US-Israel Research Proposal: Network Resonance: Revealing the Neuronal Mechanisms

高级大脑功能，如运动和认知行为，依赖于网络中神经元的协调活动。神经元网络由各种各样的细胞类型组成，每种细胞都有不同的形态和功能。神经元之间通过称为尖峰的复杂电压信号机制进行交流，这种机制可能会也可能不会随着时间的推移表现出规律性的行为。然而，从混乱中崛起的结构：神经元网络能够表现出周期性的振荡，出现在他们的集体尖峰活动中，这种活动的中断可能会导致神经系统疾病。在这些振荡中，突出的是theta频段(4-10赫兹)节奏，它被认为形成了信息处理和传输的时间框架。这些波动是如何出现的，仍然是一个悬而未决的问题。减少准备的研究表明，当被周期性输入强迫时，所谓的主细胞表现出偏爱theta频率的亚阈值振荡活动(共振)。这可能表明，网络的theta振荡是从这种共振中“继承”的。然而，我们最近发现，在行为动物中，在网络水平上观察到的共振需要单个神经元和电路属性之间的相互作用，其方式比之前认为的更复杂。在这个项目中，研究人员将使用双管齐下的方法研究网络共振的潜在机制：美国团队将进行详细的计算建模，以色列团队将对行为正常的小鼠进行实验。这项研究有望产生一个描述和理解网络共振的框架，并为总体上理解大脑振荡奠定机制基础。因此，这项工作的结果有望对健康和疾病的认知和运动功能产生影响。该项目的中心假设是，在theta频段(4-10赫兹)的尖峰神经元的共振行为可以在大脑的不同区域局部产生，关键取决于参与的神经元的内在属性和网络连接的相互作用。研究人员将在海马区CA1和CA3以及新皮质中测试这一假设，在这些区域中，theta节律是突出的。虽然单个神经元的共振研究已有近30年的历史，但神经元的亚阈值振荡特性对形成振荡网络动力学的影响直到最近才逐渐成为实验和理论关注的焦点。我们理解中的低于阈值和高于阈值的差距的一个原因是缺乏一个理论框架来提供系统研究的基础，该框架是从神经系统的生物物理学角度描述的，并以实验结果为基础。这项研究旨在填补这一空白。通过将生物物理约束的计算模型和使用多点/多颜色光遗传操作的活体实验相结合，研究人员将构建各种可能的场景，将神经元的内在振荡特性与电路联系起来，并进行实验测试。这样，无论是在理论上还是在实践中，都将通过对这些神经元回路的询问来建立因果关系。这将有助于理解在海马体和新皮质中产生节律性振荡的神经回路，这对认知和运动行为有影响。此外，这项研究将有助于发展共振理论，并有助于理解振荡网络的相互作用。此外，将在该项目中使用的创新工具将为开发混合计算-体内实验工具铺平道路，这让人想起在体外使用动态钳子。美国-以色列两国科学基金会(BSF)正在资助一个配套项目。

High-level brain functions, such as motor and cognitive behavior, rely on the concerted activity of neurons in networks. Neuronal networks consist of a wide array of cells types, each having a distinct morphology and functionality. Neurons communicate among them through complex voltage signaling mechanisms called spikes, which may or may not exhibit regular behavior along time. Yet, from chaos rises structure: neuronal networks are able to exhibit periodic oscillations emerging from their collective spiking activity, and disruption of this activity may result in diseases of the nervous system. Prominent among these oscillations is the theta band (4-10 Hz) rhythm, which is believed to form a temporal framework for information processing and transmission. How these oscillations emerge is still an open question. Studies in reduced preparations show that the so-called principal cells exhibit a preference for theta-frequency subthreshold oscillatory activity (resonance) when they are forced with periodic inputs. This might suggest that the network theta oscillations are "inherited" from this resonance. However, we have recently found that in behaving animals, the resonance observed at the network level requires the interaction between single-neuron and circuit properties in ways that are more complex than previously thought. In this project, the investigators will study the mechanisms underlying network resonance using a two-pronged approach: The US team will carry out detailed computational modeling, and the Israel team will perform experiments with behaving mice. This research is expected to generate a framework for describing and understanding network resonance and to lay mechanistic foundations for understanding brain oscillations in general. Therefore, the results of this work are expected to have implications for cognitive and motor function in both health and disease. The central hypothesis of this project is that the resonant behavior of spiking neurons in the theta frequency band (4-10 Hz) can be generated locally in various areas of the brain, and crucially depends on the interplay of the intrinsic properties of the participating neurons and the network connectivity. The investigators will test this hypothesis in hippocampal areas CA1 and CA3 and in the neocortex, regions in which the theta rhythm is prominent. While resonance in single neurons has been studied for almost three decades, the effect of the subthreshold oscillatory properties of neurons on shaping the dynamics of oscillatory networks has only recently become the focus of increasing experimental and theoretical attention. One reason for the sub vs. suprathreshold gap in our understanding is the lack of a theoretical framework that could provide the basis for a systematic study, is described in terms of the biophysics of neuronal systems, and is grounded in experimental results. This research is aimed at filling this void. By combining biophysically constrained computational modeling and in vivo experiments using multi-site/multi-color optogenetic manipulations, the investigators will construct the various plausible scenarios linking the intrinsic oscillatory properties of neurons to circuits and test them experimentally. In this way, causal relations will be established by interrogating these neuronal circuits both theoretically and in practice. This will contribute to the understanding of the neuronal circuits that underlie the generation of rhythmic oscillations in the hippocampus and the neocortex, which have implications for cognition and motor behavior. In addition, this research will contribute to the development of a theory of resonance and to the understanding of the interplay of oscillatory networks. Furthermore, the innovative tools that will be used in this project will pave the way for the development of hybrid computational-in vivo experimental tools reminiscent of the use of the dynamic clamp in vitro. A companion project is being funded by the US-Israel Binational Science Foundation (BSF).