Age-Related Cognitive Decline Occurs Without Hippocampal Neuron Loss

Rapp PR, Gallagher M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci USA 1996;93(18):9926-9930. doi: 10.1073/pnas.93.18.9926.

Background: Hippocampal neuron loss had long been regarded as a hallmark of normal aging and a major cause of age-related learning and memory decline. Earlier studies based on neuronal density measurements suggested substantial hippocampal cell death in aged animals with cognitive impairment, but these approaches were prone to distortion by age-related changes in tissue volume and cell morphology.

Hypothesis: This study hypothesized that age-related deficits in hippocampal-dependent spatial learning are associated with an actual loss of principal neurons in the hippocampus.

Methods: The authors trained young and aged male Long-Evans rats in the Morris water maze to assess spatial learning ability and then used unbiased stereological quantification to estimate total neuron numbers in the dentate gyrus and hippocampal CA fields. Neurons were counted using the Optical Fractionator method implemented in a computerized morphometry and neuron-tracing system (Neurolucida) combined with a high-resolution video camera, motorized microscope stage and focus encoder for precise three-dimensional sampling. All analyses were performed blind to the animals’ cognitive status.

Results: Despite significant age-related impairments in spatial learning, total neuron numbers in the granule cell layer, CA3/2 and CA1 regions did not differ between young, aged-unimpaired and aged-impaired rats. Neuron counts showed no correlation with behavioral performance.

Conclusions: This study demonstrated that hippocampal neuron numbers are preserved in normal aging, indicating that cognitive decline arises from functional rather than degenerative neuronal changes.