Detailed models of network bursts and oscillations

描述：（由申请人提供）网络爆发和网络振荡在认知、记忆和神经精神疾病（包括癫痫和氯胺酮模型的记忆丧失和精神病）中很重要。通过适当的电刺激、各种神经活性药物、离子或pH值操作，网络爆发和振荡可以在野生型和转基因动物的脑切片中进行研究。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)非线性固有膜特性，b)化学突触相互作用（在许多时间尺度上，并且在神经元上空间分布）；C)树突之间以及新发现的轴-轴突位置的间隙连接。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-可能是由于在癫痫发作之前遗漏了间隙连接介导的效应。现有的模型也不能解释连接蛋白36敲除小鼠中网络振荡的重要方面，在这种情况下，神经元之间变得电不耦合。

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.