Disruptions in the brain reward system through postnatal exposure to GABA agonists and anesthetics

产后接触 GABA 激动剂和麻醉剂会扰乱大脑奖励系统

• 批准号: 10440005
• 负责人: ELIF ENGIN
• 金额: $ 47.25万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440005
• 关键词: Address; Adult; Affect; Age-Years; Alcoholism; Alcohols; Anesthetics; Anhedonia; Animals; Anti-Anxiety Agents; Antiepileptic Agents; Anxiety; Anxiety Disorders; Area; Behavior; Behavioral; Benzodiazepines; Biological Models; Birth; Brain; Cations; Cells; Child; Chronic; Chronic stress; Controlled Study; Corpus striatum structure; Data; Development; Diffuse; Disease; Drug Addiction; Drug Exposure; Drug abuse; Early Intervention; Emotional; Environment; Etiology; Exposure to; Female; GABA Agonists; General anesthetic drugs; Genetic; Hand; Human; Individual; Infant; Inflammation; Interneurons; Intervention; Isoflurane; Knowledge; Lead; Link; Long-Term Effects; Mediating; Mental Depression; Mental disorders; Messenger RNA; Mission; Modeling; Molecular; Molecular Target; Mood Disorders; Moods; Motivation; Mus; Natural experiment; Neurons; Nucleus Accumbens; Outcome Study; Output; Pattern; Perinatal; Perinatal Exposure; Pharmaceutical Preparations; Pharmacology; Physiological; Population; Positioning Attribute; Predisposition; Pregnant Women; Procedures; Process; Protein Analysis; Public Health; Reporting; Research; Rewards; Risk; Risk Factors; Social Behavior; Specificity; Stress; Symptoms; System; Techniques; Therapeutic; Therapeutic Uses; Toddler; United States National Institutes of Health; Withdrawal; Work; addiction; alcohol exposure; base; behavioral study; brain shape; disability; drug of abuse; drug reward; emotional behavior; experimental study; follow-up; gamma-Aminobutyric Acid; hypnotic; innovation; mRNA Expression; mouse model; neglect; neurotransmission; nonhuman primate; novel; nursing mothers; optogenetics; postnatal; postnatal development; protein expression; receptor; receptor expression; reward circuitry; sedative; single cell proteins; social; stressor; trafficking; ward

Early developmental exposure to GABAergic drugs leads to lasting changes in brain reward systems and reward- related behaviors, possibly due to the protracted development of the brain GABA system which extends several years into postnatal development, presenting a long developmental vulnerability window. Exposed individuals are more vulnerable to mood and addiction disorders as adults. Over 1.5 million infants and toddlers go through procedures that require general anesthetics (GAs) each year. GAs achieve most of their therapeutic end-points through their interactions with GABAA receptors (GABAARs) and cause persistent changes in the expression and trafficking of GABAARs similar to those caused by other GABAergic drugs. However, there is a significant gap in knowledge when it comes to the question of whether limited early developmental exposure to GABAA-acting GAs may also induce molecular and plastic changes in brain reward systems and reward-related behaviors that last into adulthood. The overall objective of this application is to address this gap using mice as a model system, focusing on evolutionarily-conserved brain circuits in well-controlled experiments. Our central hypothesis is that early exposure to GAs, as a robust and well-controlled model of GABAergic drug exposure, induces per- manent changes in GABAAR expression and/or trafficking in the nucleus accumbens (NAc), disrupting neuro- transmission in intra-NAc microcircuits and affecting reward-related behaviors. As such, our specific aims are to determine early GA exposure induced changes at the molecular level (GABAAR expression and trafficking), circuit level (intra-NAc neurotransmission and PFC–NAc feedforward inhibition) and behavioral level (respon- sivity to natural and drug rewards, stress-susceptibility). Considering the diffuse and extensive molecular effects of early GA exposure across brain circuits, our specific aims also include establishing causality between the dif- ferent levels of analyses, by attempting to alleviate disruptions in neurotransmission and behavior by normaliz- ing NAc GABAAR expression and activity. We believe the contribution of these findings to the field will be signif- icant, as they will extend our fundamental knowledge of long-lasting changes in the GABAAR system induced by GABAAR manipulations during specific developmental vulnerability periods. Translationally, the findings will indicate whether early GA-exposed children may be at risk for addiction and mood disorders as adults and will identify a causal molecular, pharmacologically targetable culprit. The findings will have wide-ranging impli- cations for short-term postnatal exposure to other GABAergic drugs, such as anxiolytics, sedatives and antiepi- leptics. Our studies are innovative, we believe, as they represent a significant departure from the status quo in their focus on this significant, yet neglected question, in their approach that pertains to multiple levels of analyses and establishes causality between them, and in the use of state-of-the-art techniques, such as single-cell protein analysis and temporally-precise optogenetic control of receptor activity, which makes it possible to address the questions at hand with a level of detail and precision that is not possible with more conventional approaches.

早期发育性接触GABA能药物会导致大脑奖励系统和奖励的持久变化 - 相关行为，可能是由于大脑GABA系统的受保护发展所致，该系统扩展了几个 产后发展几年，展现了一个长期的发展脆弱性窗口。暴露个人 作为成年人，更容易受到情绪和成瘾障碍的影响。超过150万婴儿和幼儿经历了 每年需要全身麻醉（气）的程序。气体达到大部分的治疗终点 通过与GABAA接收器（GABAARS）的互动，并在表达式上持续变化 与其他GABA能药物相似的GABAAR贩运GABAAR。但是，存在很大的差距 当涉及到有限的早期发育暴露于GABAA作用气体的问题时，知识 也可能引起大脑奖励系统和奖励相关行为的分子和塑性变化 成年。该应用程序的总体目的是使用小鼠作为模型系统来解决此差距， 专注于良好控制的实验中的进化保存的脑电路。我们的中心假设是 早期暴露于气体，是一种强大且控制良好的GABA能药物暴露模型，可导致 伏击核（NAC）中GABAAR表达和/或运输的弯曲变化，破坏了神经 - NAC内部微电路的传播并影响与奖励相关的行为。因此，我们的具体目标是 为了确定早期GA暴露会在分子水平（Gabaar表达和运输）处引起的变化， 电路水平（NAC内神经传递和PFC – NAC馈电抑制）和行为水平（响应 自然和药物奖励的严重性，压力敏感性）。考虑弥漫性和广泛的分子效应 在跨大脑电路的早期GA暴露中，我们的具体目的还包括建立差异之间的偶然性 通过试图减轻正常化的神经递质和行为的干扰来进行分析水平 NAC GABAAR的表达和活性。我们认为，这些发现对该领域的贡献将是显着的 ICANT，因为他们将扩展我们对加巴尔系统中长期变化的基本知识 在特定的发育漏洞期间的Gabaar操纵。翻译上，发现将 指出早期公平的儿童是否有成年人有成瘾和情绪障碍的风险 确定因果分子，药物靶向的罪魁祸首。调查结果将具有大范围的暗示 短期出生后接触其他GABA能药物的阳离子，例如抗焦虑药，镇静剂和抗抗菌药物 诱饵。我们认为，我们的研究具有创新性，因为它们代表了与现状的重大不同 他们专注于这个重要但被忽视的问题，他们的方法与多个分析有关 并在它们之间建立因果关系，并在使用最新技术（例如单细胞蛋白）中 分析和暂时对受体活性的光遗传学控制，这使得解决 手头的问题具有一定的细节和精度，而更常规的方法是不可能的。