The mechanisms involved in plasticity in the nervous system are thought to support cognition, and some of these processes are affected during normal ageing. Notably, cognitive functions that rely on the medial temporal lobe and prefrontal cortex, such as learning, memory and executive function, show considerable age-related decline. It is therefore not surprising that several neural mechanisms in these brain areas also seem to be particularly vulnerable during the ageing process. In this review, we discuss major advances in our understanding of age-related changes in the medial temporal lobe and prefrontal cortex and how these changes in functional plasticity contribute to behavioural impairments in the absence of significant pathology.
During normal ageing humans and other animals experience cognitive decline even in the absence of disease. This review focuses on age-related changes in the neurobiology of the hippocampus and the prefrontal cortex (PFC) and how altered synaptic connectivity and plasticity, Ca2+ homeostasis, gene expression and network firing properties contribute to the selective behavioural deficits observed in advanced age.
Historically, it was believed that the neurobiology of normal ageing was marked by massive cell loss and deterioration of dendritic arborization. However, the application of stereological principles to cell counting methods led to the conclusion that significant cell loss does not occur during normal ageing and that changes in dendritic complexity are subtle and region-specific.
Most biophysical properties of neurons remain the same during ageing. In the hippocampus and the PFC there are no differences between old and young neurons in resting membrane potential, membrane time constant, threshold to elicit an action potential, and rise time and duration of an action potential. In both regions, however, there is a significant increase in Ca2+ conductance, which probably contributes to age-related changes in plasticity (long-term potentiation (LTP) and long-term depression (LTD)).
The maintenance of long-term memory and plasticity (for example, LTP) requires gene expression; therefore, it is not surprising that aged animals also show alterations in these processes. Notably, the immediate-early gene Arc, which is known to be involved in plasticity, shows differences in expression patterns between young and old rats.
Age-associated changes in the dynamics of neuronal ensembles contribute to cognitive impairment. In particular, electrophysiological recordings from many neurons simultaneously in the hippocampus of young and old rats have revealed age differences in the dynamics of 'place cells' that correlate with spatial memory deficits.
The hippocampus and the PFC are particularly vulnerable to the impact of ageing, so it is not surprising that behaviours relying on these brain regions decline with age. In many species, there is a decline in associative learning and spatial memory, both of which require the hippocampus. In addition, aged animals show working memory and executive function deficits, which depend on the PFC.
Although considerable advances have been made in our understanding of the neurobiology of normal ageing, much remains to be learned. Given that the average lifespan is increasing worldwide, understanding the brain mechanisms that are responsible for age-related cognitive decline becomes increasingly important.
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Brody, H. Organization of the cerebral cortex. III. A study of aging in the human cerebral cortex. J. Comp. Neurol. 102, 511–516 (1955).
Coleman, P. D. & Flood, D. G. Neuron numbers and dendritic extent in normal aging and Alzheimer's disease. Neurobiol. Aging 8, 521–545 (1987).
Ball, M. J. Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol. (Berl.) 37, 111–118 (1977).
Brizzee, K. R., Ordy, J. M. & Bartus, R. T. Localization of cellular changes within multimodal sensory regions in aged monkey brain: possible implications for age-related cognitive loss. Neurobiol. Aging 1, 45–52 (1980).
Morrison, J. H. & Hof, P. R. Life and death of neurons in the aging brain. Science 278, 412–419 (1997).
West, M. J. New stereological methods for counting neurons. Neurobiol. Aging 14, 275–285 (1993).
Pakkenberg, B. & Gundersen, H. J. Neocortical neuron number in humans: effect of sex and age. J. Comp. Neurol. 384, 312–320 (1997).
West, M. J., Coleman, P. D., Flood, D. G. & Troncoso, J. C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet 344, 769–772 (1994). A stereologically controlled investigation reporting preserved neuron number in most subregions of the hippocampus of healthy aged humans, which is distinct from individuals with Alzheimer's disease who show a significant decline in cell number.
Merrill, D. A., Roberts, J. A. & Tuszynski, M. H. Conservation of neuron number and size in entorhinal cortex layers II, III, and V/VI of aged primates. J. Comp. Neurol. 422, 396–401 (2000).
Peters, A., Leahu, D., Moss, M. B. & McNally, K. J. The effects of aging on area 46 of the frontal cortex of the rhesus monkey. Cereb. Cortex 4, 621–635 (1994).
Gazzaley, A. H., Thakker, M. M., Hof, P. R. & Morrison, J. H. Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys. Neurobiol. Aging 18, 549–553 (1997).
Keuker, J. I., Luiten, P. G. & Fuchs, E. Preservation of hippocampal neuron numbers in aged rhesus monkeys. Neurobiol. Aging 24, 157–165 (2003).
