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The Aging Mind: Opportunities in Cognitive Research Appendixes

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The Aging Mind: Opportunities in Cognitive Research This page in the original is blank.

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The Aging Mind: Opportunities in Cognitive Research A— Age-Related Shifts in Neural Circuit Characteristics and Their Impact on Age-Related Cognitive Impairments John H. Morrison INTRODUCTION Increasing chronological age carries with it a heightened risk for diseases such as Alzheimer's disease, as well as functional decline associated with senescence in the absence of any specific neurologic disease, such as age-related memory impairment. Alzheimer's disease leads to a catastrophic decline in cognitive abilities and memory performance in the affected individual. Age-related memory impairment in the context of senescence is far less catastrophic than Alzheimer's disease with respect to the quality of life, but it has a surprisingly high incidence and thus also represents a significant health problem associated with aging. With the increased life expectancy that has already occurred over the last century, let alone the projected further increase, it has become clear that one of the most important goals for neuroscientists over the next several decades will be to develop means of maintaining a high level of cognitive and memory performance in the aged population. The focus of this paper is to outline and to illustrate a circuit-based approach aimed at both revealing the neurobiological basis of age-related memory impairment and identifying targets for intervention. A Multitiered Neuroanatomic Approach to Aging The Link between Neurochemistry and Neuroanatomy Traditionally, a given cell class or circuit has been defined and/or categorized on the basis of its physiological and anatomic characteristics, i.e., the

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The Aging Mind: Opportunities in Cognitive Research information being transmitted and the origin and termination of its connections, respectively. More recently, both neuroanatomical and electrophysiological characterizations of neural circuits have incorporated biochemical and molecular biological information in order to develop a more comprehensive portrayal of the essential qualities of a circuit that relate to its role in brain function. The key biochemical attributes of a given circuit or cell class are largely a reflection of the particular gene expression patterns, dynamics of protein synthesis, degradation and distribution, and selective activation of signaling cascades that are predominant in the neurons that furnish the circuit. The resultant biochemical profile essentially represents the neurochemical phenotype of a circuit or cell class. Operationally, one might define neurochemical phenotype as the complement of specific molecules, particularly proteins and their enzymatic products, that are enriched in and utilized by a given class of neurons in a manner that is not shared by other cell classes. The neurochemical phenotype of a neuron includes molecules related to synaptic transmission (e.g., receptors, neurotransmitters, and related enzymes), structural attributes, metabolic processes, or any characteristic that is uniquely well developed in that neuron and critically important to its designated role in brain function. For example, a cortical neuron that uses GABA, the major inhibitory neurotransmitter, has a neurochemical phenotype that differs in many fundamental ways from a cortical neuron that uses glutamate, the major excitatory neurotransmitter. As implied in the definition of neurochemical phenotype, gene expression and protein distribution patterns are not uniform across the brain or even across a single brain region. In fact, brain circuits are highly heterogeneous with respect to which genes are expressed over time and space, and the intracellular distribution of gene products (i.e., proteins) is highly regulated. Therefore, a comprehensive neuroanatomic analysis of a circuit must address its particular neurochemical profile as well as its anatomic connections, since both will impact that circuit's functional characteristics and role in behavior. With respect to the task at hand, the goal is to link age-related shifts in neurochemical phenotype and neuroanatomic characteristics in key cortical and hippocampal circuits to functional decrements in memory that occur with aging. Why place the emphasis for studies of aging on cell classes and circuits rather than on brain regions? More specifically, if memory is the issue and the hippocampus is critical to memory, why not address the issue of age-related pathology at the level of the entire hippocampus, rather than isolated cells, circuits, and synapses? As described below, there are important reasons to identify and consider the brain region of interest as an important step in such analyses. However, the main rationale for bringing the analysis to a higher level of resolution and focusing on distinct cell classes and circuits is that it more accurately reflects

