Elsevier

Neuroscience

Volume 89, Issue 3, March 1999, Pages 771-780
Neuroscience

Presynaptic markers of cholinergic function in the rat brain: relationship with age and cognitive status

https://doi.org/10.1016/S0306-4522(98)00374-1Get rights and content

Abstract

The nature of age-related changes in cholinergic function and their relationship to age-related behavioral decline were examined in the present study. Male Fischer-344 rats of four ages (four, 11, 17 and 23 months) were tested in a battery of cognitive tasks. Discrete microdissections of brain areas involved in cognitive function were performed, and activity of choline acetyltransferase and levels of hemicholinium-3 binding were determined to assess the integrity of cholinergic innervation. Age-related changes in cholinergic markers occurred predominantly in the medial septal area and its target areas (hippocampus and cingulate cortex), and were also present in the posterior caudate. However, most of the age-related changes in cholinergic markers were already present at ages at which behavioral impairment was not yet maximal. There were some consistent correlations between behavioral and neurochemical measures, independent of age, but these accounted for relatively small proportions of variance in behavioral performance. For most of these correlations, lower levels of presynaptic cholinergic markers were related to better behavioral performance. In brain areas in which correlations changed with age, lower levels of presynaptic cholinergic markers were associated with better performance in young rats, whereas higher levels were associated with better performance in aged rats.

Recent lesion studies using a toxin selective for basal forebrain cholinergic neurons have suggested that these neurons do not play as central a role in learning and memory in young and aged animals as was previously thought. When considered in this context, the present results suggest that preserved cholinergic function in old age might act indirectly to sustain cognitive ability. Changes in cholinergic function may represent one of a number of age-related neurobiological events that underlie behavioral impairments, or may be a permissive factor for other age-related processes that are more directly responsible for cognitive impairments.

Section snippets

Subjects

Male Fischer-344 rats were obtained from the National Institute of Aging colony at Harlan. At the beginning of behavioral testing, the rats were four, 11, 17 or 23 months old (n=18 per group) and were housed two to three per cage in a temperature- and humidity-controlled colony room on a 12-h/12-h light/dark cycle. Behavioral testing was performed during the light portion of the cycle. Food and water were available ad libitum. Behavioral testing began approximately one week after the rats

Results

Low protein levels precluded determination of both ChAT activity and HC-3 binding in some samples. These missing points were relatively homogeneously distributed with respect to age and behavioral status. Because the microdissection procedure used resulted in small pieces of tissue, a substantial amount of variability was present in some neurochemical measures. In order to reduce overall variability, an initial screening removed data-points falling more than two standard deviations from the

Discussion

The results of this study demonstrated significant effects of age on presynaptic markers of cholinergic function as measured by ChAT activity and HC-3 binding. These changes were found predominantly in areas containing cholinergic cell bodies (the medial septal area and posterior caudate) and in target areas of the medial septal area (the hippocampus and cingulate cortex). Markers of presynaptic cholinergic function in some anatomical areas were reliably correlated with behavioral performance,

Conclusions

Although changes in the cholinergic system are most likely not the direct cause of age-related impairments in behavior, they may play a permissive role in the development of other neurobiological changes that are more directly linked to behavioral impairment. Although this study was conducted in a cross-sectional rather than a longitudinal fashion, the data suggest that alterations in cholinergic function precede the development of cognitive impairment. Loss of cholinergic function earlier in

Acknowledgements

We thank Dr Molly V. Wagster for her contributions to this research, and Karena P. Joung and Joyce A. Kotzuk for technical assistance. This research was supported by NIH Grant P50-NS20471 to D.L.P. Dr Linda K. Gorman would like to respectfully remember the contributions of Dr David Olton to this work.

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