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

记忆功能障碍和相关的前额叶-海马（PFC-HIPP）回路异常是关键 精神分裂症（SZ）。此CIDAR应用程序侧重于γ-氨基丁酸的作用 谷氨酸（GLU）和脑源性神经营养因子（BDNF）对SZ病的解释 进展，与记忆功能障碍和PFC-HIPP回路相关的领域。我们已经证明 该回路和记忆功能障碍存在显着的性别差异，男性表现出更严重的缺陷 严重程度和疾病进展的风险高于女性。动物和人类研究已经发现 在这些脑区，雌激素（ER-α和-β）和雄激素（AR）受体的共定位， 糖皮质激素受体（GR）与GABA和BDNF，这部分调节其发展和持续 physiology.这项研究将测试一系列假设，以开始解释疾病风险的增加 深圳男性与女性的进展。我们预测，记忆障碍和疾病的性别差异 在基因表达中，GR、ER和AR相关信号通路将部分解释进展 调节HIPP和PFC中的神经递质（GABA和GLU）和生长因子（如BDNF）。 提出的研究，我们将描述性别差异之间的关联赤字的大脑活动， PFC-HIPP电路响应于使用功能性磁共振成像进行的记忆任务， PFC-HIPP回路的结构异常，以及与这些大脑相关的神经内分泌功能障碍 与正常对照组相比，SZ的缺陷。此外，我们将与GABA基因，BDNF， ER、AR和GR基因的这些性别差异是由大脑异常和激素失调而开始的 目的：探讨死后HIPP和PFC中GR、ER和AR mRNA与BDNF和GABA的关系 SZ和正常对照男性和女性的组织。CIDAR财团将允许足够数量的 SZ和对照组（n=394）的前驱期、首次发作和慢性病例，以及功能和 结构磁成像、激素评估、分子遗传学和死后组织实验 检验我们关于SZ疾病进展的性别差异的假设。的调查 不同疾病进展水平的性别差异轨迹很重要，因为它可以提供 对SZ男性和女性的潜在差异激素干预时机的见解。

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.