Role of adolescent stress in postpartum mood and cognition

项目摘要/摘要 产后情绪障碍和认知障碍是产后妇女常见而严重的问题 女性的心理健康。早期的生活压力，如青春期的心理社会压力，会增加患癌症的风险 人类产后情绪和认知问题，包括产后情绪的发展 精神错乱。尽管如此，将青春期压力与产后情绪和心理健康联系起来的生物学机制 认知异常并没有得到很好的理解。我们的长期目标是研究产前生活压力 影响从青春期到青春期的激素系统、神经功能和行为 并剖析了从分子到回路和行为的机制。人体成像 已有研究将前岛叶(AI)至背侧前扣带回的投射的功能变化联系起来 皮质[dACC，与啮齿动物的初级皮质(PRL)同源]与产后行为变化有关。高架 大鼠下丘脑-垂体-肾上腺轴负反馈紊乱对糖皮质激素水平的影响 产后期会改变神经功能。为了对这些点有更多的生物学洞察，我们建立了一个 研究青春期应激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的第一次母亲的情绪和认知行为 已经出版了。因此，我们目前的目标是测试这一假设，即青少年压力，在 与怀孕/分娩的应激事件相结合，导致与以下方面相关的产后行为缺陷 情绪和社会认知通过糖皮质激素介导的AI-PRL谷氨酸能投射的功能改变。 为了解决这一假设，我们将追求以下具体目标：在目标1中，我们将检查 AI-PRL在青春期应激性PRL功能障碍和成年产后行为缺陷中的预测 小鼠使用最先进的技术组合，包括体内钙成像与 自由活动小鼠的投射特异性神经元操作。在目标2中，我们将确定 糖皮质激素受体(GR)在青春期应激性催乳素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 依赖绿色荧光蛋白(GFP)的Cre重组酶系统检测致病作用 GR介导的AI-PRL谷氨酸能投射在产后PRL功能障碍和行为缺陷中的作用 预先暴露于青春期隔离饲养的小鼠。我们的发现可能会为产后提供生物学上的见解 情绪障碍和认知障碍，这是非常普遍的，不仅对 母亲，也是孩子和家庭的其他成员。这些发现将对 世界各地妇女和儿童的福祉。

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.