Merrill, D. A., Chiba, A. A. & Tuszynski, M. H. Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats. J. Comp. Neurol. 438, 445–456 (2001).
Rapp, P. R. & Gallagher, M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc. Natl Acad. Sci. USA 93, 9926–9930 (1996). Similar to findings in humans, this stereologically controlled experiment reveals that aged rats have no neuronal loss and so cell death cannot account for age-related behavioural impairments.
Rasmussen, T., Schliemann, T., Sorensen, J. C., Zimmer, J. & West, M. J. Memory impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiol. Aging 17, 143–147 (1996).
Smith, D. E., Rapp, P. R., McKay, H. M., Roberts, J. A. & Tuszynski, M. H. Memory impairment in aged primates is associated with focal death of cortical neurons and atrophy of subcortical neurons. J. Neurosci. 24, 4373–4381 (2004).
Scheibel, M. E., Lindsay, R. D., Tomiyasu, U. & Scheibel, A. B. Progressive dendritic changes in the aging human limbic system. Exp. Neurol. 53, 420–430 (1976).
Scheibel, A. B. The hippocampus: organizational patterns in health and senescence. Mech. Ageing Dev. 9, 89–102 (1979).
Buell, S. J. & Coleman, P. D. Quantitative evidence for selective dendritic growth in normal human aging but not in senile dementia. Brain Res. 214, 23–41 (1981).
Buell, S. J. & Coleman, P. D. Dendritic growth in the aged human brain and failure of growth in senile dementia. Science 206, 854–856 (1979).
Flood, D. G., Buell, S. J., Defiore, C. H., Horwitz, G. J. & Coleman, P. D. Age-related dendritic growth in dentate gyrus of human brain is followed by regression in the 'oldest old'. Brain Res. 345, 366–368 (1985).
Flood, D. G., Buell, S. J., Horwitz, G. J. & Coleman, P. D. Dendritic extent in human dentate gyrus granule cells in normal aging and senile dementia. Brain Res. 402, 205–216 (1987).
Hanks, S. D. & Flood, D. G. Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease. I. CA1 of hippocampus. Brain Res. 540, 63–82 (1991).
Flood, D. G., Guarnaccia, M. & Coleman, P. D. Dendritic extent in human CA2–3 hippocampal pyramidal neurons in normal aging and senile dementia. Brain Res. 409, 88–96 (1987).
Flood, D. G. Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease. II. Subiculum. Brain Res. 540, 83–95 (1991).
Flood, D. G. Critical issues in the analysis of dendritic extent in aging humans, primates, and rodents. Neurobiol. Aging 14, 649–654 (1993).
Turner, D. A. & Deupree, D. L. Functional elongation of CA1 hippocampal neurons with aging in Fischer 344 rats. Neurobiol. Aging 12, 201–210 (1991).
Pyapali, G. K. & Turner, D. A. Increased dendritic extent in hippocampal CA1 neurons from aged F344 rats. Neurobiol. Aging 17, 601–611 (1996).
Markham, J. A., McKian, K. P., Stroup, T. S. & Juraska, J. M. Sexually dimorphic aging of dendritic morphology in CA1 of hippocampus. Hippocampus 15, 97–103 (2005).
Grill, J. D. & Riddle, D. R. Age-related and laminar-specific dendritic changes in the medial frontal cortex of the rat. Brain Res. 937, 8–21 (2002).
Markham, J. A. & Juraska, J. M. Aging and sex influence the anatomy of the rat anterior cingulate cortex. Neurobiol. Aging 23, 579–588 (2002).
de Brabander, J. M., Kramers, R. J. & Uylings, H. B. Layer-specific dendritic regression of pyramidal cells with ageing in the human prefrontal cortex. Eur. J. Neurosci. 10, 1261–1269 (1998).
Uylings, H. B. & de Brabander, J. M. Neuronal changes in normal human aging and Alzheimer's disease. Brain Cogn. 49, 268–276 (2002).
Williams, R. S. & Matthysse, S. Age-related changes in Down syndrome brain and the cellular pathology of Alzheimer disease. Prog. Brain Res. 70, 49–67 (1986).
Curcio, C. A. & Hinds, J. W. Stability of synaptic density and spine volume in dentate gyrus of aged rats. Neurobiol. Aging 4, 77–87 (1983).
Uemura, E. Age-related changes in the subiculum of Macaca mulatta: synaptic density. Exp. Neurol. 87, 403–411 (1985).
Barnes, C. A. Normal aging: regionally specific changes in hippocampal synaptic transmission. Trends Neurosci. 17, 13–18 (1994). A comprehensive review of hippocampal region-specific changes in synaptic transmission, along with functional sparing, which challenged the traditional concept of ageing as a process of general deterioration.
