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Riddle DR, editor. Brain Aging: Models, Methods, and Mechanisms. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

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Brain Aging: Models, Methods, and Mechanisms.

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Chapter 6Neurogenesis in the Adult and Aging Brain

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I. OVERVIEW OF NEUROGENESIS IN THE ADULT BRAIN

A. Historical Context

Long past the publication of evidence to the contrary, it was widely held that neurons were produced in the brain only during a discrete period of development. Ramon y Cajal’s contention that “in adult centers, the nerve paths are something fixed and immutable: everything may die, nothing may be regenerated” held sway even after studies by Altman in the 1960s [1–4], followed by Kaplan and Hinds in the 1970s [5], provided evidence for the birth of new neurons in the adult brain. Despite electron microscopic and morphological evidence that some adult-born cells (identified by the incorporation of tritiated thymidine into their DNA) were neurons, the concept of ongoing adult neurogenesis was slow to reach acceptance because there were no definitive phenotypic markers of neurons that could be combined with autoradiographic birth dating and no concept of adult stem cells in the brain. Moreover, the earliest attempts to demonstrate neurogenesis in primates did not provide convincing evidence for new neurons, so the rodent studies appeared to have little relevance for humans.

Interest in adult neurogenesis increased tremendously in the 1980s after Nottebohm demonstrated seasonally regulated neurogenesis in the song nuclei of songbirds and provided evidence that adult neurogenesis subserved a neural function (reviewed in [6, 7]). Nottebohm’s analyses left no doubt that tritiated thymidine labeled cells in the adult bird brain were neurons, and evidence that the production of new neurons peaks at the time birds acquire new songs provided a compelling indication that adult neurogenesis is functionally significant, at least in birds. Subsequent studies demonstrated that neurogenesis also was ongoing in the hippocampus of adult birds and that the extent of hippocampal neurogenesis correlated both seasonally and across species with seed-storing, a behavior that depends on hippocampally dependent spatial learning [8–10]. Spurred in part by the dramatic findings in avian species, interest in adult neurogenesis in mammals increased precipitously into the 1990s, with several laboratories publishing seminal investigations of the nature and extent of neurogenesis in the adult mammalian brain (e.g., [11–15]). In addition to critical studies assessing adult neurogenesis in vivo using radioactive thymidine and the thymidine analog bromodeoxyuridine (BrdU), demonstrations that cells with stem cell properties could be isolated from the adult brain established a source for new neurons in the adult brain (e.g., [16–19]). Although the debate continues regarding the extent of adult neurogenesis across brain regions and across species [20–23], clearly new neurons are continually produced in some regions of the adult mammalian brain, even in humans [24], new neurons are integrated into functional circuits, and the ongoing neuronal turnover is significant for some functions.

B. Regional Distribution of Adult Neurogenesis

That the reality of adult neurogenesis was neither easily demonstrated nor quickly accepted was a function of its limited representation with the brain. Although there is evidence that new neurons may be added to several other neural regions under some conditions, in the normal adult brain, neurogenesis appears to be restricted to three areas, each with a focal population of progenitor cells and a characteristic pattern of differentiation and migration of new neurons.

1. Neurogenesis in the Hippocampus

Neural progenitor cells in the hippocampus are located in the subgranular zone (SGZ) at the border between the granule cell layer (GCL) and hilus of the dentate gyrus (DG; see [25–29] for reviews). Some of the daughter cells produced by division of those precursor cells differentiate into neurons and develop the prominent apical dendrite that characterizes dentate granule neurons as they move into the GCL. Adult-born neurons project axons to the primary target of dentate granule neurons, the stratum lucidum of area CA3, as early as 4 to 10 days after their final mitosis [30, 31], are integrated into the hippocampal circuitry, and are electrophysiologically comparable to earlier born granule neurons within several weeks [32]. The structural [31] and functional [33] development of adult-born granule neurons is slightly slowed, however, compared to the development of those born at the developmental peak of genesis.

