Signaling Cascades in Sensory Map Development

感官地图开发中的信号级联

基本信息

批准号：
9099289
负责人：
HUI-CHEN LU
金额：
$ 34.13万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-26 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099289
关键词：
Address Affect Amyloid beta-Protein Precursor Animals Appearance Autistic Disorder Biological Models Brain CNR1 gene Cannabis Cells Congenital Epilepsy Development Drug Exposure Drug Targeting Electrodes Electroporation Endocannabinoids Enzymes Equilibrium Esthesia Evolution Exposure to Fetus Fragile X Mental Retardation Protein Genetic Glutamates Goals Health Human Individual Interneurons Knock-out Knockout Mice Knowledge Lesion Life Maps Mediating Modification Morphogenesis Mus Mutant Strains Mice Neurons Pattern Peripheral Phenotype Play Reagent Relative (related person)Role Schizophrenia Sensory Shapes Signal Transduction Structure Sum Synapses Synaptic Transmission Synaptic plasticity Testing Thalamic structure Therapeutic Intervention Trigeminal System Vibrissae Work barrel cortex cortex mapping critical period experience feeding in utero insight knock-down metabotropic glutamate receptor 5 nervous system disorder neural circuit neurodevelopment neuronal circuitry patch clamp postnatal presynaptic prevent relating to nervous system sensory stimulus somatosensory spatiotemporal synaptic function therapy development

项目摘要

DESCRIPTION (provided by applicant): In cortical sensory maps, thalamocortical afferents (TCAs) transmit peripheral sensations in organized arrays into distinct cortical neuronal modules to provide a topographic representation of the external sensory world. These cortical maps that form in every individual can be altered by exposure to abnormal sensory experience during a "critical period" of postnatal development. Mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism, schizophrenia, and congenital epilepsy. Using mouse whisker-maps as a model system, we found that metabotropic glutamate receptor 5 (mGluR5) signaling is involved in sculpting the anatomical structures and in regulating synaptic function and plasticity of thalamocortical connections. Eliminating mGluR5 function in cortical principal neurons resulted in a prolonged critical period for lesion-induced rearrangements of TCAs. Endocannabinoids (eCBs), known retrograde messengers in regulating synaptic transmission, are synthesized upon mGluR5 activation in many neurons. We hypothesize that during cortical map development mGluR5 signaling in cortical neurons instructs the anatomical modification of TCAs and that eCBs mediate, at least in part, the neural-activity dependent remodeling of thalamocortical synapses. In the proposed work we will address three specific aims: How does mGluR5 affect the development and plasticity of barrel cortex? How does mGluR5 affect functional development of cortical circuits and network activity? Do endocannabinoids mediate mGluR5 influences on developing cortical circuits? A combination of genetic, anatomical, electrophysiological, and pharmacological approaches will be employed to accomplish these aims. This study will provide a firm understanding of mGluR5 and eCBs signaling in developing neural circuits. Both mGluR5 and eCBs are potential drug targets for therapeutic interventions in humans. A detailed knowledge of their roles during neural development is critical not only for understanding normal brain function, but also to provide significant insights for the rational assessment of therapies or drug exposure (e.g., cannabis) that might affect the developing fetus.

描述（由申请人提供）：在皮质感觉图中，丘脑皮质传入神经（TCA）将有组织的阵列中的周围感觉传输到不同的皮质神经元模块中，以提供外部感觉世界的地形表示。每个人形成的这些皮质图可以通过在出生后发育的“关键时期”接触异常的感官体验而改变。生命早期神经元回路的错误连接可能是神经系统疾病的主要原因，包括自闭症、精神分裂症和先天性癫痫。使用小鼠胡须图作为模型系统，我们发现代谢型谷氨酸受体 5 (mGluR5) 信号传导参与塑造解剖结构并调节突触功能和丘脑皮质连接的可塑性。消除皮质主要神经元中的 mGluR5 功能会导致损伤诱导的 TCA 重排的关键期延长。内源性大麻素 (eCB) 是调节突触传递的已知逆行信使，在许多神经元中 mGluR5 激活后合成。我们假设，在皮质图谱发育过程中，皮质神经元中的 mGluR5 信号传导指导 TCA 的解剖修饰，而 eCB 至少部分介导丘脑皮质突触的神经活动依赖性重塑。在拟议的工作中，我们将解决三个具体目标：mGluR5 如何影响桶状皮层的发育和可塑性？ mGluR5 如何影响皮质回路和网络活动的功能发育？内源性大麻素是否介导 mGluR5 对发育中的皮质回路的影响？将采用遗传、解剖学、电生理学和药理学方法的结合来实现这些目标。这项研究将提供对神经回路发育过程中 mGluR5 和 eCB 信号传导的深入理解。 mGluR5 和 eCB 都是人类治疗干预的潜在药物靶点。详细了解它们在神经发育过程中的作用不仅对于理解正常的大脑功能至关重要，而且还为合理评估可能影响发育中胎儿的治疗或药物暴露（例如大麻）提供重要见解。