前额皮质兴奋性神经元激活减少导致小鼠工作记忆能力受损。

BACKGROUND: Working memory capacity impairment is an early sign of Alzheimer's disease, but the underlying mechanisms remain unclear. Clarifying how working memory capacity is affected will help us better understand the pathological mechanism of Alzheimer's disease. We used the olfactory working memory capacity paradigm to evaluate memory capacity in 3-month-old 5XFAD (an animal model of Alzheimer's disease) mice. Immunofluorescence staining of the prefrontal cortex was performed to detect the number of FOS-positive neurons, calmodulin-dependent protein kinase II-positive neurons, and glutamate decarboxylase-positive neurons in the prelimbic cortex and infralimbic cortex. A chemogenetic method was then used to modulate the inhibition and activation of excitatory neurons in the prelimbic cortex of wild-type and 5XFAD mice and to measure the memory capacity of mice. RESULTS: Working memory capacity was significantly diminished in 5XFAD mice compared to littermate wild-type mice. Neuronal activation of the prelimbic cortex, but not the infralimbic cortex, was attenuated in 5XFAD mice performing the olfactory working memory capacity task. Subsequently, the FOS-positive neurons were co-localized with both calmodulin-dependent protein kinase II-positive neurons and glutamate decarboxylase-positive neurons. The results showed that the activation of excitatory neurons in the prelimbic cortex was correlated with working memory capacity in mice. Our results further demonstrate that the chemogenetic inhibition of prelimbic cortex excitatory neurons resulted in reduced working memory capacity in wild-type mice, while the chemogenetic activation of prelimbic cortex excitatory neurons improved the working memory capacity of 5XFAD mice. CONCLUSION: The diminished activation of prelimbic cortex excitatory neurons in 5XFAD mice during task performance is associated with reduced working memory capacity, and activation modulation of excitatory neurons by chemogenetic methods can improve memory capacity impairment in 5XFAD mice. These findings may provide a new direction for exploring Alzheimer's disease therapeutic approaches.

背景：工作记忆容量损伤是阿尔茨海默病的早期征象，但潜在机制尚不清楚。阐明工作记忆容量如何受到影响将有助于我们更好地理解阿尔茨海默病的病理机制。我们使用嗅觉工作记忆容量范式来评估 3 月龄 5XFAD（阿尔茨海默病的动物模型）小鼠的记忆容量。对前额叶皮质进行免疫荧光染色，以检测前扣带回和下边缘皮质中 FOS 阳性神经元、钙调蛋白依赖性蛋白激酶 II 阳性神经元和谷氨酸脱羧酶阳性神经元的数量。然后使用化学遗传方法调节野生型和 5XFAD 小鼠前扣带皮质兴奋神经元的抑制和激活，并测量小鼠的记忆容量。

结果：与同窝野生型小鼠相比，5XFAD 小鼠的工作记忆容量明显降低。在执行嗅觉工作记忆容量任务时，5XFAD 小鼠前扣带皮质而非下边缘皮质的神经元激活减弱。随后，FOS 阳性神经元与钙调蛋白依赖性蛋白激酶 II 阳性神经元和谷氨酸脱羧酶阳性神经元共定位。结果表明，前扣带皮质兴奋神经元的激活与小鼠的工作记忆容量相关。我们的结果进一步表明，前扣带皮质兴奋神经元的化学遗传抑制导致野生型小鼠工作记忆容量降低，而前扣带皮质兴奋神经元的化学遗传激活改善了 5XFAD 小鼠的工作记忆容量。

结论：在任务执行过程中，5XFAD 小鼠前扣带皮质兴奋神经元的激活减弱与工作记忆容量降低有关，通过化学遗传方法调节兴奋神经元的激活可以改善 5XFAD 小鼠的记忆容量损伤。这些发现可能为探索阿尔茨海默病治疗方法提供新的方向。