Barnes, C. A. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J. Comp. Physiol. Psychol. 93, 74–104 (1979). The first report in aged rats of an increased LTP decay rate at the perforant path–granule cell synapse that correlates with the rate of forgetting a spatial problem on the Barnes circular platform task.
Barnes, C. A., Rao, G., Foster, T. C. & McNaughton, B. L. Region-specific age effects on AMPA sensitivity: electrophysiological evidence for loss of synaptic contacts in hippocampal field CA1. Hippocampus 2, 457–468 (1992).
Segal, M. Changes in neurotransmitter actions in the aged rat hippocampus. Neurobiol. Aging 3, 121–124 (1982).
Landfield, P. W. & Pitler, T. A. Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 226, 1089–1092 (1984). The first report of a significant increase in the K+-dependent afterhyperpolarization of aged hippocampal CA1 pyramidal cells that is blocked by low concentrations of Ca2+.
Niesen, C. E., Baskys, A. & Carlen, P. L. Reversed ethanol effects on potassium conductances in aged hippocampal dentate granule neurons. Brain Res. 445, 137–141 (1988).
Kerr, D. S., Campbell, L. W., Hao, S. Y. & Landfield, P. W. Corticosteroid modulation of hippocampal potentials: increased effect with aging. Science 245, 1505–1509 (1989).
Potier, B., Lamour, Y. & Dutar, P. Age-related alterations in the properties of hippocampal pyramidal neurons among rat strains. Neurobiol. Aging 14, 17–25 (1993).
Potier, B., Rascol, O., Jazat, F., Lamour, Y. & Dutar, P. Alterations in the properties of hippocampal pyramidal neurons in the aged rat. Neuroscience 48, 793–806 (1992).
Pitler, T. A. & Landfield, P. W. Aging-related prolongation of calcium spike duration in rat hippocampal slice neurons. Brain Res. 508, 1–6 (1990).
Barnes, C. A. & McNaughton, B. L. Physiological compensation for loss of afferent synapses in rat hippocampal granule cells during senescence. J. Physiol. (Lond.) 309, 473–485 (1980).
Reynolds, J. N. & Carlen, P. L. Diminished calcium currents in aged hippocampal dentate gyrus granule neurones. Brain Res. 479, 384–390 (1989).
Luebke, J. I. & Rosene, D. L. Aging alters dendritic morphology, input resistance, and inhibitory signaling in dentate granule cells of the rhesus monkey. J. Comp. Neurol. 460, 573–584 (2003).
Moyer, J. R. Jr, Thompson, L. T., Black, J. P. & Disterhoft, J. F. Nimodipine increases excitability of rabbit CA1 pyramidal neurons in an age- and concentration-dependent manner. J. Neurophysiol. 68, 2100–2109 (1992).
Thibault, O. & Landfield, P. W. Increase in single L-type calcium channels in hippocampal neurons during aging. Science 272, 1017–1020 (1996). The first evidence that the increase in voltage-activated Ca2+ influx in aged CA1 hippocampal neurons is due to an age-related increase in L-type Ca2+ channels.
Toescu, E. C., Verkhratsky, A. & Landfield, P. W. Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci. 27, 614–620 (2004).
Foster, T. C. & Norris, C. M. Age-associated changes in Ca2+-dependent processes: relation to hippocampal synaptic plasticity. Hippocampus 7, 602–612 (1997).
Landfield, P. W. Hippocampal neurobiological mechanisms of age-related memory dysfunction. Neurobiol. Aging 9, 571–579 (1988).
Tombaugh, G. C., Rowe, W. B. & Rose, G. M. The slow afterhyperpolarization in hippocampal CA1 neurons covaries with spatial learning ability in aged Fisher 344 rats. J. Neurosci. 25, 2609–2616 (2005).
Barnes, C. A., McNaughton, B. L. & O'Keefe, J. Loss of place specificity in hippocampal complex spike cells of senescent rat. Neurobiol. Aging 4, 113–119 (1983).
Markus, E. J., Barnes, C. A., McNaughton, B. L., Gladden, V. L. & Skaggs, W. E. Spatial information content and reliability of hippocampal CA1 neurons: effects of visual input. Hippocampus 4, 410–421 (1994).
Mizumori, S. J., Lavoie, A. M. & Kalyani, A. Redistribution of spatial representation in the hippocampus of aged rats performing a spatial memory task. Behav. Neurosci. 110, 1006–1016 (1996).
Barnes, C. A., Suster, M. S., Shen, J. & McNaughton, B. L. Multistability of cognitive maps in the hippocampus of old rats. Nature 388, 272–275 (1997). The first report of altered stability of hippocampal place maps in aged rats, which correlates with the bimodal performance of aged rats on the spatial version of the Morris swim task.
