Craig Laura A, Hong Nancy S, Kopp Joelle, McDonald Robert J
Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada.
Eur J Neurosci. 2008 May;27(9):2262-71. doi: 10.1111/j.1460-9568.2008.06179.x.
A consistent finding in patients suffering from Alzheimer's disease is a loss of the cholinergic neurons of the basal forebrain that project to the hippocampus. However, the role this depletion plays in the development of Alzheimer's disease remains unclear. The loss of this ascending neurotransmitter system could potentially render hippocampal neurons more susceptible to further insult, such as chronic stress, ultimately resulting in neuronal death and memory loss. We explored this possibility by using the highly specific toxin 192 IgG-Saporin to destroy the majority of cholinergic activity in the septo-hippocampal pathway in rats. Following depletion, rats were subjected to 2 weeks of restraint stress. Rats were divided into two groups and were tested either on a hippocampal-dependent (water maze) task or a hippocampal-independent task (fear conditioning to tone and context). We showed that cholinergic depletion or stress alone had no effect on the successful performance of either of the tasks. However, rats with a combination of cholinergic depletion and stress were significantly impaired on the water-maze task. No deficits were apparent in the combined group that was tested on fear conditioning to tone or context, suggesting that this impairment is specific to spatial working memory. These rats had no obvious hippocampal neuronal loss or damage; however, there were likely subtle changes in hippocampal processing that led to the observed deficit on the hippocampal-dependent task. These findings support our theory that cholinergic depletion of the medial septum increases hippocampal vulnerability to further insults such as stress.
患阿尔茨海默病的患者中一个一致的发现是投射至海马体的基底前脑胆碱能神经元的丧失。然而，这种神经元缺失在阿尔茨海默病发展过程中所起的作用仍不清楚。这种上行神经递质系统的丧失可能会使海马体神经元更容易受到进一步损伤，如慢性应激，最终导致神经元死亡和记忆丧失。我们通过使用高度特异性毒素192 IgG-皂草素破坏大鼠隔海马通路中的大部分胆碱能活性来探究这种可能性。胆碱能活性耗尽后，让大鼠经受2周的束缚应激。将大鼠分为两组，并分别在依赖海马体的任务（水迷宫）或不依赖海马体的任务（对音调及环境的恐惧条件反射）中进行测试。我们发现，单独的胆碱能活性耗尽或应激对任何一项任务的成功完成均无影响。然而，同时存在胆碱能活性耗尽和应激的大鼠在水迷宫任务中表现显著受损。在对音调或环境的恐惧条件反射测试中，联合组未出现明显缺陷，这表明这种损伤是空间工作记忆所特有的。这些大鼠没有明显的海马体神经元丧失或损伤；然而，海马体处理过程可能存在细微变化，导致在依赖海马体的任务中出现观察到的缺陷。这些发现支持了我们的理论，即内侧隔区胆碱能活性的耗尽会增加海马体对诸如应激等进一步损伤的易感性。
