Detailed models of network bursts and oscillations

产品说明：网络爆发和网络振荡在认知、记忆和神经精神疾病（包括癫痫和记忆丧失和精神病的氯胺酮模型）中是重要的。网络爆发和振荡适合于在脑切片中研究，从野生型和转基因动物，应用适当的电刺激，各种神经活性药物，或离子或pH操纵。由于系统的复杂性，对机制的理解需要生物学上忠实的详细模型：a）非线性内在膜特性，B）化学突触相互作用（在许多时间尺度上，并在空间上分布在神经元上）; c）树突之间以及新发现的轴-轴位点处的间隙连接。所有这些都有助于网络行为的形成。目前可用的模型可以解释某些实验性癫痫期间的神经元放电模式，但不能解释癫痫发作的开始-可能是由于忽略了癫痫发作前间隙连接介导的作用。现有的模型也没有解释连接蛋白36敲除小鼠网络振荡的重要方面，其中中间神经元变得电解耦。 该提案中的工作旨在扩展现有的海马网络模型，以便同时纳入：准确描述的内在特性，以及神经元之间的突触和间隙连接介导的相互作用。这些模型将与电生理学家合作研究，他们研究由代谢型谷氨酸盐和胆碱能激动剂，红藻氨酸盐，碱化和其他手段引起的网络爆发和振荡。此外，还将开发新的丘脑和新皮层神经元单细胞模型，目的是研究丘脑皮层回路中的网络爆发和振荡。这项工作有可能为药物提供新的位点，用于抑制癫痫发作，并预测药物对正常网络行为的副作用。这项工作将与旨在开发能够揭示基本数学原理的更简单（即单室和/或易于分析）模型的研究相协调。

DESCRIPTION: (provided by applicant) Network bursts and network oscillations are important in cognition, memory and in neuropsychiatric disease (including epilepsy and the ketamine model of memory loss and psychosis). Network bursts and oscillations are amenable to study in brain slices, from wild-type and from genetically modified animals, with application of appropriate electrical stimulation, various neuroactive drugs, or ionic or pH manipulations. Understanding of mechanisms requires biologically faithful detailed models, due to the complexity of the system: there are a) non-linear intrinsic membrane properties, b) chemical synaptic interactions (on many time scales, and spatially distributed over the neurons); c) gap junctions, both between dendrites as well as at newly discovered axo-axonal sites. All of the above contribute to the shaping of network behavior. Presently available models can explain the neuronal firing patterns during certain experimental epilepsies, but not the initiation of a seizure - perhaps due to omission of gap-junction-mediated effects prior to the seizure. Available models also do not explain important aspects of network oscillations in connexin-36 knockout mice, in which inter-neurons become electrically uncoupled. The work in this proposal seeks to extend existing hippocampal network models, so as to incorporate simultaneously: accurately described intrinsic properties, and also both synaptic and gap-junction mediated interactions between neurons. Such models will be studied in collaboration with electro-physiologists, who examine network bursts and oscillations induced by metabotropic glutamate and cholinergic agonists, kainate, alkalinization, and other means. In addition, new single-cell models will be developed of thalamic and neo-cortical neurons, with the aim of studying network bursts and oscillations in thalamocorticat circuits. This work has the potential of suggesting novel sites for drugs intended to suppress seizure initiation, and to anticipate side effects that drugs can exert on putatively normal network behavior. The work will be coordinated with research aimed at developing simpler (i.e. single-compartment and/or analytically tractable) models that can uncover basic mathematical principles.