Cognitive dysfunction is one of the most severe nonmotor symptoms of nigrostriatal impairment. This occurs as a result of profound functional and morphological changes of different neuronal circuits, including modifications in the plasticity and architecture of hippocampal synapses. Such alterations can be implicated in the genesis and progression of dementia associated with neurodegenerative diseases including Parkinson-like symptoms. There are few studies regarding cognitive changes in nigrostriatal animal models. The aim of this study was to characterize the onset of memory deficit after induction of neurotoxicity with 6-hydroxydopamine (6-OHDA) and its correlation with hippocampal dysfunction. For this, we bilaterally microinjected 6-OHDA in dorsolateral Caudate-Putamen unit (CPu) and then, animals were tested weekly for working memory, spatial short-term memory, and motor performance. We evaluated tyrosine hydroxylase (TH) as a dopamine marker, aldehyde dehydrogenase 2 (ALDH2), a mitochondria detoxification enzyme and astrocyte glial fibrillar acid protein (GFAP) an immunoreactivity marker involved in different areas: CPu, substantia nigra, prefrontal cortex, and hippocampus. We observed a specific prefrontal cortex and nigrostriatal pathway TH reduction while ALDH2 showed a decrease-positive area in all the studied regions. Moreover, GFAP showed a specific CPu decrease and hippocampus increase of positively stained area on the third week after toxicity. We also evaluated the threshold to induce long-term potentiation in hippocampal excitability. Our findings showed that reduced hippocampal synaptic transmission was accompanied by deficits in memory processes, without affecting motor performance on the third-week post 6-OHDA administration. Our results suggest that 3 weeks after neurotoxic administration, astrocytes and ALDH2 mitochondrial enzyme modifications participate in altering the properties that negatively affect hippocampal function and consequently cognitive behavior.

认知功能障碍是黑质纹状体损伤最严重的非运动症状之一。这是由于不同神经元回路发生深刻的功能和形态变化，包括海马突触的可塑性和结构的改变而发生的。这种改变可能与包括帕金森样症状在内的神经退行性疾病相关的痴呆症的发生和进展有关。关于黑质纹状体动物模型认知变化的研究很少。本研究的目的是表征用 6-羟基多巴胺 (6-OHDA) 诱导神经毒性后记忆缺陷的发作及其与海马功能障碍的相关性。为此，我们在背外侧尾壳核单位 (CPu) 中双侧显微注射 6-OHDA，然后每周测试动物的工作记忆，空间短期记忆和运动表现。我们评估了酪氨酸羟化酶 (TH) 作为多巴胺标志物、醛脱氢酶 2 (ALDH2)、线粒体解毒酶和星形胶质细胞原纤维酸蛋白 (GFAP) 一种涉及不同区域的免疫反应性标志物：CPu、黑质、前额叶皮层和海马. 我们观察到特定的前额叶皮层和黑质纹状体通路 TH 减少，而 ALDH2 在所有研究区域均显示减少阳性区域。此外，GFAP 在毒性后第三周显示出特定的 CPu 减少和阳性染色区域的海马增加。我们还评估了诱导海马兴奋性长期增强的阈值。我们的研究结果表明，海马突触传递的减少伴随着记忆过程的缺陷，在不影响 6-OHDA 给药后第三周的运动表现的情况下。我们的结果表明，神经毒性给药 3 周后，星形胶质细胞和 ALDH2 线粒体酶修饰参与改变对海马功能和认知行为产生负面影响的特性。