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The Aging Mind: Opportunities in Cognitive Research neuronal vulnerability to aging and Alzheimer's disease. A given brain region does not generally suffer as a whole; it is more likely that vulnerable circuits in a given region tend to suffer while other circuits are unaffected. Even a region as vulnerable to Alzheimer's disease as the hippocampus has cell classes and circuits that are highly resistant to degeneration as well as those that are vulnerable. We suspect that normal aging will exhibit an even higher degree of selectivity in affected circuits than does Alzheimer's disease, thus it is even more important to address the question of age-related neuronal vulnerability at the highest possible level of cellular and circuit resolution. In turn, as interventions are developed to prevent age-related decline, they should be targeted to the vulnerable cell classes and circuits, not to a given region. Ideally, the goal should be to sustain the health of vulnerable circuits without impacting those that are resistant to age-related decrements, and in order to do this we must first clarify the neurobiological underpinnings of age-related functional decline at the level of the selectively vulnerable cells, circuits, and synapses. In addition, it is critical that the cellular and neuroanatomic analyses be quantitative. Qualitative impressions of age-related cell loss, morphologic aberrations, or down-regulation of a particular receptor will not allow for a sufficiently precise or accurate depiction of age-related changes, nor will qualitative judgments possess the requisite statistical power to test many hypotheses. In contrast, quantitative descriptions of structural and biochemical attributes can be readily correlated with quantitative assessments of physiological and behavioral output, allowing for direct links to be established between neurobiological indices and function. This is perhaps most important when testing the effectiveness of an intervention, since one would like to be able to equate any improvement in functional output with a measurable reflection of increased neuronal viability. Throughout this article, the emphasis will be on microscopic approaches to cell and circuit analysis rather than electrophysiological approaches; however, the electrophysiological approach to the hippocampus, aging, and memory is a critical partner to the microscopic data, particularly with respect to delineating complex properties that emerge from the activity of hippocampal neurons. Targeting Multiple Levels of Resolution: From the Brain Region to the Synapse The Brain Region In any such analysis, the first task is to define the brain region(s) and circuits to be analyzed, by virtue of their hypothesized role in the neural function or behavior that is compromised by aging. In addition, the process of neural circuitry analysis becomes more focused as the behavioral measures

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The Aging Mind: Opportunities in Cognitive Research are improved and refined in their sensitivity and quantitative power. The great advances over the last few decades in the analysis of memory offer an excellent example of the manner in which behavioral data can guide neuroanatomic analysis toward a given brain region, e.g., the hippocampus, and in turn certain circuits, e.g., the perforant path (discussed below). Defining the brain region(s) of interest is particularly important if one of the experimental goals is to obtain estimates of neuron number, glial cell number, or synapse number, since such estimates are not useful if the region of interest cannot be clearly and precisely defined or its boundaries recognized. In fact, the accurate determination of neuron number in key hippocampal fields such as CA1 and the adjacent entorhinal cortex is what led to the realization that neuron death is unlikely to be at the root of age-related impairment in memory and cognition (Rapp and Gallagher, 1996; Morrison and Hof, 1997; Peters et al., 1998a), challenging the accepted dogma that people inevitably ''lose nerve cells" as they age. The use of modern stereological techniques for determining neuron number in a defined brain region has been invaluable for establishing the sustained viability of neurons during aging. One of the many attributes of the stereological techniques that make them particularly valuable for analyses of aging and neurodegenerative disorders is that they generate estimates of neuron or synapse number that are not confounded by tissue or cellular shrinkage, two major potential confounds in studies of aging (West, 1993a, 1993b). The stereologic approach (West, 1993a, 1993b, 1999; Geinisman et al., 1996; Coggeshall and Lekan, 1996) to estimates of neuron number, synapse number, axon length, etc., will continue to be powerful for such studies, particularly as a quantitative database of neuroanatomic information relevant to aging develops. Cell Classes and Circuits The next level of resolution beyond that of brain region is the analysis of specific circuits and related cell classes. With respect to the hippocampus and memory, attention is drawn to the neurons in layer II of the entorhinal cortex, which provide the perforant path that connects the entorhinal cortex to the dentate gyrus (Van Hoesen and Pandya, 1975). This circuit is highly vulnerable in aging and Alzheimer's disease (Hyman et al., 1984; Morrison and Hof, 1997; Hof et al., 1999). The entorhinal cortex receives convergent inputs from multiple neocortical association areas and in turn provides the major cortical input to the hippocampus, and thus along with associated parahippocampal and perirhinal areas, it is positioned for a critical role in memory (Squire and Zola-Morgan, 1991; Zola-Morgan and Squire, 1993). The analysis of any key circuit such as the perforant path moves quickly into the issue of cell classes or cell types with respect to the cells of origin of such a projection. While cell type has been traditionally defined exclusively by morphologic

