Department of Biology, Washington University in Saint Louis, St. Louis, MO, USA.
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in Saint Louis, St. Louis, MO, USA; Institute for Brain Science and Disease, Chongqing Medical University, Chongqing 400016, China.
Neuron. 2024 Nov 6;112(21):3567-3584.e5. doi: 10.1016/j.neuron.2024.08.006. Epub 2024 Sep 5.
Homeostatic regulation of neuronal activity is essential for robust computation; set-points, such as firing rate, are actively stabilized to compensate for perturbations. The disruption of brain function central to neurodegenerative disease likely arises from impairments of computationally essential set-points. Here, we systematically investigated the effects of tau-mediated neurodegeneration on all known set-points in neuronal activity. We continuously tracked hippocampal neuronal activity across the lifetime of a mouse model of tauopathy. We were unable to detect effects of disease in measures of single-neuron firing activity. By contrast, as tauopathy progressed, there was disruption of network-level neuronal activity, quantified by measuring neuronal pairwise interactions and criticality, a homeostatically controlled, ideal computational regime. Deviations in criticality correlated with symptoms, predicted underlying anatomical pathology, occurred in a sleep-wake-dependent manner, and could be used to reliably classify an animal's genotype. This work illustrates how neurodegeneration may disrupt the computational capacity of neurobiological systems.
神经元活动的体内平衡调节对于稳健的计算至关重要；例如，发射率等基准值会被主动稳定下来以补偿干扰。与神经退行性疾病相关的大脑功能障碍可能源于对计算至关重要的基准值的损害。在这里，我们系统地研究了 tau 介导的神经退行性变对神经元活动的所有已知基准值的影响。我们在 tau 病模型的小鼠一生中持续跟踪海马神经元的活动。我们无法在单个神经元活动的测量中检测到疾病的影响。相比之下，随着 tau 病的进展，网络水平的神经元活动受到干扰，通过测量神经元的成对相互作用和关键程度来量化，这是一种体内平衡控制的理想计算状态。关键值的偏差与症状相关，预测潜在的解剖病理学，以睡眠-觉醒依赖的方式发生，并且可以可靠地对动物的基因型进行分类。这项工作说明了神经退行性变如何破坏神经生物学系统的计算能力。
