Targets of NMDA Receptor Signaling that Promote the Maturation of Emotional Circu

描述（由申请人提供）：该项目旨在了解支持成人情绪处理的细胞和分子机制。 在这项应用中，研究人员将探索一个新的假设，该假设表明早期新生儿的经历有助于塑造控制情绪反应的神经元回路。 人们早就知道，个体与环境之间的相互作用有助于大脑发育。 因此，童年早期的事件会影响一个人成年后对与情感相关的环境线索做出反应的能力，这并不奇怪。 研究人员提出，新生儿的社会经历会触发神经元活动，从而改善从杏仁核内的各个核投射或直接神经支配的回路。 他们根据初步研究得出这一假设，该研究表明 NMDAR 相互作用蛋白 SynGAP 对于成年小鼠对恐惧和焦虑的正确反应是必要的。 已发表的研究表明，该蛋白可以调节 NMDAR 下游的信号通路。 由于这些受体对于控制感觉过程的皮层区域的活动依赖性细化至关重要，因此可以想象，SynGAP 小鼠会因为控制情绪处理的大脑区域之间的连接不当而表达异常的恐惧和焦虑。 重要的是，SynGAP 被认为是非综合征性精神发育迟滞的一个原因，这支持了研究人员的假设，即这种蛋白质对大脑发育有重要贡献。 为了直接测试这个想法，他们将生成一个小鼠品系，该品系将提供对神经系统中 SynGAP 表达的时间控制。 研究人员将比较 SynGAP 表达减少的完全发育成年小鼠的恐惧和焦虑与新生儿发育前 SynGAP 蛋白减少的成年小鼠的表型。 这些实验的结果将明确确定 NMDAR-SynGAP 信号在情绪回路成熟中的作用。 此外，他们还将测量发育过程中 SynGAP 表达减少促进控制情绪的大脑区域异常细胞死亡的可能性。 总体而言，研究人员乐观地认为，这些研究将为有助于情感保存所需回路的分子和细胞机制提供初步见解。 该应用程序很可能成熟为更实质性的研究计划，旨在了解早期童年经历如何塑造成人行为的细节。 相关性：总体而言，本申请探索了一种创新假设，旨在评估通过 NMDAR 发出的信号对控制情绪的回路的出生后发育的影响。 了解触发情绪反应成熟的分子机制可能会让我们对儿童精神疾病的原因有新的见解。

DESCRIPTION (Provided by Applicant): This project is aims to understand the cellular and molecular mechanisms that support emotional processing in adults. In this application, the investigators will explore a novel hypothesis that suggests early neonatal experience contributes to the shaping of neuronal circuits that govern emotional responses. It has long been known that interactions between an individual and the environment can contribute to brain development. Therefore, it is not surprising that events early on in childhood can impact one's ability to respond to emotionally relevant environmental cues as an adult. The investigators propose that social experiences in neonates trigger neuronal activity that refine circuits that project from, or innervate directly, various nuclei within the amygdala. They arrived at the hypothesis in response to preliminary studies indicating that an NMDAR-interacting protein, SynGAP, is necessary for proper responses to fear and anxiety in adult mice. Published studies indicate that this protein can regulate signaling pathways downstream of NMDARs. Because these receptors are essential for activity-dependent refinement of cortical areas that control sensory processes, it is conceivable that SynGAP mice express abnormal fear and anxiety because of improper wiring among brain regions that govern emotional processing. Importantly, SynGAP has been implicated as a cause of nonsyndromic mental retardation, supporting the investigators' hypothesis that this protein contributes importantly to brain development. To directly test this idea, they will generate a mouse line that will provide temporal control over SynGAP expression in the nervous system. The investigators will compare fear and anxiety from fully developed adult mice with reduced SynGAP expression to the phenotype of adult mice with SynGAP protein reduced before neonatal development. The outcome of these experiments will definitively determine the role NMDAR-SynGAP signaling serves in the maturation of emotional circuitry. In addition, they will also measure the possibility that reduced SynGAP expression during development promotes abnormal cell death in brain areas that govern emotion. Overall, the investigators are optimistic that these studies will provide initial insight into the molecular and cellular mechanisms that contribute to circuits required for emotional preservation. This application has a high probability of maturing into a more substantial research program targeted at understanding the details of how early childhood experience may shape behavior as adults. RELEVANCE: Overall, this application explores an innovative hypothesis aimed at evaluating the effects of signaling through NMDARs on the postnatal development of circuits governing emotion. Understanding the molecular mechanisms that trigger the maturation of emotional responses may give us novel insights into the causes of childhood psychiatric conditions.