Shen, J., Barnes, C. A., McNaughton, B. L., Skaggs, W. E. & Weaver, K. L. The effect of aging on experience-dependent plasticity of hippocampal place cells. J. Neurosci. 17, 6769–6782 (1997). Many hippocampal place cells were recorded simultaneously in young and aged rats to reveal that behaviourally induced plasticity mechanisms are defective in aged rats.
Tanila, H., Shapiro, M., Gallagher, M. & Eichenbaum, H. Brain aging: changes in the nature of information coding by the hippocampus. J. Neurosci. 17, 5155–5166 (1997).
Smith, A. C., Gerrard, J. L., Barnes, C. A. & McNaughton, B. L. Effect of age on burst firing characteristics of rat hippocampal pyramidal cells. Neuroreport 11, 3865–3871 (2000).
Oler, J. A. & Markus, E. J. Age-related deficits in the ability to encode contextual change: a place cell analysis. Hippocampus 10, 338–350 (2000).
Wilson, I. A., Ikonen, S., Gallagher, M., Eichenbaum, H. & Tanila, H. Age-associated alterations in place cells are subregion specific. J. Neurosci. 25, 6877–6886 (2005). The first paper to report a distinction between the impact of ageing on CA1 and CA3 networks. This makes it clear that these areas cannot be combined when age comparisons are made.
Chang, Y. M., Rosene, D. L., Killiany, R. J., Mangiamele, L. A. & Luebke, J. I. Increased action potential firing rates of layer 2/3 pyramidal cells in the prefrontal cortex are significantly related to cognitive performance in aged monkeys. Cereb. Cortex 15, 409–418 (2005).
Bondareff, W. & Geinisman, Y. Loss of synapses in the dentate gyrus of the senescent rat. Am. J. Anat. 145, 129–136 (1976).
Geinisman, Y., Bondareff, W. & Dodge, J. T. Partial deafferentation of neurons in the dentate gyrus of the senescent rat. Brain Res. 134, 541–545 (1977).
Geinisman, Y., de Toledo-Morrell, L. & Morrell, F. Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. Proc. Natl Acad. Sci. USA 83, 3027–3031 (1986).
Geinisman, Y., de Toledo-Morrell, L., Morrell, F., Persina, I. S. & Rossi, M. 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 (1992).
Barnes, C. A., Rao, G. & Houston, F. P. LTP induction threshold change in old rats at the perforant path–granule cell synapse. Neurobiol. Aging 21, 613–620 (2000).
Foster, T. C., Barnes, C. A., Rao, G. & McNaughton, B. L. Increase in perforant path quantal size in aged F-344 rats. Neurobiol. Aging 12, 441–448 (1991).
Barnes, C. A., Rao, G. & McNaughton, B. L. Increased electrotonic coupling in aged rat hippocampus: a possible mechanism for cellular excitability changes. J. Comp. Neurol. 259, 549–558 (1987).
Geinisman, Y. et al. Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum. Neurobiol. Aging 25, 407–416 (2004).
Nicholson, D. A., Yoshida, R., Berry, R. W., Gallagher, M. & Geinisman, Y. Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J. Neurosci. 24, 7648–7653 (2004).
Landfield, P. W., Pitler, T. A. & Applegate, M. D. The effects of high Mg2+-to-Ca2+ ratios on frequency potentiation in hippocampal slices of young and aged rats. J. Neurophysiol. 56, 797–811 (1986).
Deupree, D. L., Bradley, J. & Turner, D. A. Age-related alterations in potentiation in the CA1 region in F344 rats. Neurobiol. Aging 14, 249–258 (1993).
Barnes, C. A., Rao, G. & Shen, J. Age-related decrease in the N-methyl-D-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1. Neurobiol. Aging 18, 445–452 (1997).
Rosenzweig, E. S., Rao, G., McNaughton, B. L. & Barnes, C. A. Role of temporal summation in age-related long-term potentiation-induction deficits. Hippocampus 7, 549–558 (1997).
Barnes, C. A., Rao, G. & Orr, G. Age-related decrease in the Schaffer collateral-evoked EPSP in awake, freely behaving rats. Neural Plast. 7, 167–178 (2000).
Tombaugh, G. C., Rowe, W. B., Chow, A. R., Michael, T. H. & Rose, G. M. Theta-frequency synaptic potentiation in CA1 in vitro distinguishes cognitively impaired from unimpaired aged Fischer 344 rats. J. Neurosci. 22, 9932–9940 (2002).
Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).
Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).
Diana, G., Domenici, M. R., Loizzo, A., Scotti de Carolis, A. & Sagratella, S. Age and strain differences in rat place learning and hippocampal dentate gyrus frequency-potentiation. Neurosci. Lett. 171, 113–116 (1994).
