Aging, Memory, and the Brain

Memory is not a unitary function but instead encompasses a variety of dissociable processes mediated by distinct brain systems. Explicit or declarative memory refers to the conscious recollection of facts and events, and is known to critically depend on a system of anatomically related structures that includes the HIPPOCAMPUS and adjacent cortical regions in the medial temporal lobe. This domain of function contrasts with a broad class of memory processes involving the tuning or biasing of behavior as a result of experience. A distinguishing feature of these implicit or nondeclarative forms of memory is that they do not rely on conscious access to information about the episodes that produced learning. Thus, implicit memory proceeds normally independent of the medial temporal lobe structures damaged in amnesia. Although many important issues remain to be resolved concerning the organization of multiple memory systems in the brain, this background of information has enabled substantial progress toward defining the neural basis of age-related cognitive decline.

Traditionally, moderate neuron death, distributed diffusely across multiple brain regions, was thought to be an inevitable consequence of aging. Seminal studies by Brody (1955) supported this view, indicating neuron loss progresses gradually throughout life, totaling more than 50 percent in many cortical areas by age ninety-five (Brody 1955, 1970). Although not all regions of the brain seemed to be affected to the same degree, significant decreases in cell number were reported for both primary sensory and associational areas of cortex. Thus, the concept emerged from early observations that diffusely distributed neuron death might account for many of the cognitive impairments observed during aging (Coleman and Flood 1987).

In recent years, the application of new and improved methods for estimating cell number has prompted substantial revision in traditional views on age-related neuron loss. A primary advantage of these modern stereological techniques, relative to more traditional approaches, is that they are specifically designed to yield estimates of total neuron number in a region of interest, providing an unambiguous measure for examining potential neuron loss with age (West 1993a). Stereological tools have been most widely applied in recent studies to reevaluate the effects of age on neuron number in the hippocampus. In addition to the known importance of this structure for normal explicit memory, early research using older methods suggested that the hippocampus is especially susceptible to age-related cell death, and that this effect is most pronounced among aged subjects with documented deficits in hippocampal-dependent learning and memory (Issa et al. 1990; Meaney et al. 1988). The surprising conclusion from investigations using stereological techniques, however, is that the total number of principal neurons (i.e., the granule cells of the dentate gyrus, and pyramidal neurons in the CA3 and CA1 fields) is entirely preserved in the aged hippocampus. Parallel results have been observed in all species examined, including rats, monkeys and humans (Peters et al. 1996; Rapp 1995; Rapp and Gallagher 1996; Rasmussen et al. 1996; West 1993b). Moreover, hippocampal neuron number remains normal even among aged individuals with pronounced learning and memory deficits indicative of hippocampal dysfunction (Peters et al. 1996; Rapp 1995; Rapp and Gallagher 1996; Rasmussen et al. 1996). Contrary to traditional views, these findings indicate that hippocampal cell death is not an inevitable consequence of aging, and that age-related learning and memory impairment does not require the presence of frank neuronal degeneration.

Quantitative data on neuron number in aging are not yet available for all of the brain systems known to participate in LEARNING and MEMORY. However, like the hippocampus, a variety of other cortical regions also appear to maintain a normal complement of neurons during nonpathological aging. This includes dorsolateral aspects of the prefrontal cortex that participate in processing spatiotemporal attributes of memory (Peters et al. 1994), and unimodal visual areas implicated in certain forms of implicit memory function (Peters, Nigro, and McNally 1997). By contrast, aging is accompanied by substantial subcortical cell loss, particularly among neurochemically specific classes of neurons that originate ascending projections to widespread regions of the cortex. Acetylcholine containing neurons in the basal forebrain have been studied intensively in this regard, based partly on the observation that this system is the site of profound degeneration in pathological disorders of aging such as Alzhei mer's disease. A milder degree of cholinergic cell loss is also seen during normal aging, affecting cell groups that project to the hippocampus, AMYGDALA, and neocortex (Armstrong et al. 1993; de Lacalle, Iraizoz, and Ma Gonzalo 1991; Fischer et al. 1991; Stroessner-Johnson, Rapp, and Amaral 1992). Information processing functions mediated by these target regions might be substantially disrupted as a consequence of cholinergic degeneration, and, indeed, significant correlations have been documented between the magnitude of cell loss and behavioral impairment in aged individuals (Fischer et al. 1991). Together with changes in other neurochemically specific projection systems, subcortical contributions to cognitive aging may be substantial. These findings also highlight the concept that neuron loss during normal aging appears to preferentially affect subcortical brain structures, sparing many cortical regions. Defining the cell biological mechanisms that confer this regional vulnerability or protection remains a significant challenge.