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The Aging Mind: Opportunities in Cognitive Research criteria (size, shape, extent of neuritic arborization), a more comprehensive definition of cell type might be a designated class of neurons that share key characteristics with regard to morphology, location, connectivity, and neurochemical phenotype. In fact, the concepts of cell type and neurochemical phenotype bear a critical relationship to selective vulnerability in aging or neurodegenerative diseases. Selective vulnerability is most readily appreciated in the context of neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Each disease is characterized by its own, unique pattern of degeneration, with amyotrophic lateral sclerosis involving the loss of upper and lower motor neurons, Parkinson's disease noted for the selective degeneration of dopaminergic neuRons in substantia nigra, and Alzheimer's disease characterized primarily by the degeneration of key cortical circuits. In many cases, the vulnerable neurons in a given disorder share particular neurochemical characteristics that can be linked to their selective vulnerability. For example, both the neurons that provide the perforant path from the entorhinal cortex and the neurons that provide the long corticocortical interconnections are highly vulnerable in Alzheimer's disease, and both are marked by a particular cytoskeletal profile that can be linked to their vulnerability (Morrison et al., 1987; Hof et al., 1990: Hof and Morrison, 1990; Hof et al., 1999). In order to define and understand the determinants of selective vulnerability in neurodegenerative diseases as well as in normal aging, it will be important to determine neuron number according to specific classes of neurons wherein class is based on morphology, connectivity, and neurochemical phenotype. In this way, hypotheses can be tested at a finer level of cell-type resolution, and links can be drawn between a particular element of the neurochemical phenotype and vulnerability. Quantitative analyses using chemically specific approaches (e.g., immunohistochemistry, in situ hybridization) allow for direct investigation of the molecular determinants of selective vulnerability, as reflected, for example, in intracellular biochemical changes in neurons as they change with age or begin to degenerate. This approach is particularly important with respect to links to gene expression, with the goal being a quantitative dataset that links gene expression patterns with circuits, vulnerability, and, potentially, with age-related changes in cognition. Neuronal Compartments Beyond the analysis of cell class(es), it is important to determine the degree to which biochemical characteristics of neuronal compartments in individual neurons are affected by age. Given that neuron death is unlikely to be the substrate for age-related memory impairment, it has become increasingly important to investigate more subtle changes in cellular morphology

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The Aging Mind: Opportunities in Cognitive Research and neurochemical phenotype that would impact function, but not be lethal. This step will require careful quantitative analyses of individual neurons, both in terms of morphometric measures as well as in terms of subcellular analyses of protein distribution patterns. For example, age-related changes in dendritic spine number have been described that could impact neuronal function (Coleman and Flood, 1987), and in fact, in primate neocortex it appears that spine density decreases with age with no change in dendritic length or branching patterns (Duan et al., 1999), and such changes may predominate in the most distal portion of the dendrite (Peters et al., 1998b). In addition, changes in receptor distribution can affect a single portion of the dendritic tree that receives a particular input, leaving the rest of the neuron unaffected (Gazzaley et al., 1996a). Moreover, some age-related changes might preferentially affect the nerve terminal rather than the dendrite, or vice versa. Such subtle changes could profoundly affect circuits and neural transmission with no evidence of generalized cell death. The Synapse The highest-resolution morphologic analysis is directed at the synapse and represents a search for potential changes in synapse structure or molecular constituents of the synapse that are related to age and might impact circuit function and behavior. Neocortical synapse loss clearly occurs in Alzheimer's disease and correlates well with degree of cognitive impairment (DeKosky and Scheff, 1990; Terry et al., 1991). High-resolution structural analyses of the synapse suggest that there are synaptic changes in the hippocampus with normal aging in the rat (Geinisman et al., 1995), although such changes may not occur in aged primate (Peters et al., 1996). In addition, the dendritic spine is more plastic than previously thought, and structural changes in the dendritic spine may occur on a time course consistent with induction of changes in synaptic function underlying memory, such as long-term potentiation (Toni et al., 1999). Thus, age-related spine loss or loss of spine plasticity could lead to age-related decline in memory and/or learning. While purely structural analyses of the aging synapse have been and will continue to be illuminating (Geinisman et al., 1995; Tigges et al., 1996; Peters et al., 1996), perhaps the most exciting applications of electron microscopy to studies of aging will emerge from the use of immunogold postembedding electron microscopy. This immunohistochemical technique has extremely high resolution, in that the molecule of interest is identified by the presence of a discrete gold particle that is 10–25 nanometers in diameter and is highly quantifiable (Chaudhry et al., 1995). In addition, multiple antibodies bound to gold particles of different sizes can be used simultaneously to localize multiple synaptic molecules in a single synapse (He et al., 2000). The number of gold particles can be equated to the number of molecules of the targeted