Diana, G., Scotti de Carolis, A., Frank, C., Domenici, M. R. & Sagratella, S. Selective reduction of hippocampal dentate frequency potentiation in aged rats with impaired place learning. Brain Res. Bull. 35, 107–111 (1994).
Landfield, P. W. & Lynch, G. Impaired monosynaptic potentiation in in vitro hippocampal slices from aged, memory-deficient rats. J. Gerontol. 32, 523–533 (1977).
Landfield, P. W., McGaugh, J. L. & Lynch, G. Impaired synaptic potentiation processes in the hippocampus of aged, memory-deficient rats. Brain Res. 150, 85–101 (1978).
Dieguez, D. Jr & Barea-Rodriguez, E. J. Aging impairs the late phase of long-term potentiation at the medial perforant path–CA3 synapse in awake rats. Synapse 52, 53–61 (2004).
Barnes, C. A., Rao, G. & Houston, F. P. LTP induction threshold change in old rats at the perforant path–granule cell synapse. Neurobiol. Aging 21, 613–620 (2000).
Barnes, C. A., Rao, G. & McNaughton, B. L. Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats. Learn. Mem. 3, 124–137 (1996).
Deupree, D. L., Turner, D. A. & Watters, C. L. Spatial performance correlates with in vitro potentiation in young and aged Fischer 344 rats. Brain Res. 554, 1–9 (1991).
Moore, C. I., Browning, M. D. & Rose, G. M. Hippocampal plasticity induced by primed burst, but not long-term potentiation, stimulation is impaired in area CA1 of aged Fischer 344 rats. Hippocampus 3, 57–66 (1993). In contrast to earlier reports of intact hippocampal LTP induction (see references 38 and 83), the results of this study suggest that engaging plasticity-inducing mechanisms around threshold becomes more difficult with age.
Bear, M. F., Cooper, L. N. & Ebner, F. F. A physiological basis for a theory of synapse modification. Science 237, 42–48 (1987).
Bear, M. F. & Malenka, R. C. Synaptic plasticity: LTP and LTD. Curr. Opin. Neurobiol. 4, 389–399 (1994).
Thibault, O., Hadley, R. & Landfield, P. W. Elevated postsynaptic [Ca2+]i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J. Neurosci. 21, 9744–9756 (2001).
Norris, C. M., Korol, D. L. & Foster, T. C. Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J. Neurosci. 16, 5382–5392 (1996). Provides the first characterization of homosynaptic LTD/LTP reversal in aged rats and shows that plasticity induced by low-frequency stimulation is increased during ageing, probably as a result of Ca2+ dysregulation.
Kumar, A. & Foster, T. C. Intracellular calcium stores contribute to increased susceptibility to LTD induction during aging. Brain Res. 1031, 125–128 (2005).
Morgan, J. I., Cohen, D. R., Hempstead, J. L. & Curran, T. Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237, 192–197 (1987).
Cole, A. J., Saffen, D. W., Baraban, J. M. & Worley, P. F. Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340, 474–476 (1989).
Dragunow, M. et al. Long-term potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats. Neurosci. Lett. 101, 274–280 (1989).
Wisden, W. et al. Differential expression of immediate early genes in the hippocampus and spinal cord. Neuron 4, 603–614 (1990).
Guzowski, J. F., McNaughton, B. L., Barnes, C. A. & Worley, P. F. Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nature Neurosci. 2, 1120–1124 (1999).
Platenik, J., Kuramoto, N. & Yoneda, Y. Molecular mechanisms associated with long-term consolidation of the NMDA signals. Life Sci. 67, 335–364 (2000).
Clayton, D. F. The genomic action potential. Neurobiol. Learn. Mem. 74, 185–216 (2000).
Jones, M. W. et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nature Neurosci. 4, 289–296 (2001).
Reti, I. M., Reddy, R., Worley, P. F. & Baraban, J. M. Prominent Narp expression in projection pathways and terminal fields. J. Neurochem. 82, 935–944 (2002).
O'Brien, R. J. et al. Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp. Neuron 23, 309–323 (1999).
Steward, O., Wallace, C. S., Lyford, G. L. & Worley, P. F. Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites. Neuron 21, 741–751 (1998).
Lyford, G. L. et al. Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14, 433–445 (1995).
Guzowski, J. F. et al. Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J. Neurosci. 20, 3993–4001 (2000).
Jiang, C. H., Tsien, J. Z., Schultz, P. G. & Hu, Y. The effects of aging on gene expression in the hypothalamus and cortex of mice. Proc. Natl Acad. Sci. USA 98, 1930–1934 (2001).
