Synapse-specific Regulation of Transmission and Integration in the Barrel Cortex

描述（由申请人提供）：在过去的几十年里，人们对提升感觉信息如何在新皮层中整合进行了广泛的研究。这种对皮层感觉统合的持续兴趣源于这样一种信念，即感觉加工是认知功能和功能障碍的关键方面的基础，如感觉知觉、感觉辨别、创伤和其他认知功能障碍。在感觉皮层中，第4层是特定丘脑皮层传入事件的主要目标层，也是皮层感觉处理开始的层。已知只有大约5-15%的第4层神经元上的兴奋性突触来自丘脑皮质（TC）纤维，而其他大多数兴奋性突触来自皮质内（IC）纤维。然而，TC和IC连接对感觉处理的相对重要性仍然存在争议，部分原因是对这些连接的细胞和分子特性了解不足。一些研究认为，TC突触足够强大和可靠，可以将感觉信息传递到皮层，而另一些研究认为，循环的IC突触在放大和动态调节TC输入中是必不可少的，此外，TC和IC连接的突触强度是如何维持和调节的尚不清楚。结合电生理学、分子生物学和遗传学技术，我们最近发现IC和TC突触的突触反应表现出不同的动力学，这可能代表了整合和放大感觉输入的一种新颖而重要的策略。我们的初步数据还表明，这些突触的动力学差异是由于突触特异性递送不同的ampa敏感谷氨酸受体（-Rs）。基于这些结果，我假设突触后的传递调节在第4层皮质神经元中是突触特异性的。我们将研究是什么控制突触动力学和IC突触的传输效率。此外，我们将确定是什么调节突触动力学和传导效率在TC突触。最后，我们将研究IC和TC突触如何维持突触强度。由于不同的AMPA-Rs在介导突触传递和控制突触效能方面表现出不同的特性，本项目的研究结果将有助于理解新皮层的感觉生理和皮层病理。

DESCRIPTION (provided by applicant): How ascending sensory information is integrated in the neocortex has been extensively studied in the last several decades. This sustained interest in cortical sensory integration stems from the belief that sensory processing underlies key aspects of cognitive functions and dysfunctions, such as sensory perception, sensory discrimination, trauma and other cognitive dysfunctions. In sensory cortices, layer 4 constitutes the main target layer for specific thalamocortical afferents and is the layer in which cortical sensory processing begins. It is known that only approximately 5-15% of excitatory synapses onto layer 4 neurons are from thalamocortical (TC) fibers, whereas the majority of other excitatory synapses are from intracortical (IC) fibers. However, the relative importance of TC and IC connections to sensory processing is still in debate, due in part to the poor understanding of the cellular and molecular properties of these connections. Some studies have suggested that TC synapses are strong and reliable enough to convey sensory information into the cortex, while others have argued that recurrent IC synapses are indispensable in amplifying and dynamically regulating TC inputs, hi addition, how synaptic strengths of TC and IC connections are maintained and regulated is unclear. Combining electrophysiology, molecular biology and genetics techniques, we have recently found that synaptic responses at IC and TC synapses display different kinetics, which may represent a novel and important strategy for integrating and amplifying sensory inputs. Our preliminary data also suggest that the differences of kinetics at these synapses are due to synapse-specific delivery of distinct AMPA-sensitive glutamate receptors (-Rs). Based on these results, I hypothesize that postsynaptic regulation of transmission is synapse-specific in layer 4 cortical neurons. We will examine what controls the synaptic kinetics and efficacy of transmission at IC synapses. Moreover, we will determine what regulates synaptic kinetics and efficacy of transmission at TC synapses. Finally, we will investigate how IC and TC synapses maintain synaptic strength. Because different AMPA-Rs exhibit distinct properties in mediating synaptic transmission and in controlling synaptic efficacy, the results from this project should aid the understanding of sensory physiology of neocortex and cortical pathologies.