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.

项目总结