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

促进情绪循环成熟的 NMDA 受体信号传导靶点

• 批准号: 7787943
• 负责人: GAVIN R RUMBAUGH
• 金额: $ 9.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-20 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787943
• 关键词: Abnormal Cell; Address; Adult; Amygdaloid structure; Anxiety; Apoptotic; Area; Behavior; Behavioral; Behavioral Paradigm; Binding; Biochemical; Biological Preservation; Brain; Brain region; Calcium; Cell Death; Cell Nucleus; Child; Childhood; Cognitive; Cues; Cytoplasm; Data; Development; Developmental Process; Diagnosis; Emotional; Emotions; Environment; Etiology; Event; Extinction (Psychology); Forebrain Development; Fright; Functional disorder; Funding; Funding Mechanisms; Future; Genetic; Growth; Hippocampus (Brain); Individual; Lead; Learning; Life; MAP Kinase Gene; Measures; Memory; Mental Retardation; Mental disorders; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; Neonatal; Nervous system structure; Neurologic; Neurons; Organelles; Outcome; Partner in relationship; Pathway interactions; Performance; Phenotype; Play; Prefrontal Cortex; Probability; Process; Proteins; Publishing; Reagent; Receptor Signaling; Reporting; Research; Research Personnel; Resources; Rodent; Rodent Model; Role; Sensory; Sensory Process; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Synapses; Synaptic Transmission; Testing; Time; critical period; design; early childhood; early experience; experience; human RIPK1 protein; human data; in vivo; innovation; insight; juvenile animal; learning extinction; mutant; neonate; neural circuit; neurodevelopment; neuron apoptosis; novel; postnatal; programs; receptor; receptor expression; receptor function; recombinase; research study; response; sensory system; social; somatosensory; synaptogenesis

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.

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。 在这个应用程序中，研究人员将探索一个新的假设，表明早期新生儿的经验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情感相关环境线索做出反应的能力，这并不奇怪。 研究人员提出，新生儿的社会经历触发了神经元活动，这些活动改善了从杏仁核内的各种核团投射或直接支配的回路。 他们得出了这一假设，初步研究表明，NMDAR相互作用蛋白SynGAP是成年小鼠对恐惧和焦虑做出适当反应所必需的。 已发表的研究表明，这种蛋白质可以调节NMDAR下游的信号通路。 由于这些受体对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小鼠表达异常恐惧和焦虑是因为控制情绪处理的大脑区域之间的布线不当。 重要的是，SynGAP被认为是非综合征性精神发育迟缓的原因，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，他们将产生一个小鼠线，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的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。 这些实验的结果将最终确定NMDAR-SynGAP信号在情感回路成熟中的作用。 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。 总的来说，研究人员乐观地认为，这些研究将为有助于情绪保存所需电路的分子和细胞机制提供初步见解。 这一应用很有可能成熟为一个更实质性的研究计划，旨在了解儿童早期经历如何塑造成年人行为的细节。 相关性：总的来说，本申请探索了一个创新的假设，旨在评估通过NMDARs信号对控制情绪的电路的出生后发展的影响。 了解引发情绪反应成熟的分子机制可能会给我们带来对儿童精神疾病原因的新见解。