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.

早期发育接触 GABA 能药物会导致大脑奖励系统和奖励系统发生持久变化 相关行为，可能是由于大脑 GABA 系统的长期发育所致，该系统扩展了几个 出生后发育多年，暴露个体存在较长的发育脆弱期。 超过 150 万婴儿和幼儿在成年后更容易患上情绪障碍和成瘾障碍。 每年需要全身麻醉 (GA) 的手术都能达到大部分治疗终点。 通过与 GABAA 受体 (GABAAR) 的相互作用，引起表达和表达的持续变化 GABAAR 的贩运与其他 GABA 能药物引起的贩运相似，但存在显着差距。 涉及 GABAA 作用 GA 的早期发育暴露是否有限的问题时的知识 还可能引起大脑奖励系统的分子和可塑性变化以及持续的奖励相关行为 该应用程序的总体目标是使用小鼠作为模型系统来解决这一差距， 我们的中心假设是在严格控制的实验中关注进化保守的大脑回路。 早期暴露于 GA，作为 GABA 能药物暴露的稳健且控制良好的模型，可诱导 per- 伏隔核 (NAc) 中 GABAAR 表达和/或运输的显着变化，破坏神经 NAc 内微电路中的传输并影响奖励相关行为因此，我们的具体目标是。 确定早期 GA 暴露引起的分子水平变化（GABAAR 表达和运输）， 电路水平（NAc 内神经传递和 PFC-NAc 前馈抑制）和行为水平（反应 对自然和药物奖励的敏感性、压力敏感性）。 早期 GA 暴露在大脑回路中的研究，我们的具体目标还包括建立差异之间的因果关系 通过尝试通过正常化来减轻神经传递和行为的干扰，进行不同层次的分析 我们相信这些发现对该领域的贡献将是重大的。 很重要，因为它们将扩展我们对由 GABAAR 系统引起的长期变化的基础知识 换言之，研究结果将在特定的发育脆弱期进行 GABAAR 操纵。 表明早期接触 GA 的儿童成年后是否可能面临成瘾和情绪障碍的风险，并且会 确定一个分子上的、药理学上可靶向的罪魁祸首。这些发现将具有广泛的意义。 产后短期接触其他 GABA 能药物，如抗焦虑药、镇静剂和抗癫痫药 我们相信，我们的研究是创新的，因为它们代表了与现状的重大背离。 他们在涉及多层次分析的方法中关注这个重要但被忽视的问题。 并建立它们之间的因果关系，并使用最先进的技术，例如单细胞蛋白质 受体活性的分析和时间精确的光遗传学控制，这使得解决 手头的问题的细节和精确程度是更传统的方法所不可能的。