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

发育过程中血清素水平的调节会对多巴胺能功能产生持久的变化

• 批准号: 10378770
• 负责人: Catia Teixeira
• 金额: $ 40.82万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-11 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378770
• 关键词: Adult; Affect; Amphetamines; Anhedonia; Animals; Antidepressive Agents; Anxiety; Arousal; Behavior; Behavioral; Brain; Cells; Clinical; Complex; Consumption; Data; Development; Disease; Dopamine; Dopamine Receptor; Dopaminergic Cell; Dorsal; Dose; Electrophysiology (science); Emotions; Environmental Risk Factor; Exposure to; Female; Fiber; Fluoxetine; Future; Human; Inflammation; Injections; Lead; Life; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Mood Disorders; Moods; Motivation; Mus; Negative Valence; Neurobiology; Neuromodulator; Neuroregulator; Nucleus Accumbens; Operant Conditioning; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Photometry; Positive Valence; Predisposition; Pregnancy; Pregnancy Trimesters; Preparation; Process; Regulation; Rewards; Rodent; Role; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Signal Transduction; Social Behavior; Social Interaction; Stress; Sucrose; System; Testing; Third Pregnancy Trimester; Time; Umbilical Cord Blood; Ventral Tegmental Area; Western Blotting; Woman; Work; anxiety-like behavior; approach avoidance behavior; autism spectrum disorder; base; behavior test; behavioral impairment; critical period; dopamine system; dopamine transporter; dopaminergic neuron; dorsal raphe nucleus; early life exposure; emotion regulation; experimental study; fetal; genetic manipulation; improved; inhibitor; maladaptive behavior; male; motivated behavior; neuronal circuitry; neuropsychiatric disorder; offspring; optogenetics; perinatal period; prevent; pup; response; reuptake; social; willingness

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.

项目概要 围产期的可塑性很强，因此很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人的适应不良行为。期间血清素水平较高 由基因操作、母体炎症或选择性施用引起的发育 血清素再摄取抑制剂（SSRIs）会导致大脑发育改变和/或行为缺陷 成年啮齿动物，例如快感缺失、焦虑样行为和社交互动缺陷。在我们的前期工作中， 我们发现，围产期血清素能的增加会导致探索的减少， 对安非他明挑战的反应减弱和动力不足。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调节器。 在发育过程中，血清素能系统比多巴胺能系统和中缝背侧发育早 核强烈投射到腹侧被盖区，使血清素能系统能够调节 多巴胺能的一种。虽然大多数研究都集中在异常发育血清素水平的影响上 对血清素能系统本身或皮质发育的影响，它如何影响多巴胺能系统和功能 未知。根据初步数据，我们假设发育过程中高水平的血清素会干扰 通过中缝背侧 > 腹侧被盖区 > 伏隔核通路的多巴胺能功能 导致成人的行为缺陷。结合行为测试、光遗传学和 电生理学，我们将评估发育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，我们扩展了初步数据来描述多巴胺- 围产期暴露于 SSRIs 的小鼠的依赖性行为受到影响。在目标 2 中，我们描绘了 我们初步观察到的多巴胺依赖性任务缺陷的分子、细胞和电路基础 数据。了解血清素和多巴胺在这方面的调节和相互作用 单胺能回路可能具有从情绪障碍到自闭症和动机等多种临床意义 行为方面。此外，尽管我们的血清素能操作从实验和结果来看是最佳的 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。确实，有些 怀孕需要使用抗抑郁药，这通常会增加胎儿的血清素水平。增强型 了解早期升高的行为后果和中介机制 血清素能水平可能对改善此类后代的终生结果产生重大影响 将来怀孕。