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同活动。神经网络由多种类型的细胞组成，每种细胞都有不同的形态和功能。神经元之间通过复杂的电压信号机制进行交流，这种机制被称为尖峰，随着时间的推移，它可能会也可能不会表现出规律的行为。然而，从混沌中产生结构：神经元网络能够从它们的集体尖峰活动中表现出周期性振荡，这种活动的破坏可能导致神经系统疾病。在这些振荡中，突出的是θ波段（4-10 Hz）节奏，它被认为形成了信息处理和传输的时间框架。这些振荡是如何产生的仍然是一个悬而未决的问题。研究表明，所谓的主细胞在周期性输入的强迫下表现出对频率阈下振荡活动（共振）的偏好。这可能表明网络振荡是从这种共振“继承”来的。然而，我们最近发现，在有行为的动物中，在网络水平上观察到的共振需要单个神经元和电路特性之间的相互作用，其方式比以前认为的要复杂得多。在这个项目中，研究人员将采用双管齐下的方法研究网络共振的机制：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老鼠进行实验。本研究有望产生一个描述和理解网络共振的框架，并为理解一般的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中的认知和运动功能产生影响。这个项目的中心假设是，在θ波段（4-10赫兹）的尖峰神经元的共振行为可以在大脑的各个区域局部产生，并且关键取决于参与神经元的内在特性和网络连接的相互作用。研究人员将在海马区CA1和CA3以及新皮层（θ节奏突出的区域）测试这一假设。虽然单个神经元的共振已经研究了近三十年，但神经元的阈下振荡特性对振荡网络动力学的影响直到最近才成为实验和理论关注的焦点。在我们的理解中，阈下与阈上差距的一个原因是缺乏一个理论框架，该框架可以为系统研究提供基础，以神经元系统的生物物理学来描述，并以实验结果为基础。这项研究旨在填补这一空白。通过结合生物物理约束的计算模型和使用多位点/多色光遗传学操作的体内实验，研究人员将构建各种似是而非的情景，将神经元的固有振荡特性与电路联系起来，并进行实验测试。通过这种方式，通过在理论上和实践中询问这些神经元回路，将建立因果关系。这将有助于理解在海马体和新皮层中产生有节奏振荡的神经元回路，这对认知和运动行为有影响。此外，这项研究将有助于共振理论的发展和对振荡网络相互作用的理解。此外，该项目中使用的创新工具将为混合体内计算实验工具的发展铺平道路，让人想起体外动态钳的使用。美国-以色列两国科学基金会（BSF）正在资助一个伙伴项目。

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).