Lee, C. K., Weindruch, R. & Prolla, T. A. Gene-expression profile of the ageing brain in mice. Nature Genet. 25, 294–297 (2000).
Blalock, E. M. et al. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J. Neurosci. 23, 3807–3819 (2003). A report of the first gene-expression microarray experiment in behaviourally characterized rats, which shows an age-associated change in the resting levels of expression of several genes that correlates with cognitive decline.
Smith, D. R., Hoyt, E. C., Gallagher, M., Schwabe, R. F. & Lund, P. K. Effect of age and cognitive status on basal level AP-1 activity in rat hippocampus. Neurobiol. Aging 22, 773–786 (2001).
Lanahan, A., Lyford, G., Stevenson, G. S., Worley, P. F. & Barnes, C. A. Selective alteration of long-term potentiation-induced transcriptional response in hippocampus of aged, memory-impaired rats. J. Neurosci. 17, 2876–2885 (1997).
Small, S. A., Chawla, M. K., Buonocore, M., Rapp, P. R. & Barnes, C. A. Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging. Proc. Natl Acad. Sci. USA 101, 7181–7186 (2004). The authors used different imaging methods in rats and monkeys and report a cross-species consensus that the dentate gyrus of the hippocampus is particularly vulnerable to the impact of ageing. These results are consistent with a previous report in humans.
Small, S. A., Tsai, W. Y., DeLaPaz, R., Mayeux, R. & Stern, Y. Imaging hippocampal function across the human life span: is memory decline normal or not? Ann. Neurol. 51, 290–295 (2002).
Kentros, C. et al. Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science 280, 2121–2126 (1998).
Ekstrom, A. D., Meltzer, J., McNaughton, B. L. & Barnes, C. A. NMDA receptor antagonism blocks experience-dependent expansion of hippocampal 'place fields'. Neuron 31, 631–638 (2001).
O'Keefe, J. & Dostrovsky, J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 34, 171–175 (1971).
Jung, M. W. & McNaughton, B. L. Spatial selectivity of unit activity in the hippocampal granular layer. Hippocampus 3, 165–182 (1993).
Wilson, M. A. & McNaughton, B. L. Dynamics of the hippocampal ensemble code for space. Science 261, 1055–1058 (1993).
McNaughton, B. L., Barnes, C. A. & O'Keefe, J. The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats. Exp. Brain Res. 52, 41–49 (1983).
Muller, R. U., Bostock, E., Taube, J. S. & Kubie, J. L. On the directional firing properties of hippocampal place cells. J. Neurosci. 14, 7235–7251 (1994).
Markus, E. J. et al. Interactions between location and task affect the spatial and directional firing of hippocampal neurons. J. Neurosci. 15, 7079–7094 (1995).
Mehta, M. R., Barnes, C. A. & McNaughton, B. L. Experience-dependent, asymmetric expansion of hippocampal place fields. Proc. Natl Acad. Sci. USA 94, 8918–8921 (1997).
Hebb, D. The Organization of Behavior: A Neurophysiological Theory (Wiley, New York, 1949).
Thompson, L. T. & Best, P. J. Long-term stability of the place-field activity of single units recorded from the dorsal hippocampus of freely behaving rats. Brain Res. 509, 299–308 (1990).
Agnihotri, N. T., Hawkins, R. D., Kandel, E. R. & Kentros, C. The long-term stability of new hippocampal place fields requires new protein synthesis. Proc. Natl Acad. Sci. USA 101, 3656–3661 (2004).
Tanila, H., Sipila, P., Shapiro, M. & Eichenbaum, H. Brain aging: impaired coding of novel environmental cues. J. Neurosci. 17, 5167–5174 (1997).
Lee, I., Yoganarasimha, D., Rao, G. & Knierim, J. J. Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3. Nature 430, 456–459 (2004).
Leutgeb, S., Leutgeb, J. K., Treves, A., Moser, M. B. & Moser, E. I. Distinct ensemble codes in hippocampal areas CA3 and CA1. Science 305, 1295–1298 (2004).
Vazdarjanova, A. & Guzowski, J. F. Differences in hippocampal neuronal population responses to modifications of an environmental context: evidence for distinct, yet complementary, functions of CA3 and CA1 ensembles. J. Neurosci. 24, 6489–6496 (2004).
Marr, D. Simple memory: a theory for archicortex. Phil. Trans. R. Soc. Lond. B 262, 23–81 (1971).
McNaughton, B. L. & Morris, R. G. Hippocampal synaptic enhancement and information storage within a distributed memory system. Trends Neurosci. 10, 408–415 (1987).
Spencer, W. D. & Raz, N. Differential effects of aging on memory for content and context: a meta-analysis. Psychol. Aging 10, 527–539 (1995).
