Impact of early life adversity on caregiving behaviors and reward-related brain function: testing a mechanistic role for corticosterone

项目摘要 在人类和啮齿动物中，父母的照顾受到环境逆境的干扰，包括低 资源条件（即，贫困、匮乏）。母亲的逆境与母亲的素质受损有关- 婴儿依恋和增加的不良依恋模式（即，虐待，忽视），这会扰乱大脑 以及后代的行为发展。重要的是，母性行为是代际行为， 一个女性所经历的母亲照顾的质量影响到她将给予自己后代的照顾的质量。 事实上，临床和临床前研究都表明，有早期生活逆境史的女性 在护理者的环境中（即，虐待（abuse，maltreatment）虐待自己的孩子。然而，神经 与生命早期逆境引起的适应不良的母亲行为状态相关的变化仍然很差， 明白一个潜在的途径是中脑边缘多巴胺（DA）系统，它起源于腹侧 被盖区（VTA），对早期生活压力敏感，并与奖励相关的过程密切相关- 包括母性行为此外，腹侧被盖区和中脑边缘DA信号的功能完整性也发挥了重要作用。 在母性行为的充分表达中的因果作用。因此，VTA DA神经元的活性受损 由早期逆境引起的焦虑可能会干扰母性动机所必需的与奖励相关的过程， 响应能力。然而，关于DA系统的功能调节及其与衰老的关系，目前还知之甚少 产后啮齿动物在早期生活逆境后的行为。为此，我聘请了一个特征鲜明的 基于在产后第2 - 9天（PD）期间创建贫困筑巢环境的操作， 为鼠坝提供有限的垫料和筑巢（LBN）材料，这增加了应激激素（即， 皮质酮（CORT）水平，并破坏母婴互动，从而模仿 压力环境对人类虐待/忽视的影响。我发现负性增加 母亲对幼崽的行为，受损的动机性母亲反应和钝化的VTA DA神经元 在LBN暴露的母鼠中PD 9 - 10的活性。这个提案的总体目标是复制我的博士后研究成果 产后逆境（LBN）对母体行为和中脑边缘DA功能的影响（在我的研究中） 独立实验室），并将其扩展到母性行为和中脑边缘系统的代际检查 DA在成年雌性后代中的功能，同时测试幼犬CORT增加的机制作用。的 总体假设是，早期生活稀缺-逆境（LBN dam，PD 2 - 9）将诱导受损的孕产妇 行为/破坏的母婴相互作用和中脑边缘DA下调（即，VTA活动减退） 成年雌性后代以皮质醇依赖的方式。我将通过防止CORT的出现来测试CORT的机械作用。 非典型的婴儿增加幼鼠CORT水平，并评估它是否可以规避早期逆境的影响， 母亲行为和产后DA功能。通过这种方式，我希望能提供一些见解， 多巴胺能机制有助于早期逆境诱导的母婴依恋变化。

PROJECT SUMMARY In both humans and rodents, parental care is disturbed by exposure to environmental adversity, including low resource conditions (i.e., poverty, scarcity). Maternal adversity is associated with compromised quality of mother- infant attachment and increased adverse caregiving patterns (i.e., maltreatment, neglect), which disrupt brain and behavioral development in the offspring. Importantly, maternal behavior is an intergenerational behavior, as the quality of maternal care a female experiences influences the quality of care she will give her own offspring. Indeed, clinical and preclinical research converge in showing that females with a history of early life adversity within the context of the caregiver (i.e., abuse, maltreatment) mistreat their own offspring. However, the neural changes associated with early life adversity-induced maladaptive maternal behavioral states remain poorly understood. One potential pathway is the mesolimbic dopamine (DA) system, which originates in the ventral tegmental area (VTA), is sensitive to early life stress, and is critically involved in reward-related processes- including maternal behavior. Moreover, the functional integrity of the VTA and mesolimbic DA signaling play a causal role in the adequate expression of maternal behavior. Thus, compromised activity of VTA DA neurons induced by early adversity may interfere with reward-related processes necessary for maternal motivation and responsiveness. However, little is known about the regulation of DA system function and its relation to caregiving behaviors in postpartum rodents following early life adversity. To this end, I employed a well-characterized manipulation based on creating an impoverished nesting environment during postpartum days (PD) 2-9 by providing the rat dam with limited bedding and nesting (LBN) materials, which increases stress hormone (i.e., corticosterone- CORT) levels in the dam and pups and disrupts mother-infant interactions, thereby mimicking the effects of a stressful environment in potentiating maltreatment/neglect in humans. I found increased negative maternal behaviors directed at pups, impaired motivated maternal responses and blunted VTA DA neuron activity at PD 9-10 in LBN-exposed dams. The overall goal of this proposal is to replicate my postdoctoral findings of postpartum adversity (LBN) effects on maternal behavior and mesolimbic DA function in the dam (in my independent lab) and extend them into an intergenerational examination of maternal behavior and mesolimbic DA function in the adult female offspring, while testing a mechanistic role for pup increases in CORT. The overarching hypothesis is that early life scarcity-adversity (LBN dam, PD 2-9) will induce impaired maternal behavior/disrupted mother-infant interactions and mesolimbic DA downregulation (i.e., VTA hypoactivity) in the adult female offspring in a CORT-dependent manner. I will test a mechanistic role for CORT by preventing the atypical infant increase in pup CORT levels and assessing whether it can circumvent early adversity effects on maternal behaviors and postpartum DA function in female offspring. In this way, I hope to provide insights into dopaminergic mechanisms contributing to early-adversity induced changes in mother-infant attachment.