It has traditionally been accepted that moderate neural death occurs as an inevitable consequence of normal aging. Significant age-related neural loss has been reported in almost every region examined. Studies involving unbiased quantitative techniques for esti mating cell numbers in tissue samples have led to a significant revision of traditional views on age-related neural loss. This is due to the fact that most investigators had been focusing their attention on cell density, measured as the number of neurons in a fixed volume of tissue within a brain region. The counting was typically accomplished using standard histological staining procedures to visualize and count cells microscopically. If a strategy like this is employed without taking into account the fact that gliosis within a brain region may actually alter the size of a brain structure, it can lead to the possibly erroneous conclusion that the total number of neurons is decreased. Instead, studies taking into account volumetric differences between young and aged brains have led to a reevaluation of the traditional view on age-related neural loss. Modern stereological tools have been widely used to investigate neural numbers in the aged hippocampus. Earlier studies had suggested that the hippocampus is especially susceptible to age-related cell death and that this may be the explanation for decreases in hippocampal-dependent learning and memory within aged subjects. Instead, investigations have revealed that the number of granule cells of the dentate gyrus and pyramidal neurons within fields CA2, CA3, and CA1 remain unaffected in the aged hippocampus (Fig. 3). Studies also suggest that the number ofhippocampal neurons remains normal even among aged individuals with pronounced learning and memory deficits, which are normally associated with hippocampal dysfunction. Other studies have even suggested that granule cells within the dentagyrus are formed continuously throughout life. Instead, age-related neural loss associated with memory deficits preferentially targets subcortical brain systems. Aging does result in substantial subcortical cell loss, especially among neurons with ascending projections to cortical regions. The loss of cholinergic neurons in the basal forebrain has been studied extensively because of its assumed role in Alzheimer's disease. A hallmark of this degenerative condition is an accelerated degeneration of acetylcholine-containing neurons affecting cell groups that project to the hippocampus, the amygdala, and the neocortex. The loss of cholinergic cells might disrupt the circuitry responsible for information processing in these target regions. The number of remaining cholinergic neurons correlates with a magnitude of behavioral impairments in dementia patients and aged individuals. Although the loss of cholinergic neurons may not be directly responsible for the cognitive deficits seen in these patients, it probably indirectly affects other neurochemically specific
Figure 3 (a) MRI image of the human brain showing the location of the hippocampi (arrows) within the medial portions of the temporal lobe. (b) Confocal image of granule cells within the human dentate gyrus (hippocampus). The arrows show the nucleus of a newborn, NeuN immunoreactive, neuron within the adult human brain. Astroglial cells are immunostained for glial fibrillary protein. From Eriksson, P. S., et al. (1998). Neurogenesis in the adult human hippocampus. Nature Med. 4, 1313-1317. (See color insert in Volume 1).
projection systems responsible for memory and learning. Thus, cholinergic neurons within the basal fore-brain represent an example of a limited number of neurons that have a pronounced impact on behavior.
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