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

项目摘要 围产期以强烈的可塑性为标志，使其容易受到可能脱轨的环境因素的影响。 正常的大脑发育，并导致成年人的不适应行为。体内高水平的5-羟色胺 由基因操作、母体炎症或选择性- 5-羟色胺再摄取抑制物(SSRI)导致脑发育改变和/或行为缺陷 成年啮齿动物如快感缺乏、焦虑样行为和社交缺陷。在我们的前期工作中， 我们发现，围产期增加5-羟色胺能张力会导致探查活动减少， 对安非他命挑战的反应减弱，动力不足。有趣的是，这些行为 依赖于多巴胺能系统，这是一种已知的情绪、奖励寻求和动机行为的调节器。 在发育过程中，5-羟色胺能系统的发育早于多巴胺能系统和中缝背侧。 核团强烈投射到腹侧被盖区，使5-羟色胺能系统能够调节 多巴胺能一号。虽然大多数研究都集中在发育异常的5-羟色胺水平的影响上 5-羟色胺能系统本身或皮质发育，它如何影响多巴胺能系统和功能 是未知的。根据初步数据，我们推测，在发育过程中，高水平的5-羟色胺会干扰 中缝腹侧被盖区伏核通路对多巴胺能神经的作用 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，我们将评估在发育过程中升高的5-羟色胺水平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的小鼠的依赖行为受到影响。在目标2中，我们描绘了 我们初步观察到的多巴胺依赖任务缺陷的分子、细胞和电路基础 数据。了解5-羟色胺和多巴胺在该钥匙中的调节和相互作用 单胺能环路可能具有从情绪障碍到自闭症和动机障碍的临床意义 行为的各个方面。此外，尽管我们的5-羟色胺能操纵是从实验和 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相关。的确，有些人 怀孕需要使用抗抑郁药，这通常会增加胎儿的血清素水平。增强版 对早期海拔高度的行为后果及其调节机制的理解 5-羟色胺能水平可能对改善此类后代的终生结局具有重要意义 未来的怀孕情况。

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.