Gestational Stress and Oxytocin-Dopamine Interactions in New Mothers

 描述（由申请人提供）：产后抑郁症是一种使人衰弱的疾病，影响估计20%的新妈妈，使其成为妇女最普遍的心理健康状况之一。除了典型的抑郁症状，产后抑郁症还伴随着中断的生育，这可能对后代的发育产生长期的有害影响。该项目的长期目标是确定关键的大脑区域和神经化学物质在这些区域中起作用，这些区域负责抑郁母亲的发育障碍，以便更好地了解这种障碍的病因以及如何有效治疗。为了实现这一目标，结合已知产后抑郁症风险因素的动物模型提供了一个有价值的转化工具。流行病学研究表明，怀孕期间的慢性压力是产后抑郁症的主要危险因素。与人类一样，暴露于慢性妊娠应激的妊娠啮齿动物在产后期间表现出增加的抑郁样行为，沿着母性行为缺陷。因此，本申请的目的是使用妊娠压力来机械地研究产后抑郁症的特征性育儿缺陷。对此，产妇 照顾是一种奖励性、动机性行为，与其他类型的动机性行为一样，涉及中脑边缘多巴胺（DA）系统，特别是从腹侧被盖区（VTA）到丘脑核（NAc）壳的DA投射。越来越多的研究表明，来自下丘脑室旁核（PVN）和视前内侧区（mPOA）的催产素（OT）回路与DA系统密切相关，共同调控母婴互动。这个建议的中心假设是，妊娠压力减少的动机，通过OT-DA相互作用的中断从事孕产妇保健。我们将使用行为，神经解剖学和神经化学的方法来测试我们的中心假设在两个特定的目标。目的1将确定在何种程度上与产后NAc中DA活性的改变有关的妊娠应激对产妇动机和产妇护理的不良影响。目的2将研究妊娠应激对OT和OT输入到中脑边缘DA系统的影响。在这些目标中，有针对性的药理学操作DA和OT也将被用来检查在何种程度上可以扭转压力引起的赤字在孕产妇保健和孕产妇的动机。这项研究意义重大，因为它将为了解与产后抑郁症相关的母体功能受损的基本神经生物学机制提供急需的见解。

 DESCRIPTION (provided by applicant): Postpartum depression is a debilitating disorder affecting an estimated 20% of new mothers making it one of the most prevalent mental health conditions in women. In addition to classical depressive symptoms, postpartum depression is accompanied by disrupted caregiving which can have long-lasting deleterious effects on offspring development. The long-term goal of this project is to identify the key brain regions and neurochemicals acting in those regions that are responsible for impaired caregiving in depressed mothers in order to better understand the etiology of such impairments and how they can be effectively treated. To achieve that goal, animal models that incorporate known risk factors for postpartum depression provide a valuable translational tool. Epidemiological studies have shown that chronic stress during pregnancy is a major risk factor for postpartum depression. Like humans, pregnant rodents exposed to chronic gestational stress exhibit increased depressive-like behaviors during the postpartum period along with deficits in maternal behavior. Thus, the objective in this application is to use gestational stress to mechanistically study parenting deficits that are characteristic of postpartum depression. In this regard, maternal care is a rewarding, motivated behavior that like other types of motivated behaviors, involves the mesolimbic dopamine (DA) system, particularly DA projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) shell. An increasing number of studies suggest that oxytocin (OT) circuits from the paraventricular nucleus (PVN) and medial preoptic area (mPOA) of the hypothalamus closely interact with the DA system to regulate mother-infant interactions. The central hypothesis of this proposal is that gestational stress diminishes the motivation to engage in maternal care through a disruption in OT-DA interactions. We will use behavioral, neuroanatomical and neurochemical approaches to test our central hypothesis in two Specific Aims. Aim 1 will determine the extent to which the adverse effects of gestational stress on maternal motivation and maternal care are associated with altered DA activity in the postpartum NAc. Aim 2 will examine the effects of gestational stress on OT and OT inputs to the mesolimbic DA system. In these aims, targeted pharmacological manipulations of DA and OT will also be employed to examine the extent to which stress-induced deficits in maternal care and maternal motivation can be reversed. The proposed research is significant because it will provide much needed insight into the fundamental neurobiological mechanisms underlying impaired maternal functioning associated postpartum depression.