Dynamic control of sensory processing by an active network of interneurons

 描述（由申请人提供）：抑制性中间神经元在神经元网络中至关重要地控制信息处理，但其巨大的分子和解剖学多样性使得难以剖析其功能作用。小脑皮质结构简单，神经元亚型少，是研究中间神经元功能的理想模型回路。在小脑皮质，苔藓纤维（MF）将感觉信息传递给颗粒细胞（GC），颗粒细胞将其轴突发送到分子层以激发浦肯野细胞（PC）。作为小脑输入层唯一的中间神经元，高尔基体细胞（GoCs）的战略地位，以控制感觉信息的传播到小脑输出层。自发激活的GoC以两种不同的时间过程抑制GC：快速阶段性抑制，其缩小兴奋性输入整合的时间窗口，以及持续性紧张性抑制，其控制传入信号的增益。此外，GoC被认为介导在运动行为开始之前在GC层中观察到的缓慢振荡。GOCs之间的强电耦合允许这些振荡，协调GC的大组件。虽然它是公认的，关键的决定，在小脑皮质内的信息流，较少的是已知的机制，协调GoC发射，调节GoC的活动，并动态控制GC兴奋性。与目前在该领域的信念相反，初步数据支持这一假设，即活性GoC树突增强电耦合。因此，该提案旨在确定使GoCs能够使用双光子钙成像，膜片钳电生理学，电压成像和阵列断层扫描同步发射的细胞机制。初步结果还表明，GoC活性决定树突钙浓度。因此，计划中的实验将检查GoC活性和树突钙动力学之间的功能关系，并确定兴奋性PF和MF输入的突触可塑性的后果。初步数据表明，GoCs上的代谢型受体的激活抑制放电，并且这种抑制伴随着GC的紧张性抑制的减少。因此，在电生理学和光遗传学的帮助下，该提议将测试GoC放电率的动态调节控制GC兴奋性和MF输入整合的假设。完成概述的工作将阐明的机制，控制通过改变一个单一的中间神经元亚型在小脑皮层的活动的感觉信息的整合。它还将扩展我们对抑制如何控制神经网络中的计算过程的一般理解。

 DESCRIPTION (provided by applicant): Inhibitory interneurons crucially control information processing in neuronal networks, but their vast molecular and anatomical diversity has made it difficult to dissect their functional roles. The cerebellar cortex with its relatively simple architecture and few neuron subtypes constitutes an ideal model circuit to study interneuron function. In the cerebellar cortex, mossy fibers (MFs) relay sensory information to granule cells (GCs) that send their axons to the molecular layer to excite Purkinje cells (PCs). As the only interneurons of the cerebellar input layer, Golgi cells (GoCs) are strategically positioned to control the propagation of sensory information to the cerebellar output layer. Spontaneously active GoCs inhibit GCs with two distinct time courses: rapid phasic inhibition that narrows the time window for excitatory input integration, and persistent tonic inhibition that controls the gai of incoming signals. Moreover, GoCs are thought to mediate the slow oscillations observed in the GC layer prior to the onset of motor behaviors. Strong electrical coupling between GoCs permits these oscillations that coordinate large assemblies of GCs. Although it is well established that GoCs crucially determine the flow of information within the cerebellar cortex, less is known about the mechanisms that orchestrate GoC firing, regulate GoC activity, and dynamically control GC excitability. Contrary to current beliefs in the field, preliminary data supports the hypothesis that active GoC dendrites enhance electric coupling. This proposal thus seeks to determine the cellular mechanisms that enable GoCs to fire synchronously using two-photon calcium imaging, patch clamp electrophysiology, voltage imaging and array tomography. Preliminary results also suggest that GoC activity dictates dendritic calcium concentration. The planned experiments will therefore examine the functional relationship between GoC activity and dendritic calcium dynamics, and determine the consequences for synaptic plasticity of excitatory PF and MF input. Preliminary data indicates that activation of metabotropic receptors on GoCs suppresses firing, and that this suppression is accompanied by a decrease in tonic inhibition of GCs. With the help of electrophysiology and optogenetics, this proposal will therefore test the hypothesis that dynamic modulation of GoC firing rate controls GC excitability and MF input integration. Completion of the outlined work will elucidate the mechanisms that control integration of sensory information by varying the activity of a single interneuron subtype in the cerebellar cortex. It will also extend our general understanding of how inhibition governs computational processes in neural networks.