CRCNS: Gamma Rhythms and Cell Assemblies

描述（由申请人提供）：在神经系统的许多部位发现伽马频率振荡（30- 90hz），包括海马体，新皮层，内嗅皮层和杏仁核。它们被认为对一系列功能都很重要，包括注意力、早期感觉处理、短期记忆、运动活动。精神疾病，特别是精神分裂症，与这种节律的病理有关，许多人现在正在研究这些病理，以寻找疾病病理生理学的线索。在一个简单的描述层面上，伽马振荡被认为是小白蛋白阳性（PV+）快速尖峰（FS）中间神经元和锥体细胞的相互作用。然而，已知其他类型的细胞，特别是中间神经元，参与伽马节律和/或可能调节这些节律的强度和一致性。为了理解这些节律的功能重要性，有必要更好地了解产生和调节它们的机制。在这里，我们首次提出将数学建模与一系列新兴技术的应用相结合，包括分子生物学、光学和电生理学，以研究在皮层中产生伽马振荡的网络的细胞类型特异性和电路特性。我们将使用初级听觉皮层的体外模型，使用谷氨酸能激动剂kainate或胆碱能激动剂carbachol诱导伽马振荡。特定种类的细胞会被短时间或长时间的光照激活或抑制。重点研究锥体细胞、PV+细胞、表达胆囊收缩素（CCK+）细胞和含有生长抑素（SOM+）的中间神经元。最小模型将由这些细胞类型和包含所有这些细胞类型的网络构建。该模型网络将用于了解CCK+和SOM+中间神经元如何与PV+细胞相互作用以改变伽马节律，并与不同细胞类型活动的实验操作相关联。实验和模型也将用于了解CCK+和SOM+细胞如何影响细胞组装的产生。更广泛的影响：这项工作是这些实验室关于动态在认知功能中的重要性的更广泛研究的一部分。这位研究者是波士顿地区认知节律合作组织（Cognitive rhythm Collaborative）的负责人，该组织由大约20名资深科学家组成，其目标是创建和支持新的合作，包括在疾病研究中利用基础科学和建模的合作，包括癫痫、帕金森病、自闭症和精神分裂症。在这个项目中所做的工作将提供新的科学，将与该小组的许多其他人的工作相互作用。这项实验工作首次将分子生物学、光学和电生理学结合起来，研究了网络的细胞类型特异性和电路特性；这些技术，由这个小组的一名成员开创，然后可以在这个小组之外的许多其他环境中使用。这些技术和结果将有助于提供有关精神疾病病理生理学的信息；这有可能通过纠正与症状相关的“振荡冷漠”（脑动力学缺陷）来控制这类疾病。最后，具体项目还将帮助培养两名研究生和一名博士后。

DESCRIPTION (provided by applicant): Gamma frequency oscillations (30-90 Hz) are found in many parts of the nervous system, including the hippocampus, neocortex, entorhinal cortex and amygdala. They are believed to be important for a range of functions, including attention, early sensory processing, short term memory, motor activity. Mental illnesses, notably schizophrenia, are associated with pathologies in this rhythm, and many people are now studying these pathologies for clues to the pathophysiology of the diseases. At a simple level of description, gamma oscillations are thought to come about as interactions of parvalbumin positive (PV+) fast-spiking (FS) interneurons and pyramidal cells. However, it is known that other cell types, especially interneurons, participate in gamma rhythms and/or may modulate power and coherence of those rhythms. To understand the functional importance of these rhythms, it is necessary to better understand mechanisms that create and modulate them. Here we propose to use, for the first time, the combination of mathematical modeling with application of a set of emerging techniques involving molecular biology, optics, and electrophysiology to study the cell-type specific and circuitry properties of networks that produce gamma oscillations in the cortex. We will use in vitro models of the primary auditory cortex, with gamma oscillations induced using the glutamatergic agonist kainate or the cholinergic agonist carbachol. Specific classes of cells will be activated or suppressed by brief or longer periods of light. The work will focus on pyramidal cells, PV+ cells, cholecystokinin-expressing (CCK+) cells and somatostatin-containing (SOM+) interneurons. Minimal models will be constructed of these cells types and networks containing all of them. The model networks will be used to understand how the CCK+ and SOM+ interneurons interact with the PV+ cells to alter the gamma rhythms, in connection with experimental manipulations of the activity of different cell types. The experiments and models will also be used to understand how the CCK+ and SOM+ cells may affect the creation of cells assemblies. Broader Impacts: This work is part of a broader set of research by these labs on the importance of dynamics in cognitive function. The investigator is head of the Cognitive Rhythms Collaborative in the Boston area, a group of about 20 senior scientists, whose aim is to create and support new collaborations, including those making use of basic science and modeling in the study of disease, including Epilepsy, Parkinson's Disease, Autism and Schizophrenia. The work done in this project will provide new science that will interact with the work of many others in that group. The experimental work provides, for the first time, a combination of molecular biology, optics, and electrophysiology to study the cell-type specific and circuitry properties of networks; these techniques, pioneered by a member of this group, can then be used in many other contexts, beyond this group. The techniques and results will help provide information about the pathophysiology of mental illnesses; this has the potential of controlling such diseases by correcting the "oscillapathy" (defects in brain dynamics) associated with the symptoms. Finally, the specific project will also help train two graduate students and a postdoctoral fellow.