McIntyre, J. S. & Craik, F. I. Age differences in memory for item and source information. Can. J. Psychol. 41, 175–192 (1987).
Wilkniss, S. M., Jones, M. G., Korol, D. L., Gold, P. E. & Manning, C. A. Age-related differences in an ecologically based study of route learning. Psychol. Aging 12, 372–375 (1997).
Newman, M. & Kasznaik, A. Spatial memory and aging: performance on a human analog of the Morris water maze. Aging Neuropsychol. Cogn. 7, 86–93 (2000). Similar to rats and monkeys, in a dry version of the Morris swim task, healthy aged humans are impaired in remembering the location of a landmark in relation to room cues.
Lai, Z. C., Moss, M. B., Killiany, R. J., Rosene, D. L. & Herndon, J. G. Executive system dysfunction in the aged monkey: spatial and object reversal learning. Neurobiol. Aging 16, 947–954 (1995).
Rapp, P. R., Kansky, M. T. & Roberts, J. A. Impaired spatial information processing in aged monkeys with preserved recognition memory. Neuroreport 8, 1923–1928 (1997). These results reveal substantial correspondence between rat and monkey data, showing that aged animals are impaired in tasks that test spatial memory.
Head, E. et al. Spatial learning and memory as a function of age in the dog. Behav. Neurosci. 109, 851–858 (1995).
Markowska, A. L. et al. Individual differences in aging: behavioral and neurobiological correlates. Neurobiol. Aging 10, 31–43 (1989).
Gallagher, M. & Rapp, P. R. The use of animal models to study the effects of aging on cognition. Annu. Rev. Psychol. 48, 339–370 (1997).
Bach, M. E. et al. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc. Natl Acad. Sci. USA 96, 5280–5285 (1999).
Rosenzweig, E. S. & Barnes, C. A. Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Prog. Neurobiol. 69, 143–179 (2003).
Christian, K. M. & Thompson, R. F. Neural substrates of eyeblink conditioning: acquisition and retention. Learn. Mem. 10, 427–455 (2003).
Kishimoto, Y., Suzuki, M., Kawahara, S. & Kirino, Y. Age-dependent impairment of delay and trace eyeblink conditioning in mice. Neuroreport 12, 3349–3352 (2001).
Knuttinen, M. G., Gamelli, A. E., Weiss, C., Power, J. M. & Disterhoft, J. F. Age-related effects on eyeblink conditioning in the F344 × BN F1 hybrid rat. Neurobiol. Aging 22, 1–8 (2001).
Thompson, L. T., Moyer, J. R. Jr & Disterhoft, J. F. Trace eyeblink conditioning in rabbits demonstrates heterogeneity of learning ability both between and within age groups. Neurobiol. Aging 17, 619–629 (1996).
Solomon, P. R. & Groccia-Ellison, M. E. Classic conditioning in aged rabbits: delay, trace, and long-delay conditioning. Behav. Neurosci. 110, 427–435 (1996).
Finkbiner, R. G. & Woodruff-Pak, D. S. Classical eyeblink conditioning in adulthood: effects of age and interstimulus interval on acquisition in the trace paradigm. Psychol. Aging 6, 109–117 (1991).
Funahashi, S., Bruce, C. J. & Goldman-Rakic, P. S. Dorsolateral prefrontal lesions and oculomotor delayed-response performance: evidence for mnemonic 'scotomas'. J. Neurosci. 13, 1479–1497 (1993).
Mair, R. G., Burk, J. A. & Porter, M. C. Lesions of the frontal cortex, hippocampus, and intralaminar thalamic nuclei have distinct effects on remembering in rats. Behav. Neurosci. 112, 772–792 (1998).
Godefroy, O., Cabaret, M., Petit-Chenal, V., Pruvo, J. P. & Rousseaux, M. Control functions of the frontal lobes. Modularity of the central-supervisory system? Cortex 35, 1–20 (1999).
Dunnett, S. B., Evenden, J. L. & Iversen, S. D. Delay-dependent short-term memory deficits in aged rats. Psychopharmacology (Berl.) 96, 174–180 (1988).
Moss, M. B., Rosene, D. L. & Peters, A. Effects of aging on visual recognition memory in the rhesus monkey. Neurobiol. Aging 9, 495–502 (1988).
Rapp, P. R. & Amaral, D. G. Evidence for task-dependent memory dysfunction in the aged monkey. J. Neurosci. 9, 3568–3576 (1989).
Moss, M. B., Killiany, R. J., Lai, Z. C., Rosene, D. L. & Herndon, J. G. Recognition memory span in rhesus monkeys of advanced age. Neurobiol. Aging 18, 13–19 (1997).
