Jackson Megan G, Brennan Laura J, Henderson Emily J, Robinson Emma S J
School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Brain Neurosci Adv. 2022 Mar 22;6:23982128221088794. doi: 10.1177/23982128221088794. eCollection 2022 Jan-Dec.
Falls resulting from multifactorial deficits are common in both normal ageing and Parkinson's disease. Resultant injuries can lead to increased hospitalisation and excess mortality. As the disease progresses, gait and balance deficits are relatively refractory to dopaminergic treatments suggesting another system is involved. Attentional impairment is a significant risk factor for falls, and disruption to both the cortical cholinergic system and striatal dopaminergic system increases falls in rats undergoing a complex motor task with high attentional load. However, it is unclear whether this translates to mice and whether normal ageing induces similar deficits. In this study, we use a complex motor task to test the effects of acute dopaminergic and cholinergic antagonism using alpha-flupentixol and scopolamine, respectively, in mice. We also test the effects of normal ageing on complex motor performance and whether these changes are sensitive to a clinical dose of the non-steroidal anti-inflammatory Rimadyl. Consistent with previous work, we show that cholinergic but not dopaminergic antagonism impaired task performance. However, a combined approach did not potentiate the deficit beyond observed with cholinergic antagonism alone. We also show that task performance is impaired in aged mice relative to younger controls, and that Rimadyl reduces number of foot slips in an age-specific manner. Overall, these data support prior work showing the importance of the cholinergic system in falls. The studies in aged mice found age-related impairments and a role for inflammation but did not find evidence of an interaction with attentional load, although only one manipulation was tested.
由多因素缺陷导致的跌倒在正常衰老和帕金森病中都很常见。由此产生的损伤会导致住院率增加和死亡率上升。随着疾病进展，步态和平衡缺陷对多巴胺能治疗相对难治，提示涉及另一种系统。注意力损害是跌倒的一个重要危险因素，皮质胆碱能系统和纹状体多巴胺能系统的破坏都会增加进行高注意力负荷复杂运动任务的大鼠的跌倒次数。然而，尚不清楚这是否适用于小鼠，以及正常衰老是否会导致类似的缺陷。在本研究中，我们使用一项复杂运动任务来测试分别使用氟哌噻吨和东莨菪碱对小鼠进行急性多巴胺能和胆碱能拮抗的效果。我们还测试了正常衰老对复杂运动表现的影响，以及这些变化是否对临床剂量的非甾体抗炎药瑞莫迪敏感。与先前的研究一致，我们发现胆碱能而非多巴胺能拮抗会损害任务表现。然而，联合方法并未使缺陷超过单独胆碱能拮抗所观察到的程度。我们还表明，与年轻对照组相比，老年小鼠的任务表现受损，并且瑞莫迪以年龄特异性方式减少了足部滑倒次数。总体而言，这些数据支持先前的研究结果，即胆碱能系统在跌倒中的重要性。对老年小鼠的研究发现了与年龄相关的损伤以及炎症的作用，但没有发现与注意力负荷相互作用的证据，尽管只测试了一种操作。
