Maintaining Activity Set-Points in the Hippocampus: From Long-Term Dynamics of Excitatory and Inhibitory Synapses to Functional Stability of CA1 Circuits.

维持海马体的活动设定点：从兴奋性和抑制性突触的长期动态到 CA1 回路的功能稳定性。

• 批准号: 448865644
• 负责人: Dr. Alessio Attardo
• 金额: --
• 依托单位: Department of Physiology and Pharmacology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/448865644?language=en
• 关键词: Maintaining; Activity; Set; Points; Hippocampus

How neuronal circuits maintain the balance between stability and plasticity in a constantly changing environment remains a fundamental question in neuroscience. Empirical and theoretical studies suggest that homeostatic control systems stabilize neuronal activity at a specific set-point. In the hippocampus, the high levels of synaptic turnover and neuronal plasticity together with the constant generation of new neurons pose a challenge for homeostatic systems. Here, we propose to explore the relationship between structural and functional plasticity of hippocampal synapses and firing rate stability in hippocampal circuits in vivo by addressing three key open questions. First, is high turnover of synapses part of a homeostatic system, necessary to stabilize neuronal activity? Second, is invariance of population activity a function of the ability of single neurons to maintain stable firing properties or rather is an emerging property of a network of intrinsically unstable neurons? Third, how do molecular homeostatic mechanisms that stabilize neuronal activity affect hippocampal synaptic plasticity?To address these questions, we will use chronic optical imaging to track excitatory and inhibitory synapse dynamics and neuronal activity at the level of individual neurons and neuronal populations in the hippocampal CA1 area of live mice for extended periods of time. We will then investigate the relationship between synaptic plasticity, firing homeostasis and adaptive mechanisms by employing chemogenetic and electrical approaches to induce chronic hyperactivity in the CA3 area. Finally, we will explore the causal relationship between synapse loss and renormalization of activity upon temporary hyper activation by reducing synaptic loss by knockdown of AMPK signaling pathway and testing the effects of this manipulation on firing homeostasis in CA1. As aberrant network activity and impaired synaptic plasticity represent a hallmark of numerous brain disorders, including temporal lobe epilepsy and Alzheimer’s disease, our study will offer novel conceptual insights into the pathogenesis of these disorders.

神经元回路如何在不断变化的环境中保持稳定性和可塑性之间的平衡仍然是神经科学的一个基本问题。经验和理论研究表明，稳态控制系统稳定在一个特定的设定点的神经元活动。在海马中，高水平的突触更新和神经元可塑性以及新神经元的不断产生对稳态系统构成了挑战。在这里，我们建议探讨海马突触的结构和功能可塑性和放电率稳定性在海马电路在体内通过解决三个关键的开放问题之间的关系。首先，突触的高转换率是稳态系统的一部分，是稳定神经元活动所必需的吗？第二，群体活动的不变性是单个神经元维持稳定放电特性的能力的函数，还是本质上不稳定的神经元网络的新兴特性？第三，稳定神经元活动的分子稳态机制如何影响海马突触可塑性？为了解决这些问题，我们将使用慢性光学成像来跟踪兴奋性和抑制性突触动力学和神经元活动的水平上的单个神经元和神经元群体在海马CA1区的活小鼠延长的时间。然后，我们将研究突触可塑性，放电稳态和适应机制之间的关系，采用化学遗传学和电的方法来诱导慢性过度活跃的CA3区。最后，我们将探讨突触丢失和重新规范化的活动后，暂时超激活的因果关系，通过敲低AMPK信号通路，减少突触丢失和测试这种操作的影响，在CA 1放电稳态。由于异常的网络活动和受损的突触可塑性代表了许多大脑疾病的标志，包括颞叶癫痫和阿尔茨海默病，我们的研究将提供新的概念见解这些疾病的发病机制。