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: 10609846
• 负责人: Catia Teixeira
• 金额: $ 39.44万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609846
• 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; Locomotion; Measures; Mediating; Mediator; 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.

项目摘要 围产期以强大的可塑性为特征，使其容易受到可能脱轨的环境因素的攻击 正常的大脑发育并导致成年人的适应不良行为。高水平的5-羟色胺 遗传操纵，母体炎症或选择性 - 选择性 - 5-羟色胺 - 再摄取抑制剂（SSRIS）导致大脑发育和/或行为缺陷的改变 成年啮齿动物（例如Anhedonia，焦虑般的行为和社交互动缺陷）。在我们的初步工作中 我们发现，在围产期期间，血清素能张力的增加导致探索减少， 减少对苯丙胺挑战和动机缺陷的反应。有趣的是，这些行为是 取决于多巴胺能系统，这是一种已知的情绪调节者，寻求和动机行为。 在开发过程中，血清素能系统的发展比多巴胺能和背raphe更早 细胞核强烈投射到腹侧对段区域，使血清素能系统能够调节 多巴胺能一种。虽然大多数研究都集中在异常发育性羟色胺水平的影响上 在血清素能系统本身或皮质发育上，它如何影响多巴胺能系统和功能 是未知的。我们根据初步数据假设，发育过程中高水平的5-羟色胺干扰 多巴胺能通过背面raphe>腹侧换段区域>伏隔核途径 导致成人行为缺陷。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的5-羟色胺水平升高如何影响我们的目标 多巴胺能电路。在AIM 1中，我们扩展了我们的初步数据，以表征多巴胺的程度 在围产期暴露于SSRI的小鼠中，依赖行为受到影响。在AIM 2中，我们描绘 在我们的初步中观察到的多巴胺依赖性任务中缺陷的分子，细胞和电路碱基 数据。了解该键中5-羟色胺和多巴胺之间的调节和相互作用 单胺能电路可能具有从情绪障碍到自闭症和激励性的临床意义 行为方面。此外，尽管我们的血清素能操作是实验和 神经生物学的观点，它也可能与现实世界中的临床情况有关。确实，有些 怀孕需要使用抗抑郁药，这通常会增加胎儿5-羟色胺水平。增强 了解行为后果和早期高程的中介机制 血清素能水平可能对改善这种后代的终生结果具有重大影响 未来的怀孕。