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The Aging Mind: Opportunities in Cognitive Research protein in a very small, discrete region, such as a single synapse (see Figure A-1). Such an approach allows for a very high-resolution analysis of the molecular constituents of identified synapses and presumably will be able to reveal shifts in the molecular constituents with experimental manipulations and/or aging at a quantitative level. When such studies are done in behaviorally characterized aged animals, we will be able to draw direct correlations between the distribution of key synaptic molecules and age-related behavioral impairment. No such studies have been completed to date, but they are now under way. As is apparent from the above discussion, key studies of aging have been and will continue to be directed at questions requiring different levels of resolution in the analysis. The illustrations cited below will focus on the microscopic delineation of vulnerable circuits and cell classes, as well as changes in protein distribution in specific cell classes, circuits, and neuronal compartments. While these examples will hopefully highlight the power of a circuit-based approach, they will also illuminate the present shortcomings of the data, such as a paucity of chemically specific synaptic data and the need for more interdisciplinary analyses. Electrophysiological data will be crucial in the interdisciplinary context, since they are particularly powerful at revealing the emergent properties and information content of hippocampal circuits coding for memory (Barnes et al., 1997a, 1997b; Eichenbaum et al., 1999; Shapiro and Eichenbaum, 1999; Wood et al., 1999). As the data emerge, it will be crucial to develop a set of models and/or databases that link data across studies, such that the synaptic and cellular data will be in a context that is easily linked to the functional role of a known circuit, in a region that is clearly implicated in a function that is compromised in aging, such as memory. DIFFERENTIATING ALZHEIMER'S DISEASE FROM SENESCENCE: THE CRITICAL ROLE OF THE ENTORHINAL CORTEX AND ITS PROJECTION TO DENTATE GYRUS At the outset, it is important to draw a distinction between the neurobiological events underlying the dementia of Alzheimer's disease and those that underlie age-related memory impairment (Morrison and Hof, 1997). In Alzheimer's disease and neurodegenerative disorders in general, neuron death occurs that results in circuit disruption and profound impairment of the neural functions dependent on the degenerating circuits (see Hof et al., 1999, for a review). As mentioned above, neuron death is not ubiquitous in neurodegenerative disorders, in that neurons display a particular pattern of selective vulnerability in each disorder. In Alzheimer's disease, the highly vulnerable circuits are: (1) neurons that interconnect functionally linked neocortical areas (Pearson et al., 1985; Rogers and Morrison, 1985; Lewis et al., 1987); (2) the projection from the entorhinal cortex to the hippocampus, referred to

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The Aging Mind: Opportunities in Cognitive Research FIGURE A-1 This is a photograph of an electron microscope image that illustrates the postembedding immunogold method. The tissue has been treated with a primary antibody directed against the NMDA receptor subunit NR2A, followed by a secondary antibody that is both conjugated to a gold particle of 10 nanometer diameter, and binds to the primary antibody, thereby forming a bridge and revealing the location of the receptor protein NR2A. This electron micrograph demonstrates intense NR2A immunogold localization between an axon terminal(ax) and dendritic spine(sp) forming an asymmetric (Type 1) synapse on the dendrites of pyramidal cells in CA1 of monkey hippocampus. The majority of the gold particles, each of which probably represents an individual receptor, are associated with the postsynaptic specialization of the dendritic spine and synaptic cleft, and thus are in a position to mediate NMDA receptor activity at this particular synapse. In addition, two particles are clearly associated with the presynaptic axon terminal, suggesting that NR2A may also participate in autoreceptors that modulate glutamate release presynaptically. Thus, with this approach we can resolve the molecular constituents of the synapse and quantify their relative distribution in specific regions of the synapse. The boxed area is represented at higher magnification in lower left corner (Scale bar = 0.13µm). The author thanks William Janssen and Prabhakar Vissavajjhalla for providing this illustration.

