Collaborative Research: Dynamic interactions of individual neurons in supporting hippocampal network oscillations during behavior

大脑中的认知和运动行为是由高度互联的神经元网络控制的。神经元通过一种叫做“尖峰”的信号进行交流，这种信号是由复杂的生物机制产生的。这些机制关键取决于阈下膜电位活性，而阈下膜电位活性是由离子电流和其他因素的复杂相互作用控制的。虽然单个神经元的尖峰模式通常是不规则的，但某些神经元网络产生周期性振荡模式。其中重要的是theta节律（4- 10hz），它已通过脑电图（EEG）或细胞外局部场电位（LFPs）等全球活动测量方法记录在大脑的各个区域。在运动活动和快速眼动睡眠期间观察到θ波振荡，并被认为在导航、情景记忆和学习中发挥重要作用。在脑切片制备的阈下膜电位水平和行为动物的海马CA1区也观察到θ波振荡。然而，网络水平的振荡活动如何与单个神经元的生物物理特性联系在一起，在很大程度上仍然未知。在这个项目中，研究人员将使用实验/理论相结合的方法来解决这个问题。波士顿大学的研究小组将在CA1的行为动物身上进行实验，新泽西理工大学的研究小组将进行详细的计算建模。这项研究有望产生一个框架，用于描述和理解高级神经元振荡如何通过复杂的网络相互作用依赖于单个神经元的振荡活动。pi还将努力向科学界传播其成像技术。该项目将有助于实验和计算神经科学的学生和博士后的跨学科培训。这个项目的中心假设是，海马体中的θ波振荡是由共振机制产生的，涉及单个神经元的内在特性，以及回路的相互作用，这些相互作用被调谐以放大来自内侧隔和可能的其他外部来源的θ波频率输入。我们将从涉及体内实验、计算建模和动力系统分析的跨学科角度来解决这一假设。我们的目标是了解体内海马theta振荡的细胞和电路机制，并创建一个理论框架来描述单个神经元振荡特性与网络振荡之间的生物物理和动态联系。波士顿大学的研究小组将采用一种新的电压成像技术来测量特定细胞类型的海马神经元的阈下电压动态和尖峰活动，这些细胞类型包括锥体细胞和局部中间神经元（例如，在不同水平的LFP θ振荡的行为状态下，parvalbuimum （PV）和somatostatin (SOM)-阳性）。此外，为了测试这些中间神经元在支持θ波振荡中的因果作用，将使用精确的光遗传激活和沉默。新泽西理工大学的研究小组将建立海马体网络的生物物理模型，其中包括参与神经元的内在阈下振荡特性和来自其他区域（例如，中隔）的输入，以产生θ LFP振荡。本研究的结果将为海马CA1网络振荡的形成提供机制见解，并对学习、记忆和其他认知功能产生影响。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Cognitive and motor behavior in the brain is controlled by networks of highly interconnected neurons. Neurons communicate via signals called spikes, which are generated by complex biological mechanisms. These mechanisms crucially depend on the subthreshold membrane potential activity, which is controlled by the complex interaction of ionic currents among other factors. Although the spiking patterns of the individual neurons are typically not regular, certain neuronal networks produce periodic oscillatory patterns. Important among them is the theta rhythm (4-10 Hz), which has been recorded in various brain areas by global activity measures, such as electroencephalography (EEG) or extracellular local field potentials (LFPs). Theta oscillations have been observed during motor activity and REM sleep, and are thought to play important roles in navigation, episodic memory and learning. Theta oscillations have also been observed at the subthreshold membrane potential level in brain slice preparations, and in behaving animals in the hippocampal CA1 area. However, how the oscillatory activity at the network level is linked to the biophysical properties of individual neurons remains largely unknown. In this project, the investigators will address this question using a combined experimental/theoretical approach. The Boston University team will perform experiments in behaving animals in CA1, and the NJIT team will carry out detailed computational modeling. This research is expected to generate a framework for describing and understanding how high-level neuronal oscillations depend on the oscillatory activity of individual neurons through complex network interactions. The PIs will also work to disseminate their imaging technology to the scientific community. This project will contribute to the cross-disciplinary training of students and postdoctoral trainees in both experimental and computational neuroscience. The central hypothesis of this project is that theta oscillations in the hippocampus are generated by resonant mechanisms involving the intrinsic properties of individual neurons, and circuit interactions that are tuned to amplify theta frequency inputs from the medial septum and possibly other external sources. We will address this hypothesis from an interdisciplinary perspective involving in vivo experiments, computational modeling, and dynamical systems analysis. We aim to understand the cellular and circuit mechanisms of hippocampal theta oscillations in vivo, and to create a theoretical framework to describe the biophysical and dynamic links between the oscillatory properties of individual neurons and network oscillations. The Boston University team will deploy a novel voltage imaging technique to measure subthreshold voltage dynamics and spiking activity from individual hippocampal neurons of defined cell types, including pyramidal cells and local interneurons (e.g. parvalbumim (PV)- and somatostatin (SOM)- positive ones) during behavioral states with varying levels of LFP theta oscillations. Additionally, to test the causal role of these interneurons in supporting theta oscillations, precision optogenetic activation and silencing will be used. The NJIT team will build biophysical models of the hippocampal network that include the intrinsic subthreshold oscillatory properties of the participating neurons and inputs from other areas (e.g., medial septum) to produce theta LFP oscillations. The results of the proposed research will provide mechanistic insights on the formation of hippocampal CA1 network oscillations with implications to learning, memory and other cognitive functions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.