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

早期发育暴露于GABA能药物导致大脑奖励系统和奖励系统的持久变化。 相关行为，可能是由于大脑GABA系统的长期发展， 在出生后的几年里，呈现出一个长的发育脆弱性窗口。暴露个体 成年后更容易受到情绪和成瘾的影响。超过150万婴幼儿 每年都需要使用全身麻醉剂（GAs）的手术。GA实现了大多数治疗终点 通过它们与GABAA受体（GABAAR）的相互作用，并引起表达的持续变化， GABAAR的贩运类似于其他GABA能药物引起的贩运。然而，在以下方面存在重大差距： 当涉及到有限的早期发育暴露于GABAA作用的GAs是否 还可能诱导大脑奖励系统和奖励相关行为的分子和可塑性变化， 长大成人本申请的总体目标是使用小鼠作为模型系统来解决这一差距， 专注于在严格控制的实验中进化保守的大脑回路。我们的核心假设是 早期暴露于GAs，作为GABA能药物暴露的一个稳健和良好控制的模型，诱导了每- GABAAR表达的显著变化和/或丘脑核（NAc）中的运输，破坏了神经元的功能。 在NAc内微电路中的传输和影响奖励相关的行为。因此，我们的具体目标是 为了确定早期GA暴露诱导的分子水平的变化（GABAAR表达和运输）， 回路水平（NAc内神经传递和PFC-NAc前馈抑制）和行为水平（响应）， 对自然和药物奖励的敏感性，压力敏感性）。考虑到扩散和广泛的分子效应 早期GA暴露在大脑回路中，我们的具体目标还包括建立差异之间的因果关系， 不同层次的分析，试图通过正常化来减轻神经传递和行为的中断， NAc GABAAR的表达和活性。我们相信这些发现对该领域的贡献将是显著的- 因为它们将扩展我们对GABAAR系统长期变化的基本知识， GABAAR在特定发育脆弱期的操作。从翻译的角度来看，调查结果将 表明早期暴露于GA儿童是否可能像成年人一样有成瘾和情绪障碍的风险， 找出一个有因果关系的分子，可锁定目标的罪犯。这些发现将产生广泛的影响， 用于产后短期暴露于其他GABA能药物的阳离子，如抗焦虑药、镇静剂和抗癫痫药， 安定剂我们认为，我们的研究是创新的，因为它们代表了对现状的重大偏离， 他们在涉及多层次分析的方法中关注这一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，如单细胞蛋白质 分析和受体活性的时间精确的光遗传学控制，这使得有可能解决 以更传统的方法所不可能达到的细节和精确程度来处理手头的问题。

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.