Elsevier

Neuroscience

Volume 75, Issue 1, 6 September 1996, Pages 29-35
Neuroscience

Increased vulnerability of septal cholinergic neurons to partial loss of target neurons in aged rats

https://doi.org/10.1016/0306-4522(96)00240-0Get rights and content

Abstract

To investigate whether the ageing process might affect neuron–target interactions which influence the phenotype of septal cholinergic neurons, we compared the response of these neurons to partial loss of target tissue in young adult and aged animals. Groups of young adult (four to six months) or aged (24–33 months) male Sprague–Dawley rats received unilateral infusions into the hippocampus of either the excitotoxic amino acid N-methyl-d-aspartate, or vehicle. The resulting excitotoxic lesions reduced the mean cross-sectional area of the hippocampus by 55–60%. Ipsilateral septal cholinergic neurons immunohistochemically stained for either choline acetyltransferase or low-affinity neurotrophin receptor (p75NTR) were morphometrically evaluated. In young adult rats with partial hippocampal lesions, the number and staining intensity of ipsilateral septal cholinergic neurons were not significantly different from age-matched control values, but these cholinergic neurons exhibited a significant 12% reduction in cross-sectional area. In aged rats with hippocampal lesions of equivalent size, ipsilateral cholinergic neurons showed a significant 29% reduction in cross-sectional area, a significant 19% reduction in choline acetyltransferase staining intensity as measured by densitometry, and a significant 21% reduction in the number of choline acetyltransferase- but not p75NTR-stained septal neurons, as compared with age-matched control animals.

These findings show that in aged rats, septal cholinergic neurons atrophy more severely in response to the partial loss of their target neurons than in young adult rats, in the form of pronounced cell shrinkage and down-regulation of intracellular levels of the transmitter-synthesizing enzyme, choline acetyltransferase, in some cases to the point of the absence of detectable staining for this marker in some cells. The continued detection of p75NTR indicates that significant neuronal cell death did not take place. These findings suggest that basal forebrain cholinergic neurons have an increased vulnerability to disturbances of neuron–target interactions in aged animals, which may contribute to the degenerative changes exhibited by these cholinergic neurons in ageing and age-related conditions such as Alzheimer's disease.

Section snippets

Animals and surgical procedures

Thirty-two young adult (four to six months) and aged (24–30 months) male Sprague–Dawley rats from the same ( in house) breeding colony were used in this study. The animals were not behaviourally characterized and were assigned randomly to experimental groups: two groups of young adults (n = 7 per group) and two groups of aged rats (n = 9 per group). Under ketamine and xylazine anaesthesia, each animal was given nine stereotaxically placed injections of either N-methyl-d-aspartate (NMDA) solution or

Degree of excitotoxic ablation of hippocampus

In both young adult and aged rats, injection of vehicle did not significantly change hippocampal surface area, whereas unilateral injection of the excitotoxic amino acid NMDA at the dosing regimen used in this study caused a partial reduction in the mean hippocampal surface area of 55–60% relative to the uninjected sided (Table 1, Fig. 1). Analysis of variance with post hoc pairwise tests confirmed the significance of the differences in mean hippocampal surface area between vehicle- and

Discussion

These findings show that in aged rats partial loss of hippocampal target tissue can lead to degenerative changes in septal cholinergic neurons in the form of substantial cell shrinkage and a pronounced down-regulation of intracellular levels of the transmitter-synthesizing enzyme ChAT. In young adult rats, partial loss of target tissue to a similar degree caused only a small cell shrinkage of septal cholinergic neurons, and did not cause a reduction in staining intensity. These findings

Conclusions

The observations of this study suggest that basal forebrain cholinergic neurons react more severely to the loss of their target neurons and are more vulnerable to disturbances of neuron–target interactions in aged than in young adult animals. This increased vulnerability may contribute to the degenerative changes exhibited by basal forebrain cholinergic neurons in ageing and age-related conditions such as Alzheimer's disease.

Acknowledgements

The authors thank K. J. Baker and S. J. Stevens for expert technical assistance and J. Bashford for photography. This work was supported by grants from MRC, the Wellcome Trust and Merck, Sharp and Dohme Research Laboratories.

References (37)

Cited by (19)

  • Neurokinin3-R agonism in aged rats has anxiolytic-, antidepressant-, and promnestic-like effects and stimulates ACh release in frontal cortex, amygdala and hippocampus

    2011, European Neuropsychopharmacology
    Citation Excerpt :

    A decline in cholinergic activity in the brain has been observed during aging (Araujo et al., 1990; Takei et al., 1989). Also, cholinergic projection neurons in the basal forebrain undergo significant atrophy in the aged rodent (Cooper and Sofroniew, 1996; De Lacalle et al., 1996). The degree of atrophy is highly correlated with the cognitive impairment (Armstrong et al., 1988; Gage et al., 1988).

View all citing articles on Scopus
1

Present address: Department of Neurochemistry, Max-Planck-Institute for Psychiatry, Am Klopferspitz 18A, D-82152 Planegg-Martinsried, Germany.

View full text