Role of adolescent stress in postpartum mood and cognition

项目概要/摘要 产后情绪障碍和认知障碍是产后常见且严重的问题 女性心理健康。早期生活压力，例如青春期的社会心理压力，会增加患此病的风险 人类产后情绪和认知问题，包括产后情绪的发展 失调。尽管如此，将青春期压力与产后情绪和情绪联系起来的生物学机制 认知异常尚不清楚。我们的长期目标是研究产前生活压力如何 影响从青春期到成年的发育轨迹中的荷尔蒙系统、神经功能和行为 产后期并剖析从分子到电路和行为的机制。人体成像 研究已将前岛叶 (AI) 到背侧前扣带回的投影功能变化联系起来 皮层 [dACC，与啮齿类动物的前边缘皮层 (PrL) 同源] 与产后行为变化的关系。高架 下丘脑-垂体-肾上腺轴负反馈干扰导致糖皮质激素水平下降 产后期会改变神经功能。为了对这些要点获得更多的生物学见解，我们建立了一个 研究青少年压力对产后影响的生物学机制的新平台 基于青少年社会隔离范式，我们研究了初为人母的情绪和认知行为 已经发布了。因此，我们当前的目标是检验以下假设：青少年压力 与怀孕/分娩的压力事件相结合，会导致与以下相关的产后行为缺陷 通过糖皮质激素介导的 AI-PrL 谷氨酸能投射功能改变来调节情绪和社会认知。 为了解决这一假设，我们将追求以下具体目标：在目标 1 中，我们将研究 AI-PrL 对青少年应激诱导的成年产后小鼠 PrL 功能障碍和行为缺陷的预测 结合使用最先进的技术，包括体内钙成像与 自由移动小鼠的投射特异性神经元操作。在目标 2 中，我们将确定以下角色： 糖皮质激素受体（GR）在青少年应激诱导的 PrL 功能障碍和成人行为缺陷中的作用 产后小鼠。在目标 3 中，我们将使用逆行追踪和细胞类型特异性操作相结合 绿色荧光蛋白 (GFP) 依赖性 Cre 重组酶系统来检查因果作用 GR 介导的 AI-PrL 谷氨酸能投射对成人产后 PrL 功能障碍和行为缺陷的影响 小鼠预先接受青少年隔离饲养。我们的研究结果可能为产后提供生物学见解 情绪障碍和认知障碍非常普遍，不仅对人产生有害影响 母亲，也包括孩子和其他家庭成员。这些发现将产生广泛的影响 全世界妇女和儿童的福祉。

PROJECT SUMMARY/ABSTRACT Mood disturbance and cognitive impairment during the postpartum period are common and serious problems in women's mental health. Early life stress, such as psychosocial stress during adolescence, increases the risk for postpartum emotional and cognitive problems in humans, including the development of postpartum mood disorders. Nonetheless, the biological mechanisms linking adolescent stress to postpartum emotional and cognitive abnormalities are not well understood. Our long-term goal is to examine how pre-partum life stress affects hormonal systems, neural function, and behaviors in the developmental trajectory from adolescence to the postpartum period and dissect the mechanisms from molecules to circuits and behavior. Human imaging studies have linked functional changes in the projections from the anterior insula (AI) to dorsal anterior cingulate cortex [dACC, homologous to the prelimbic cortex (PrL) in rodents] to postpartum behavioral changes. Elevated levels of glucocorticoids by disturbance of negative feedback of the hypothalamic-pituitary-adrenal axis during the postpartum period can alter neural function. To gain more biological insight into these points, we have built a novel platform to study the biological mechanisms underlying the effects of adolescent stress on postpartum emotional and cognitive behaviors in first-time mothers, based on the adolescent social isolation paradigm we have already published. Hence, our current objective is to test the hypothesis that adolescent stress, in conjunction with the stressful events of pregnancy/delivery, leads to deficits in postpartum behaviors related to mood and social cognition via glucocorticoid-mediated functional alterations of AI-PrL glutamatergic projections. To address this hypothesis, we will pursue the following specific aims: In Aim 1, we will examine the role of AI-PrL projections in adolescent stress-induced PrL dysfunction and behavioral deficits in adult postpartum mice using a combination of state-of-the-art techniques, including in vivo calcium imaging in conjunction with projection-specific neuronal manipulation in freely moving mice. In Aim 2, we will determine the role of glucocorticoid receptor (GR) in adolescent stress-induced PrL dysfunction and behavioral deficits in adult postpartum mice. In Aim 3, we will combine retrograde tracing and cell type-specific manipulation using the green fluorescent protein (GFP)-dependent Cre recombinase system to examine the causal role of GR-mediated AI-PrL glutamatergic projections in the PrL dysfunction and behavioral deficits in adult postpartum mice pre-exposed to adolescent isolation rearing. Our findings may provide biological insights into postpartum mood disturbance and cognitive impairment, which are highly prevalent and have deleterious effects not only on the mother, but also on the children and the rest of the family. These findings will have a broad impact on the well-being of women and children worldwide.