Menschik E D, Finkel L H
Institute of Neurological Sciences, University of Pennsylvania, Philadelphia 19104, USA.
Artif Intell Med. 1998 May;13(1-2):99-121. doi: 10.1016/s0933-3657(98)00006-2.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of cognitive function whose cellular pathology and molecular etiology have been increasingly and dramatically unraveled over the last several years. Despite this substantial knowledge base, the disease remains poorly understood due to a basic lack of understanding of how memories are stored and recalled in the brain. We describe a preliminary attempt at constructing a detailed model of these basic neural mechanisms; in particular, the natural dynamics of neuronal activity in hippocampal region CA3 and the modulation and control of these dynamics by subcortical cholinergic and GABAergic input to the hippocampus. We view the construction of such a model, with sufficient detail at the cellular and subcellular level, to be a necessary first step in understanding the effect of AD pathology on the functional behavior of the underlying neural circuitry. The network is based on the 66-compartment hippocampal pyramidal cell model of Traub and colleagues and their 51-compartment interneuron interconnected with realistic AMPA-, NMDA-, and GABA(A)-mediated synapses. Traub and others have shown that a network composed of these modeled cells is capable of synchronization in the gamma frequency range. We demonstrate here that this synchronization mechanism can implement an attractor-based autoassociative memory. A new input pattern arrives at the beginning of each theta cycle (comprised of 5-10 gamma cycles), and the pattern of activity across the network converges, over several gamma cycles, to a stable attractor that represents the stored memory. In this model, cholinergic deprivation, one of the hallmarks of AD, leads to a slowing of the gamma frequency which reduces the number of "cycles" available to reach an attractor state. We suggest that this may be one mechanism underlying the memory loss and cognitive slowing seen in AD. Our results also support the idea that acetylcholine acts on individual neurons to induce and maintain a transition from intrinsic bursting to spiking in pyramidal cells. These results are consistent with the hypothesis that spiking and bursting in CA3 pyramidal cells mediate separate behavioral functions, and that cholinergic input is required for the transition to and support of behavioral states associated with the online processing and recall of information.
阿尔茨海默病（AD）是一种认知功能进行性神经退行性疾病，在过去几年中，其细胞病理学和分子病因学已得到越来越多且显著的揭示。尽管有了这个坚实的知识基础，但由于对记忆在大脑中如何存储和回忆基本缺乏了解，该疾病仍然知之甚少。我们描述了一次初步尝试，旨在构建这些基本神经机制的详细模型；特别是海马体CA3区神经元活动的自然动态，以及海马体的皮层下胆碱能和GABA能输入对这些动态的调节和控制。我们认为，构建这样一个在细胞和亚细胞水平具有足够细节的模型，是理解AD病理学对潜在神经回路功能行为影响的必要第一步。该网络基于Traub及其同事的66节段海马锥体细胞模型以及他们的51节段中间神经元，这些神经元通过逼真的AMPA、NMDA和GABA(A)介导的突触相互连接。Traub等人已经表明，由这些建模细胞组成的网络能够在γ频率范围内同步。我们在此证明，这种同步机制可以实现基于吸引子的自联想记忆。一个新的输入模式在每个θ周期（由5 - 10个γ周期组成）开始时到达，并且在几个γ周期内，网络中的活动模式会收敛到一个代表存储记忆的稳定吸引子。在这个模型中，胆碱能剥夺是AD的标志之一，它会导致γ频率减慢，从而减少了达到吸引子状态所需的“周期”数量。我们认为，这可能是AD中记忆丧失和认知减慢的一种潜在机制。我们的结果还支持这样一种观点，即乙酰胆碱作用于单个神经元，以诱导并维持锥体细胞从固有爆发转变为发放。这些结果与以下假设一致：CA3锥体细胞中的发放和爆发介导不同的行为功能，并且胆碱能输入是向与信息的在线处理和回忆相关的行为状态转变以及维持该状态所必需的。
