Prenatal & Adult Immune Biomarkers of the Negative Valence Biosignature

描述（由申请人提供）：“负效价刺激引起的应激反应”涉及精神疾病，在健康人群中存在差异。本研究（响应RFA PAR-14-008的RO 3）旨在通过识别与免疫通路失调相关的生物特征1（特别是潜在基因、回路、生理学和病理学），了解负效价域潜在的神经生物学机制。我们先前的研究表明，负效价域的应激反应具有胎儿起源，因此我们相信，其与免疫失调相关的生物特征在产前和成年期都是可识别的。我们和其他人在人类和动物水平上证明，胎儿对应激反应回路发育的编程（即，下丘脑前部（aHYPO）、杏仁核（AMYG）、海马（HIPP）、内侧前额叶和前扣带皮层（mPFC，ACC）和中脑导水管周围灰质（PAG）9-13）对于理解人类特定诊断中的成人应激反应电路缺陷、类固醇激素和自主神经系统（ANS）失调7，8，14-16以及动物中的相关情绪和焦虑相关行为17 -20至关重要。在本RO 3中，我们将把这种成人表型与产前暴露和精神病理学的多基因风险联系起来。样本将由102名受试者组成，按性别平均分配（健康和患病个体的社区人群混合），来自一个独特的产前队列（随访至约50岁），其中在NIMH RO 1 MH 56956（精神病/健康对照）和P50 MH 082679（抑郁症/健康对照）中评价了表明妊娠中期母体对应激的免疫反应的生物样本。作为成年人，他们完成了功能磁共振成像使用视觉应激挑战负价刺激串联在扫描仪心电图，激素评价，和垂体病理学。此外，我们将对这些个体进行基因分型（GWAS），并根据精神病遗传学联盟的发现26，根据精神病和重度抑郁症分配多基因风险评分。因此，我们将开始：1）表征负价结构域的成人生物特征的免疫组分，因为它涉及脑回路激活、生理学和神经病学;和2）鉴定与该成人生物特征相关的产前免疫生物标志物和多基因风险。在此过程中，我们将提供关键信息， 该域作为精神病理学的核心组成部分的验证跨越诊断类别，在健康人群中变化，并且可以用作免疫相关治疗的功能靶点。

DESCRIPTION (provided by applicant): The "stress response engendered by negative valence stimuli" has been implicated across psychiatric disorders and varies in the healthy population. This study (an RO3 in response to RFA PAR-14-008) seeks to understand the neurobiologic mechanisms underlying the negative valence domain by identifying its biosignature1 (specifically here, underlying genes, circuits, physiology, and symptomatology) associated with immune pathway dysregulation. Our prior studies suggest that stress responses in the negative valence domain have fetal origins, and thus we believe that its biosignature associated with immune dysregulation will be identifiable both prenatally and in adulthood. We and others demonstrated at the human and animal levels that the fetal programming of stress response circuitry development (i.e., anterior hypothalamus (aHYPO), amygdala (AMYG), hippocampus (HIPP), medial prefrontal and anterior cingulate cortices (mPFC, ACC), and periaqueductal gray (PAG)9-13) is critical to understand adult stress response circuitry deficits, steroid hormone and autonomic nervous system (ANS) dysregulation in specific diagnoses in humans7,8,14-16 and associated mood- and anxiety-related behaviors in animals17-20. In this RO3, we will relate this adult phenotyping to prenatal exposures and polygenic risk for psychopathology. The sample will consist of 102 subjects, equally divided by sex (a community-population mix of healthy and ill individuals) from a unique prenatal cohort (followed to age ~50) in which biosamples indicating maternal immune responses to stress at mid-gestation have been evaluated in NIMH RO1 MH56956 (psychoses/healthy controls) and P50MH082679 (depression/healthy controls). As adults, they completed fMRI using a visual stress challenge to negative valence stimuli in tandem with in-scanner electrocardiogram, hormone evaluations, and symptomatology. Further, we will genotype (GWAS) these individuals and assign a polygenic risk score based on psychoses and major depressive disorder from the Psychiatric Genetics Consortium findings26. Thus, we will begin to: 1) characterize immune components of the adult biosignature of the negative valence domain as it relates to brain circuitry activation, physiology, and symptomatology; and 2) identify prenatal immune biomarkers and polygenic risk associated with this adult biosignature. In so doing, we will provide critical information for the validation of this domain as a core component of psychopathology that crosses diagnostic categories, varies within the healthy population, and can be used as functional targets for immune-related therapeutics.