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The Aging Mind: Opportunities in Cognitive Research as the perforant path, as well as certain circuits intrinsic to the hippocampus (Hyman et al., 1984); and (3) key diffuse projections to the cerebral cortex, such as the cholinergic projection from nucleus basalis (Whitehouse et al., 1982; for a review, see Kemper, 1999). In contrast to the selective but extensive neuron loss reflective of Alzheimer's disease, neuron death is minimal in the regions classically associated with cognition and memory in the normal course of aging (Peters et al., 1998a). The lack of significant hippocampal and neocortical neuron death in normal aging has now been demonstrated in humans, monkeys, and rats (West et al., 1993b; Gomez-Isla et al., 1996; Rapp and Gallagher, 1996; Gazzaley et al., 1997; Peters et al., 1998a), although some neuron loss appears to occur in humans in the hilus of the dentate and in the subiculum (West, 1993b). However, a lack of quantifiable neuron loss does not necessarily mean that no degenerative changes are occurring in a given brain region, and it does not rule out more subtle changes that lead to compromised function without cell loss. The entorhinal cortex is a particularly instructive case in this regard. It appears that the neurons within layer II of entorhinal cortex, which serve as a neocortical conduit to the hippocampus through the perforant path, are likely to be the single most vulnerable class of neurons in the brain with respect to both aging and Alzheimer's disease. While these neurons are clearly devastated early in Alzheimer's disease, their status in cognitively normal, aged individuals and those with mild cognitive impairment has been more difficult to pinpoint. Neuron counts in neurologically normal individuals suggest that there is no neuron loss in the entorhinal cortex (Gomez-Isla et al., 1996; West, 1993b). However, analyses of neurofibrillary tangles (NFT), the classic reflection of a degenerating neuron in Alzheimer's disease, suggest that virtually all humans over the age of 55 have some NFT in layer II of entorhinal cortex (Vickers et al., 1992; Bouras et al., 1994). How does one reconcile these two findings and draw a distinction between age-related degenerative events in the entorhinal cortex that are progressive and those that are not? While the answer to this question continues to be elusive, one approach that appears promising is the use of a comprehensive panel of antibodies in a quantitative experimental design in order to distinguish and quantify transitional events in the neurons within the entorhinal cortex that can be correlated with the clinical dementia rating scale. This approach has led to a focus on patients with a rating of 0.5 that have mild cognitive impairment, yet it is unclear whether their condition represents early Alzheimer's disease or a more stable condition that might be referred to as age-related memory impairment. The key to reconciling the presence of NFT in this region with the fact that there does not appear to be neuron loss is that the various neuronal profile counts that have been done have not taken into consideration "transitional neurons," i.e., neurons that are still intact and included in an analysis

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The Aging Mind: Opportunities in Cognitive Research survive, differentiate, and presumably function in a different organ; an example is the conversion of neural stem cells into a variety of blood cells that circulate and reside in the bone marrow (Bjornson et al., 1999; Scheffler et al., 1999). The reverse appears to be true as well, in that bone marrow stem cells can survive and migrate within the brain and differentiate into cells that developed a phenotype for astrocytes and, in some cases, neurons (Kopen et al., 1999). Also, embryonic and neural stem cells can replace oligodendrocytes in a brain deficient in such cells and the newly derived oligodendrocytes successfully myelinate axons (Brustle et al., 1999; Yandava et al., 1999). These studies serve as a powerful animal model for testing potential therapies for such diseases as multiple sclerosis. It may also be possible to replace damaged neural circuits with such an approach. In such a study, neural embryonic stem cells from a healthy mouse were transplanted into a rat's spinal cord several days after traumatic injury (McDonald et al., 1999). His-tological analysis showed that the transplant-derived cells from the mouse had not only survived but had differentiated into astrocytes as well as neurons, and the investigators were able to demonstrate some functional recovery in these animals. The potential of such approaches that utilize neural stem cells for therapies directed at age-related pathology and functional decline is profound, and while this research arena is still in its infancy, the progress that has already occurred is very impressive (see Shihabuddin et al., 1999, for a review). The most likely limitation of the stem cell approaches will be the need for a high degree of circuit specificity in any devised therapy. The use of neural stem cells to achieve some recovery of function after spinal cord injury suggests that, at least in some cases, an adequate level of circuit specificity may emerge with little direct coaxing. However, it is not clear at this point whether or not this will occur in the key brain circuits affected in aging. For example, if we were to try and use stem cell therapy to replace the entorhinal neurons that provide the perforant path, how would we guide the neural stem cells and the differentiated neurons into becoming the particularly highly differentiated neurons that reside in layer II of entorhinal cortex with the appropriate afferents and efferents? Perhaps even more difficult, how would we replace the neurons that furnish the corticocortical circuits that interconnect frontal and temporal regions that are so damaged in Alzheimer's disease, while leaving the intact circuits unaffected? As described below, in some cases the brain may solve this problem itself by continuing to generate neurons that can replace certain circuits throughout life. Neurogenesis in the Adult Hippocampus The recent data on neurogenesis in the adult brain have demonstrated clearly that we need to reevaluate the accepted dogma that when neurons die

