Markussen Nanna Bertin, Knopper Rasmus West, Hasselholt Stine, Skoven Christian Stald, Nyengaard Jens Randel, Østergaard Leif, Hansen Brian
Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing, China.
Front Cell Neurosci. 2023 Apr 27;17:1138624. doi: 10.3389/fncel.2023.1138624. eCollection 2023.
The Locus Coeruleus (LC) is in the brainstem and supplies key brain structures with noradrenaline, including the forebrain and hippocampus. The LC impacts specific behaviors such as anxiety, fear, and motivation, as well as physiological phenomena that impact brain functions in general, including sleep, blood flow regulation, and capillary permeability. Nevertheless, the short- and long-term consequences of LC dysfunction remain unclear. The LC is among the brain structures first affected in patients suffering from neurodegenerative diseases such as Parkinson's disease and Alzheimer's Disease, hinting that LC dysfunction may play a central role in disease development and progression. Animal models with modified or disrupted LC function are essential to further our understanding of LC function in the normal brain, the consequences of LC dysfunction, and its putative roles in disease development. For this, well-characterized animal models of LC dysfunction are needed. Here, we establish the optimal dose of selective neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP-4) for LC ablation. Using histology and stereology, we compare LC volume and neuron number in LC ablated (LCA) mice and controls to assess the efficacy of LC ablation with different numbers of DSP-4 injections. All LCA groups show a consistent decrease in LC cell count and LC volume. We then proceed to characterize the behavior of LCA mice using a light-dark box test, Barnes maze test, and non-invasive sleep-wakefulness monitoring. Behaviorally, LCA mice differ subtly from control mice, with LCA mice generally being more curious and less anxious compared to controls consistent with known LC function and projections. We note an interesting contrast in that control mice have varying LC size and neuron count but consistent behavior whereas LCA mice (as expected) have consistently sized LC but erratic behavior. Our study provides a thorough characterization of an LC ablation model, firmly consolidating it as a valid model system for the study of LC dysfunction.
蓝斑（LC）位于脑干，为包括前脑和海马体在内的关键脑结构提供去甲肾上腺素。蓝斑影响特定行为，如焦虑、恐惧和动机，以及一般影响脑功能的生理现象，包括睡眠、血流调节和毛细血管通透性。然而，蓝斑功能障碍的短期和长期后果仍不清楚。蓝斑是帕金森病和阿尔茨海默病等神经退行性疾病患者首先受影响的脑结构之一，这表明蓝斑功能障碍可能在疾病发展和进展中起核心作用。具有改变或破坏蓝斑功能的动物模型对于增进我们对正常大脑中蓝斑功能、蓝斑功能障碍的后果及其在疾病发展中的假定作用的理解至关重要。为此，需要特征明确的蓝斑功能障碍动物模型。在这里，我们确定了用于蓝斑损毁的选择性神经毒素N-（2-氯乙基）-N-乙基-溴苄胺（DSP-4）的最佳剂量。使用组织学和体视学方法，我们比较了蓝斑损毁（LCA）小鼠和对照组的蓝斑体积和神经元数量，以评估不同注射次数的DSP-4对蓝斑损毁的效果。所有LCA组的蓝斑细胞计数和蓝斑体积均持续下降。然后，我们使用明暗箱试验、巴恩斯迷宫试验和非侵入性睡眠-觉醒监测来表征LCA小鼠的行为。在行为上，LCA小鼠与对照小鼠略有不同，与已知的蓝斑功能和投射一致，LCA小鼠通常比对照小鼠更好奇、更不焦虑。我们注意到一个有趣的对比，即对照小鼠的蓝斑大小和神经元数量各不相同，但行为一致，而LCA小鼠（正如预期的那样）蓝斑大小一致，但行为不稳定。我们的研究对蓝斑损毁模型进行了全面表征，将其牢固地确立为研究蓝斑功能障碍的有效模型系统。
