Emergence of spatial impairment in rats following specific cholinergic depletion of the medial septum combined with chronic stress.

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.