Lyons-Warren, A., Lillie, R. & Hershey, T. Short- and long-term spatial delayed response performance across the lifespan. Dev. Neuropsychol. 26, 661–678 (2004).
Wiig, K. A. & Burwell, R. D. Memory impairment on a delayed non-matching-to-position task after lesions of the perirhinal cortex in the rat. Behav. Neurosci. 112, 827–838 (1998).
Buffalo, E. A. et al. Dissociation between the effects of damage to perirhinal cortex and area TE. Learn. Mem. 6, 572–599 (1999).
Rhodes, M. G. Age-related differences in performance on the Wisconsin card sorting test: a meta-analytic review. Psychol. Aging 19, 482–494 (2004). When educational status and test modality are considered, compared with younger adults, aged humans show deficits on measures of executive function as assessed by the Wisconsin card sorting task, which correlates with an age-related decline in prefrontal cortex functioning.
Moore, T. L., Killiany, R. J., Herndon, J. G., Rosene, D. L. & Moss, M. B. Impairment in abstraction and set shifting in aged rhesus monkeys. Neurobiol. Aging 24, 125–134 (2003). Relative to young adult monkeys, aged monkeys are impaired on an animal analogue of the Wisconsin card sorting task, which suggests an age-related decline in prefrontal cortex functioning. This is consistent with human studies.
Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates 4th edn (Academic, San Diego, 1998).
Gothard, K. M., Skaggs, W. E., Moore, K. M. & McNaughton, B. L. Binding of hippocampal CA1 neural activity to multiple reference frames in a landmark-based navigation task. J. Neurosci. 16, 823–835 (1996).
McNaughton, B. L., O'Keefe, J. & Barnes, C. A. The stereotrode: a new technique for simultaneous isolation of several single units in the central nervous system from multiple unit records. J. Neurosci. Methods 8, 391–397 (1983).
Gray, C. M., Maldonado, P. E., Wilson, M. & McNaughton, B. Tetrodes markedly improve the reliability and yield of multiple single-unit isolation from multi-unit recordings in cat striate cortex. J. Neurosci. Methods 63, 43–54 (1995).
Rao, G., Barnes, C. A. & McNaughton, B. L. Intracellular fluorescent staining with carboxyfluorescein: a rapid and reliable method for quantifying dye-coupling in mammalian central nervous system. J. Neurosci. Methods 16, 251–263 (1986).
We would like to thank G. Rao for help with carboxyfluorescein images, M. R. Penner and M. K. Chawla for c-fos data, and A. P. Maurer and Z. Navratilova for critical reading of this manuscript. The authors' work was supported by a grant from the National Institute on Aging (NIA).
The authors declare no competing financial interests.
- Stereological principles
A set of rules that allows objective counting of the number of objects in a three-dimensional structure independent of the size of the objects. Among these is the dissector principle, which ensures that objects are sampled with a probability that is proportional to their number and not their size.
- Long-term potentiation
The physiological mechanism for selectively increasing synaptic weight distributions to develop the associations between neurons that are necessary for learning and memory.
- Long-term depression
A mechanism for selectively decreasing synaptic weights so that new associations can be stored in the network without reaching saturation.
- Immediate-early gene
(IEG). Any gene whose expression does not require the activation of any other responsive genes or de novo protein synthesis.
- Reverse northern strategy
A technique in which levels of tissue mRNA are assessed by monitoring the intensity of the hybridization signal of radiolabelled cDNA prepared from tissue RNA to Southern blots containing cloned cDNAs of multiple candidate genes. The hybridization signal for each gene is indicative of the tissue mRNA level.
- Morris swim task
The most widely used test of spatial learning and memory in rats. In this task, rats are placed into a tank of cloudy water. To escape from the water the rats need to find the location of a platform hidden just below the surface. The platform is always in the same location relative to the room and the distal cues.
- Pattern completion
The ability of a network to retrieve an entire stored pattern when only a fragment of the pattern is presented.
- Pattern separation
The ability of a network to make the stored representations of similar input patterns more dissimilar.
- Delayed non-matching-to-sample task
(DNMS task). A sample stimulus is presented to the subject. After a delay, the sample is presented again, along with a new stimulus. The subject is rewarded for selecting the new stimulus.
- Perirhinal cortex
High level association cortex in the medial temporal lobe that receives highly processed polymodal information from the entire cortical mantel and sends direct projections to the entorhinal cortex and hippocampus as well as back-projections to the cortex.
- Wisconsin card sorting task
(WCST). Participants are required to sort response cards of different dimensions (shape, colour and number) by a particular category, which is determined by an experimenter-defined rule. Card sorting principles must be inferred. Once the sorting rule is discovered and a determined number of correct responses are made, the experimenter changes the rule and the subject must then infer the new rule.
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