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The Aging Mind: Opportunities in Cognitive Research they cannot be replaced by the generation of new neurons. While it has been known for a long time from work in rodents that some neurogenesis occurs in the adult dentate gyrus (Altman and Das, 1965), it was demonstrated only recently that this also occurs in the nonhuman primate (Gould et al., 1999b) and in humans as well (Eriksson et al., 1998). In addition, while the functional status of the new neurons in the dentate gyrus is unclear, it has been demonstrated that they project to CA3 and thus may form normal connections (Hastings and Gould, 1999). Furthermore, the prevailing notion that the hippocampus is the only telencephalic region in which neurogenesis occurs has now been challenged by a report that neurogenesis occurs in the nonhuman primate neocortex, particularly in cortical regions that would presumably play a dominant role in learning, memory, and cognition (Gould et al., 1999c); however, these data on neocortex are presently controversial and will need to be expanded and replicated. How are we to integrate the notion of new neurons into our prevailing attitudes regarding age-related functional decline and neurodegenerative disorders? While much work lies ahead, several interesting recent reports demonstrate the potential importance of neurogenesis to aging, at least with respect to the dentate gyrus. For one thing, neurogenesis in the dentate gyrus is decreased in aging (Kuhn et al., 1996). There are also positive influences on neurogenesis that may be exploited in preventing the age-related decrease in neurogenesis. The simple process of training animals on a learning task that requires the hippocampus enhanced neurogenesis and the viability of the new neurons in the dentate gyrus of rats (Gould et al., 1999a). Similarly adult mice living in an enriched environment have increased neurogenesis in the hippocampus (Kempermann et al., 1997). Moreover, increased experience and social interaction led to an enhancement of neurogenesis in the dentate gyrus of aged animals (Kempermann et al., 1998). Finally, simple physical exercise (e.g., running) increased cell proliferation in the adult mouse dentate gyrus (van Praag et al., 1999). The potential for hormonal impact on these processes makes this issue even more relevant to aging. For example, estrogen has been demonstrated to stimulate a transient increase in neurogenesis in the dentate gyrus of the adult female rat (Tanapat et al., 1999). Furthermore, it was recently demonstrated that the level of neurogenesis typical of a young animal could be restored in an aged animal by decreasing the high levels of circulating corticosteroids that commonly occur in aged animals (Cameron and McKay, 1999). Thus, while it is not yet possible to fit these data on neurogenesis into the present context of aging and the neurobiological substrate for age-related functional decline, it is clear that this will be an area of intense investigation in the future and an area of paramount importance in aging research. It will be especially important to determine the quantitative extent of neurogenesis and the functional implications of adding neurons to the aged brain. Do the new neurons par-

