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

早期暴露于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系统的长期发展，它延伸了几个 在出生后发育的几年中，出现了一个漫长的发育脆弱性窗口。暴露者 成年后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 每年需要全身麻醉剂(GAS)的手术。GAS达到了大多数治疗终点 通过它们与GABAA受体(GABAARs)的相互作用，并导致表达和 GABAAR的贩运类似于其他GABA能药物造成的贩运。然而，有一个显著的差距， 当涉及到是否限制早期发育暴露于GABAA作用气体的问题时 也可能导致大脑奖赏系统和奖赏相关行为的分子和可塑性变化 进入成年期。该应用程序的总体目标是使用MICE作为模型系统来解决这一差距， 在良好控制的实验中，专注于进化保守的大脑回路。我们的中心假设是 早期暴露于GAS，作为GABA能药物暴露的一个强大和良好控制的模型，诱导Per- 伏隔核(NAC)GABAAR表达和/或运输的显著变化，扰乱神经- 在NAC内部微电路中的传递，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暴露在分子水平上诱导的变化(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、应激敏感性)。考虑到扩散和广泛的分子效应 对于跨大脑回路的早期GA暴露，我们的具体目标还包括建立不同的 不同级别的分析，通过尝试通过正常化来缓解神经传递和行为的中断- ING 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- ICANT，因为它们将扩展我们对GABAAR系统中由 在特定发育脆弱时期的GABAAR操作。换言之，这些发现将 指出早期暴露于GA的儿童成年后是否会有成瘾和情绪障碍的风险 确定一个因果分子，药理上有针对性的罪魁祸首。这些发现将产生广泛的影响-- 出生后短期接触其他GABA能药物的阳离子，如抗焦虑药、镇静剂和抗癫痫药- 减肥药。我们相信，我们的研究是创新的，因为它们代表了对#年现状的重大偏离。 他们把重点放在这个重要但被忽视的问题上，因为他们的方法涉及到多个层次的分析 并建立了它们之间的因果关系，并在使用最先进的技术，如单细胞蛋白质 受体活性的分析和时间精确的光遗传控制，这使得有可能解决 手头问题的细节和精确度是更传统的方法所不可能的。

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.