Research on the neuroanatomy of cognitive aging has also examined the possibility that changes in connectivity might contribute to age-related deficits in learning and memory supported by the hippocampus. The entorhinal cortex originates a major source of cortical input to the hippocampus, projecting via the perforant path to synapse on the distal dendrites of the dentate gyrus granule cells, in outer portions of the molecular layer. Proximal dendrites of the granule cells, in contrast, receive an intrinsic hippocampal input arising from neurons in the hilar region of the dentate gyrus. This strict laminar segregation, comprised of non-overlapping inputs of known origin, provides an attractive model for exploring potential age-related changes in hippocampal connectivity. Ultrastructural studies, for example, have demonstrated that a morphologically distinct subset of synapses is depleted in the dentate gyrus molecular layer during aging in the rat (Geinisman et al. 1992). Moreover, the magnitude of this loss in the termination zone of the entorhinal cortex is greatest among aged subjects with documented deficits on tasks sensitive to hippocampal damage, and in older animals that display impaired cellular plasticity in the hippocampus (de Toledo-Morrell, Geinisman, and Morrell 1988; Geinisman, de Toledo-Morrell, and Morrell 1986).

The same circuitry has been examined in the aged monkey using confocal laser microscopy to quantify the density of N-methyl-D-aspartate (NMDA) and non-NMDA receptor subunits. Aged monkeys display a substantial reduction in NMDA receptor labeling that is anatomically restricted to outer portions of the molecular layer that receive entorhinal cortical input (Gazzaley et al. 1996). The density of non-NMDA receptor subunits is largely preserved. Although the impact of this change on cognitive function has not been evaluated directly, the findings are significant because NMDA receptor activity is known to play a critical role in cellular mechanisms of hippocampal plasticity (i.e., LTP). Thus, a testable prediction derived from these observations is that the status of hippocampal-dependent learning and memory may vary as a function of the magnitude of NMDA receptor alteration in the aged monkey. Studies of this sort, combining behavioral and neurobiological assessment in the same individuals, are a prominent focus of current research on normal aging.

A solid background of evidence now exists concerning the nature, severity and distribution of structural alterations in the aged brain. The mechanisms responsible for these changes, however, are only poorly understood. Molecular biological techniques are increasingly being brought to bear on this issue, revealing a broad profile of age-related effects with significant implications for cell structure and function (Sugaya et al. 1996). Although incorporating these findings within a neuropsychological framework will undoubtedly prove challenging, current progress suggests that molecular, neural-systems, and behavioral levels of analysis may soon converge on a more unified understanding of normal cognitive aging.

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-- Peter Rapp

References

Armstrong, D. M., R. Sheffield, G. Buzsaki, K. Chen, L. B. Hersh, B. Nearing, and F. H. Gage. (1993). Morphologic alterations of choline acetyltransferase-positive neurons in the basal forebrain of aged behaviorally characterized Fisher 344 rats. Neurobiology of Aging 14:457-470.

Brody, H. (1955). Organization of the cerebral cortex. III. A study of aging in the human cerebral cortex. Journal of Comparative Neurology 102:511-556.