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The Aging Mind: Opportunities in Cognitive Research ticipate in the appropriate circuits? To what degree does adult neurogenesis occur in areas other than the dentate gyrus? In a related fashion, to what degree can the natural process of neurogenesis in the hippocampus be used to replace neurons in a neurodegenerative disorder such as Alzheimer's disease? Obviously it will take time to obtain answers to these questions, but the field is moving rapidly, and we must now incorporate the potential for new neurons into our thinking about malfunctioning neurons and degenerating neurons in the aging brain. CONCLUDING REMARKS This report outlines a microscopic and neuroanatomic approach to understanding neurobiological events that underlie memory decline with aging. The available data suggest that the focus of such analyses should be the vulnerable circuit, and the delineation of phenotypic characteristics that render a cell class or circuit selectively vulnerable to aging. With respect to Alzheimer's disease, the key reflection of vulnerability is degeneration, whereas memory decline in the context of normal aging is likely due to subtle neurochemical and morphologic alterations that lead to functional impairment in the absence of frank neuronal degeneration. This differentiation is not absolute, however, in that degenerative events are clearly under way in the entorhinal cortex of neurologically normal elderly people. Many of these neurons appear as "transitional' with respect to degenerative profiles typical of Alzheimer's disease, and it will be critical to focus more attention on these transitional events if we are to adequately differentiate a stable, relatively high-functioning state from the early stages of a progression toward Alzheimer's disease. In addition, much of the work on animal models suggests that functional decline in the context of normal aging or senescence (e.g., age-related memory impairment) is unlikely to be due primarily to neuron loss and is more likely to be a reflection of shifts in gene expression or key neurochemical attributes that impair function in an intact circuit. This suggests that therapy targeted at restoring a youthful phenotype to vulnerable circuits may be particularly effective, and data exist demonstrating the rescue of age-impaired cholinergic and dopaminergic circuits. In addition, replacing dead neurons or impaired circuits through the use of stem cells may be more realistic than previously thought, although obtaining the requisite circuit specificity from such an approach may be problematic. Finally, naturally occurring neurogenesis, particularly in the adult dentate gyrus, offers another avenue for restoration of function, and data exist showing that the generation of new hippocampal neurons and their continued viability are responsive to behavioral and endocrine intervention. Thus, while conditions such as Alzheimer's disease clearly involve devastating neuron loss, the scenario for normal aging is far more dynamic and

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The Aging Mind: Opportunities in Cognitive Research adaptable than we once thought, and even neuron loss might not be as irreversible as we assumed just a few years ago. However, the development of helpful interventions will have to be carefully guided by a healthy respect for the specificity and heterogeneity of neural circuits, and the fact that even in regions considered vulnerable (e.g., the hippocampus), individual circuits vary enormously in their vulnerability to aging. Therapies that are not adequately specific with respect to targeting vulnerable circuits are likely to have unanticipated behavioral and functional consequences that will compromise their effectiveness. ACKNOWLEDGMENTS The author thanks Patrick Hof, Michelle Adams, Peter Rapp, and Bill Janssen for helpful discussions and comments regarding this manuscript. REFERENCES Abel, T.W., M.L. Voytko, and N.E. Rance 1999 The effects of hormone replacement therapy on hypothalamic neuropeptide gene expression in a primate model of menopause. Journal of Clinical Endocrinology and Metabolism 84:2111–2118. Adams, M.M., T.D. Smith, P.R. Rapp, M. Gallagher, and J.H. Morrison 1999 Immunofluorescence intensity in CA3 of hippocampus predicts spatial learning in young and aged rats. Society for Neuroscience Abstracts 25:2163. Altman, J., and G.D. Das 1965 Autoradiographic and histological evidence of postnatal neurogenesis in rats. Journal of Comparative Neurology 124:319–335. Barnes, C.A. 1994 Normal aging: Regionally specific changes in hippocampal synaptic transmission. Trends in Neurosciences 17:13–18. Barnes, C.A., G. Rao, and J. Shen 1997a Age-related decrease in the N-methyl-D-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CAI. Neurobiology of Aging 18:445–452. Barnes, C.A., M.S. Suster, J. Shen, and B.L. McNaughton 1997b Multistability of cognitive maps in the hippocampus of old rats. Nature 388:272–275. Bjorklund, A., U. Stenevi, S.B. Dunnett, and S.D. Iversen 1981 Functional reactivation of the deafferented neostriaturn by nigral transplants. Nature 289:497–499. Bjornson, C.R., R.L. Rietze, B.A. Reynolds, M.C. Magli, and A.L. Vescovi 1999 Turning brain into blood: A hematopoietic fate adopted by adult neural stem cells in vivo. Science 283:534–537. Blomer, U., T. Kafri, L. Randolph-Moore, I.M. Verma, and F.H. Gage 1998 Bcl-xL, protects adult septal cholinergic neurons from axotomized cell death. Proceedings of the National Academy of Sciences of the United States of America 95:2603–2608.

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