmortem tissue in SZ and normal control men and women. The CIDAR consortium will allow for an adequate number of prodromal, first episode, and chronic cases of SZ and controls (n=394) and the use of functional and structural magnetic imaging, hormonal evaluations, molecular genetics, and postmortem tissue experiments to test our hypotheses regarding sex differences in illness progression in SZ. An investigation of the trajectory of sex differences at different levels of illness progression is important in that it may provide insights into the timing of potential differential hormonal interventions for men and women with SZ.

记忆障碍和相关的前额-海马区(PFC-HIPP)回路异常是关键 精神分裂症的脆弱性(SZ)。本CIDAR应用重点是γ-氨基丁酸的作用 酸(GABA)、谷氨酸(GLU)和脑源性神经营养因子(BDNF)在SZ病发病机制中的作用 进展，与记忆功能障碍和PFC-HIPP回路相关的区域。我们已经证明了 在这一回路和记忆功能障碍方面存在显著的性别差异，男性表现出更严重的缺陷 而且严重程度和疾病进展的风险比女性更高。动物和人体研究发现 在这些脑区，雌激素(ER-α和-β)和雄激素(AR)受体的共同定位以及 糖皮质激素受体(GR)与GABA和BDNF结合，在一定程度上调节它们的发育和进行 生理学。这项研究将检验一系列假设，以开始解释患病风险的增加。 SZ男性与女性的进展。我们预测，在记忆障碍和疾病方面的性别差异 基因表达中与GR、ER和AR相关的信号通路将在一定程度上解释这一进程 调节Hipp和PFC的神经递质(GABA和GLU)和生长因子(如BDNF)。在 拟议的研究，我们将表征性别差异之间的大脑活动缺陷之间的联系 PFC-HIPP电路响应于使用功能磁共振成像进行的记忆任务， 与这些大脑相关的PFC-HIPP回路的结构异常和神经内分泌功能障碍 SZ的缺陷与正常对照组相比。此外，我们还将与GABA基因、BDNF、 ER、AR和GR基因与这些性别差异的脑异常和激素失调有关 尸检验证HIPP和PFC中GR、ER和AR mRNA、BDNF和GABA的相关性 SZ和正常对照男女的组织。CIDAR财团将允许足够的数量 先兆、首发和慢性SZ病例和对照组(n=394)以及功能性和 结构磁性成像、荷尔蒙评估、分子遗传学和死后组织实验 来检验我们关于深圳疾病进展中的性别差异的假设。一项关于调查的报告 不同疾病进展水平上的性别差异轨迹很重要，因为它可能提供 对患有SZ的男性和女性进行潜在差异激素干预的时机的洞察。