Brody, H. (1970). Structural changes in the aging nervous system. Interdisciplinary Topics in Gerontology 7:9-21.

Coleman, P. D., and D. G. Flood. (1987). Neuron numbers and dendritic extent in normal aging and Alzheimer"s disease. Neurobiology of Aging 8(6):521-545.

de Lacalle, S., I. Iraizoz, and L. Ma Gonzalo. (1991). Differential changes in cell size and number in topographic subdivisions of human basal nucleus in normal aging. Neuroscience 43(2/3): 445-456.

de Toledo-Morrell, L., Y. Geinisman, and F. Morrell. (1988). Individual differences in hippocampal synaptic plasticity as a function of aging: Behavioral, electrophysiological and morphological evidence. Neural Plasticity: A Lifespan Approach. Alan R. Liss, Inc., pp. 283-328.

Fischer, W., K. S. Chen, F. H. Gage, and A. Björklund. (1991). Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging. Neurobiology of Aging 13:9-23.

Gazzaley, A. H., S. J. Siegel, J. H. Kordower, E. J. Mufson, and J. H. Morrison. (1996). Circuit-specific alterations of N-methyl-D-aspartate receptor subunit 1 in the dentate gyrus of aged monkeys. Proceedings of the National Academy of Science, USA 93:3121-3125.

Geinisman, Y., L. de Toledo-Morrell, and F. Morrell. (1986). Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. Proceedings of the National Academy of Science USA 83:3027-3031.

Geinisman, Y., L. de Toledo-Morrell, F. Morrell, I. S. Persina, and M. Rossi. (1992). Age-related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique. Hippocampus 2:437-444.

Issa, A. M., W. Rowe, S. Gauthier, and M. J. Meaney. (1990). Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. Journal of Neuroscience 10(10):3247-3254.

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Peters, A., D. Leahy, M. B. Moss, and K. J. McNally. (1994). The effects of aging on area 46 of the frontal cortex of the rhesus monkey. Cerebral Cortex 4(6):621-635.

Peters, A., N. J. Nigro, and K. J. McNally. (1997). A further evaluation of the effect of age on striate cortex of the rhesus monkey. Neurobiology of Aging 18:29-36.

Peters, A., D. L. Rosene, M. B. Moss, T. L. Kemper, C. R. Abraham, J. Tigges, and M. S. Albert. (1996). Neurobiological bases of age-related cognitive decline in the rhesus monkey. Journal of Neuropathology and Experimental Neurology 55:861-874.

Rapp, P. R. (1995). Cognitive neuroscience perspectives on aging in nonhuman primates. In T. Nakajima and T. Ono, Eds., Emotion, Memory and Behavior. Tokyo: Japan Scientific Societies Press, pp 197-211.

Rapp, P. R., and M. Gallagher. (1996). Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proceedings of the National Academy of Science, USA 93:9926-9930.

Rasmussen, T., T. Schliemann, J. C. Sorensen, J. Zimmer and M. J. West. (1996). Memory impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiology of Aging 17(1):143-147.

Stroessner-Johnson, H. M., P. R. Rapp, and D. G. Amaral. (1992). Cholinergic cell loss and hypertrophy in the medial septal nucleus of the behaviorally characterized aged rhesus monkey. Journal of Neuroscience 12(5):1936-1944.

Sugaya, K., M. Chouinard, R. Greene, M. Robbins, D. Personett, C. Kent, M. Gallagher, and M. McKinney. (1996). Molecular indices of neuronal and glial plasticity in the hippocampal formation in a rodent model of age-induced spatial learning impairment. Journal of Neuroscience 16(10):3427-3443.

West, M. J. (1993a). New stereological methods for counting neurons. Neurobiology of Aging 14:275-285.

West, M. J. (1993b). Regionally specific loss of neurons in the aging human hippocampus. Neurobiology of Aging 14:287-293.

Aging, Memory, and the Brain

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