Fetal Hormonal Programming of Sex Differences in Aging of the Memory Circuitry

胎儿荷尔蒙编程对记忆回路老化的性别差异

基本信息

批准号：
8501744
负责人：
JILL M GOLDSTEIN
金额：
$ 18.29万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501744
关键词：
Adrenal Glands Adrenal hormone preparation Adult Affect Age Aging Androgens Animals Anisotropy Anterior Attenuated Biological Markers Blood Brain Brain region CRH gene Chronic Disease DNA Data Set Development Diffusion Magnetic Resonance Imaging Disease Economics Estradiol Estrogen Receptors Estrogens Evaluation Exhibits Fascicle Female Functional Magnetic Resonance Imaging Functional disorder Funding Gender Genes Genetic Genetic Polymorphism Genotype Gerontology Glucocorticoid Receptor Glucocorticoids Gonadal Hormones Hippocampus (Brain)Hormonal Hormone Receptor Hormones Human Human Chorionic Gonadotropin Hydrocortisone Hypothalamic structure Impaired cognition Incidence Inferior Inflammation Interleukin-6 Interleukins Life Magnetic Resonance Magnetic Resonance Imaging Measures Medial Mediating Memory Memory Disorders Memory impairment Menopause Methyltransferase Nerve Growth Factors Neurosciences Neurosecretory Systems Ovarian Parietal Parietal Lobe Performance Pituitary Gland Prefrontal Cortex Pregnancy Prevention Public Health Recruitment Activity Regulation Risk Risk Factors Serum Sex Characteristics Short-Term Memory Siblings Signal Transduction Structure Testing Time Tumor Necrosis Factor-alpha Woman age related attenuation base blood oxygen level dependent brain volume burden of illness cingulate gyrus cohort critical period cytokine disability experience fetal follow-up human data hypercortisolemia hypothalamic-pituitary-adrenal axis in vivo interest long term memory male maternal serum men middle age novel preclinical study prenatal prevent programs sex social therapy development white matter

项目摘要

DESCRIPTION (provided by applicant): Few studies focus on sex differences in aging, and even fewer on early antecedents to this critical adult onset problem, even though women are at twice the risk of memory (MEM) deficits with aging than men. Animal studies have demonstrated fetal antecedents to adult MEM circuitry deficits, implicating disruption of the hypothalamic-pituitary-adrenal (HPA) axis on hippocampal (HIPP) and prefrontal cortex (PFC) development, structure and function in adulthood, brain regions that are sexually dimorphic and relatively dense in glucocorticoid and gonadal hormone receptors. The proposed study is based on the premise that the developmental period of the sexual differentiation of the brain in mid-to-late gestation is a critical window during which sex differences in MEM deficits associated with aging arise. We hypothesize that loss of estrogenic support during the menopausal transition, particularly women exposed to fetal HPA disruption, will have significant effects on sexually dimorphic brain regions that impact MEM and working MEM function. We have a rare opportunity to investigate fetal antecedents to sex differences in adult MEM/wMEM deficits in human in vivo studies because the PI and her collaborators have been conducting 40-year follow-up studies of a prenatal cohort, consisting of subjects (now ages 44-51) followed from gestation. We are funded in MH074835 to evaluate adult subjects on multiple domains (e.g., prenatal sera for HPA disruption; adult MEM performance) on 350 discordant siblings, one of whom experienced fetal HPA disruption. In the proposed study, we will re recruit 200 of these same-sex discordant siblings, equally divided by gender, and use functional and structural MRI, diffusion tensor imaging to evaluate white matter abnormalities, and hormonal evaluations to test our hypotheses that fetal HPA disruption and genetic polymorphisms contribute to explaining midlife sex differences in aging of MEM/wMEM circuitries as ovarian function declines, which is THE critical period to study sex-specific MEM deficits. Identifying early hormonal biomarkers (even fetal) of sex-specific vulnerability to cognitive decline will be significant for the development of interventions that would prevent or attenuate age related disability and maintain intact MEM function in women and men.

描述（由申请人提供）：很少有研究关注衰老过程中的性别差异，甚至很少有研究关注这一关键的成人发病问题的早期前因，尽管女性因衰老而出现记忆（MEM）缺陷的风险是男性的两倍。动物研究表明，成人 MEM 电路缺陷有胎儿先兆，这意味着海马 (HIPP) 和前额叶皮层 (PFC) 上的下丘脑 - 垂体 - 肾上腺 (HPA) 轴的破坏，成年后的结构和功能，以及性别二态性的大脑区域糖皮质激素和性腺激素受体相对密集。这项研究的前提是，妊娠中晚期大脑性别分化的发育期是一个关键窗口，在此期间，与衰老相关的 MEM 缺陷出现性别差异。我们假设，在绝经过渡期间雌激素支持的丧失，尤其是暴露于胎儿 HPA 破坏的女性，将对影响 MEM 和工作 MEM 功能的性别二态性大脑区域产生重大影响。我们有一个难得的机会在人类体内研究中调查成人 MEM/wMEM 缺陷的胎儿前因，因为 PI 和她的合作者一直在对产前队列进行 40 年的随访研究，该队列由受试者（现在年龄44-51）从妊娠开始。我们获得 MH074835 的资助，对 350 名不一致的兄弟姐妹进行多个领域（例如，HPA 破坏的产前血清；成人 MEM 表现）的成人受试者评估，其中一名经历了胎儿 HPA 破坏。在拟议的研究中，我们将重新招募 200 名同性不一致的兄弟姐妹，按性别平均分配，并使用功能和结构 MRI、扩散张量成像来评估白质异常，并使用激素评估来检验我们的假设，即胎儿 HPA 破坏遗传多态性有助于解释中年时期随着卵巢功能下降，MEM/wMEM 电路老化的性别差异，这是研究性别特异性 MEM 缺陷的关键时期。识别性别特异性认知能力下降脆弱性的早期激素生物标志物（甚至胎儿）对于制定预防或减轻与年龄相关的残疾并维持女性和男性完整的 MEM 功能的干预措施具有重要意义。