Immunohistochemical and neurochemical correlates of learning deficits in aged rats.

This study examined whether cholinergic and monoaminergic dysfunctions in the brain could be related to spatial learning capabilities in 26-month-old, as compared to three-month-old, Long-Evans female rats. Performances were evaluated in the water maze task and used to constitute subgroups with a cluster analysis statistical procedure. In the first experiment (histological approach), the first cluster contained young rats and aged unimpaired rats, the second one aged rats with moderate impairment and the third one aged rats with severe impairment. Aged rats showed a reduced number of choline acetyltransferase- and p75(NTR)-positive neurons in the nucleus basalis magnocellularis, and choline acetyltransferase-positive neurons in the striatum. In the second experiment (neurochemical approach), the three clusters comprised young rats, aged rats with moderate impairment and aged rats with severe impairment. Alterations related to aging consisted of reduced concentration of acetylcholine, norepinephrine and serotonin in the striatum, serotonin in the occipital cortex, dopamine and norepinephrine in the dorsal hippocampus, and norepinephrine in the ventral hippocampus. In the first experiment, there were significant correlations between water maze performance and the number of; (i) choline acetyltransferase- and p75(NTR)-positive neurons in the nucleus basalis magnocellularis; (ii) choline acetyltransferase-positive neurons in the striatum and; (iii) p75(NTR)-positive neurons in the medial septum. In the second experiment, water maze performance was correlated with the concentration of; (i) acetylcholine and serotonin in the striatum; (ii) serotonin and norepinephrine in the dorsal hippocampus; (iii) norepinephrine in the frontoparietal cortex and; (iv) with other functional markers such as the 5-hydroxyindoleacetic acid/serotonin ratio in the striatum, 3,4-dihydroxyphenylacetic acid/dopamine ratio in the dorsal hippocampus, 5-hydroxyindoleacetic acid/serotonin and homovanillic acid/dopamine ratios in the frontoparietal cortex, and 3,4-dihydroxyphenylacetic acid/dopamine ratio in the occipital cortex. The results indicate that cognitive deficits related to aging might involve concomitant alterations of various neurochemical systems in several brain regions such as the striatum, the hippocampus or the cortex. It also seems that these alterations occur in a complex way which, in addition to the loss of cholinergic neurons in the basal forebrain, affects dopaminergic, noradrenergic and serotonergic processes.