Modulation of serotonin levels during development produce long-lasting changes in dopaminergic function

项目摘要 围产期的特点是强烈的可塑性，使其容易受到环境因素的影响，可能脱轨 正常的大脑发育，并导致成人的适应不良行为。高水平的血清素 遗传操作、母体炎症或选择性- 多巴胺再摄取抑制剂（SSRIs）导致大脑发育的改变和/或行为缺陷， 成年啮齿类动物，如快感缺乏，焦虑样行为和社会互动缺陷。在我们的初步工作中， 我们已经发现在围产期增加的肾上腺素能紧张性导致探查减少， 对安非他明挑战的反应降低和动机缺陷。有趣的是，这些行为 依赖于多巴胺能系统，一种已知的情绪、奖励寻求和动机行为的调节器。 在发育过程中，多巴胺能系统的发育早于多巴胺能系统和中缝背核 神经核强烈投射到大脑皮层区，使多巴胺能系统能够调节神经元的活动。 多巴胺能1。虽然大多数研究都集中在异常的发育血清素水平的影响， 对多巴胺能系统本身或皮质发育的影响，以及它如何影响多巴胺能系统和功能 不明基于初步数据，我们假设，在发育过程中高水平的血清素干扰了 多巴胺能通过中缝背核>中脑被盖区>伏隔核途径发挥作用 导致成年人的行为缺陷。使用行为测试、光遗传学和 电生理学，我们将评估在发展过程中血清素水平升高如何影响我们的目标， 多巴胺能回路在目标1中，我们扩展了我们的初步数据，以表征多巴胺- 在围产期暴露于SSRIs的小鼠中，依赖行为受到影响。在目标2中，我们描述了 在我们的初步研究中观察到的多巴胺依赖性任务缺陷的分子，细胞和电路基础 数据了解调节和血清素和多巴胺之间的相互作用，在这个关键 单胺能回路可以具有从情绪障碍到自闭症和动机障碍的临床意义。 行为的方面。此外，虽然我们的β-肾上腺素能操作是最佳的实验和 从神经生物学的角度来看，它也可能与现实世界的临床情况有关。事实上， 怀孕需要使用抗抑郁药，这通常会增加胎儿血清素水平。增强的 了解早期海拔的行为后果和介导机制， β-肾上腺素能水平可能对改善这种疾病的后代的终身结局具有重要意义。 怀孕在未来

Project Summary The perinatal period is marked by intense plasticity, making it vulnerable to environmental factors that can derail normal brain development and lead to maladaptive behaviors in the adult. High levels of serotonin during development resulting from genetic manipulations, maternal inflammation or administration of selective- serotonin-reuptake-inhibitors (SSRIs) lead to alterations in brain development and/or to behavioral deficits in adult rodents such as anhedonia, anxiety-like behaviors and social interaction deficits. In our preliminary work, we have found that increasing serotonergic tone during the perinatal period leads to decreased exploration, decreased response to an amphetamine challenge and motivation deficits. Interestingly, these behaviors are dependent on the dopaminergic system, a known regulator of mood, reward seeking and motivated behavior. During development, the serotonergic system develops earlier than the dopaminergic one and the Dorsal Raphe nucleus projects strongly to the Ventral Tegmental Area, enabling the serotonergic system to modulate the dopaminergic one. While most studies have focused on the effects of abnormal developmental serotonin levels on the serotonergic system itself or on cortical development, how it affects the dopaminergic system and function is unknown. We hypothesize, based on preliminary data, that high levels of serotonin during development disturb dopaminergic function through the Dorsal Raphe > Ventral Tegmental Area > Nucleus Accumbens pathway resulting in behavioral deficits in the adult. Using a combination of behavioral testing, optogenetics and electrophysiology, we will assess how elevated serotonin levels during development affect our target dopaminergic circuit. In Aim 1, we expand on our preliminary data to characterize the extent to which dopamine- dependent behaviors are affected in mice exposed to SSRIs during the perinatal period. In Aim 2, we delineate the molecular, cellular and circuit bases of the deficits in dopamine-dependent tasks observed in our preliminary data. Understanding the regulation and the interactions between serotonin and dopamine in this key monoaminergic circuit can have clinical implications spanning from mood disorders to autism and motivational aspects of behavior. Furthermore, although our serotonergic manipulation is optimal from experimental and neurobiological perspectives, it is also potentially relevant to real-world clinical situations. Indeed, some pregnancies require the use of antidepressants, which typically increase fetal serotonin levels. An enhanced understanding of the behavioral consequences and the mediating mechanisms of early elevations in serotonergic levels may have substantial implications for improving the lifelong outcomes of the offspring of such pregnancies in the future.