2. Neurogenesis in the Subventricular Zone and Rostral Migratory Stream

Quantitatively, the extent of adult neurogenesis in the hippocampus is only a fraction of that in the anterior portion of the adult subventricular zone (SVZ), a thin, persistent remnant of the secondary proliferative zone of the developing brain. Although not readily identifiable by cell-type specific markers, neural stem cells can be isolated from the adult SVZ and shown in culture to be both self-renewing and multipotent, capable of generating both neurons and glia. Studies indicate that the neural stem cells have some characteristics of astrocytes, but clearly not all astrocytes in the region are neural stem cells [34–36]. Extensive analysis of the adult SVZ indicates that the region comprises several cell types in addition to the slowly dividing stem cells, including a more rapidly dividing population of transit amplifying progenitor (TAP) cells, neuroblasts, glial cells, and a monolayer of ependymal cells lining the ventricle [35]. Neuroblasts born in the SVZ maintain the ability to proliferate as they migrate through the SVZ, into the rostral migratory stream (RMS), and anteriorly to the olfactory bulb (OB), finally differentiating into interneurons (e.g., [37–40]). Throughout their migration, chains of neuroblasts are ensheathed by slowly proliferating astrocytes, which presumably help maintain an appropriate microenvironment for migration and cell division. The division of neuroblasts within the RMS, far from the SVZ, demonstrates that the environment that supports the division of neuronal progenitors is much more extensive in the SVZ/RMS than in the DG, where the division of progenitor cells is spatially restricted. It also is important to note that the stem/progenitor cell populations differ between the SVZ and the SGZ [41], and that the progenitor population in the adult hippocampus lacks true stem cells, containing only more restricted progenitor cells [42, 43].

3. Neurogenesis in the Olfactory Epithelium

Concurrent with the early demonstrations of neuronal addition in the adult hippocampus and OB, several laboratories described the birth of new olfactory receptor neurons (ORNs) within the adult olfactory epithelium (OE; reviewed in [44]). Progenitor cells in the basal layer of the olfactory epithelium give rise to new receptor neurons that migrate superficially as they develop their characteristic apical dendrite and project an axon to the glomerular layer of the OB. Quantitative studies indicate that ORNs may have lifespans as short as a few weeks or months (influenced in part by ongoing damage to the exposed olfactory mucosa); thus, neurogenesis in the adult olfactory epithelium supports a process of wholesale turnover, compared to the more selective replacement of new neurons within the granule cell and interneuron populations of the DG and OB. Although less extensively studied than the RMS/SVZ and hippocampus, the mechanisms of regulation on neurogenesis in the peripheral olfactory system are beginning to be elucidated [44]. Because olfactory loss may be an early indicator of age-related neural decline and Alzheimer’s disease pathogenesis (discussed in [45]), understanding aging-related changes in the peripheral olfactory system may provide particularly important translational and clinical benefits.

4. Neurogenesis in Other Neural Regions?

Although it generally is agreed that the three regions above are the only sites of (relatively) large-scale, ongoing neuronal replacement in the normal adult brain, there is evidence that at least the potential for adult neurogenesis is more widespread. Cells with properties similar to the stem cells obtained from the hippocampus and anterior SVZ have been isolated from other brain regions, including the striatum, cerebral cortex, septum, spinal cord, hypothalamus, and even white matter (reviewed in [46]). These cells show at least some capacity for self-renewal in culture, as well as the ability to give rise to both neuronal and glial lineages. Despite the apparently wide distribution of such progenitor cells, however, evidence for constitutive neuronal replacement in areas other than the three regions above remains controversial, in part because of methodological challenges in analyzing cells that divide slowly or seldom and critical questions of what constitutes adequate proof that a particular cell is newly born and that a cell identified as newly born is a neuron [22, 47]. Such debates notwithstanding, it is clear that if neurogenesis does occur in the cerebral cortex [20, 23, 48], amygdala [49], spinal cord [50], or other regions, it is at a level that is orders of magnitude below that in the DG and SVZ/RMS.

There is more compelling evidence that neurogenesis may be induced in normally nonneurogenic regions of the adult brain in response to injury and neuronal death. There are reports of both injury-induced activation of local precursor cells to generate new neurons and migration of precursor cells from neurogenic to nonneurogenic regions, upon injury to the latter. Regions of the brain exhibiting such induced neurogenesis include the cerebral cortex, striatum, and CA1 region of the hippocampus, with neurogenesis occurring in response to focal neuronal degeneration and ischemia [51–54]. Whether such induced neurogenesis is or can be made sufficient to facilitate functional recovery remains to be established, but it offers exciting translational and clinical possibilities [46].

The isolation of progenitor cells from, and presence of “inducible” neurogenesis within, normally nonneurogenic regions of the adult brain illustrates that the characteristically neurogenic regions differ from the remainder of the brain primarily in their permissiveness for neurogenesis, rather than simply representing the sole repositories of neuronal progenitor cells. Elucidating the aspects of the cellular microenvironment that are critical for permitting or promoting the generation of new neurons is a fundamental challenge in understanding the regulation of neurogenesis and how that regulation is affected under a variety of physiological conditions, including aging. This task is made particularly challenging by the recognition that the neurogenic microenvironment reflects a complex and dynamic molecular state, rather than a fixed cellular environment (discussed in [46]). Changes in the neurogenic environment represent one possible contributor to the profound decrease in neurogenesis that occurs with brain aging.

II. DECREASED NEUROGENESIS IN THE AGING BRAIN

A. Extent of Aging-Related Changes

Evidence that neurogenesis is sustained in the senescent brain, albeit at a lower level than in young adults, was provided among early studies of adult neurogenesis using thymidine labeling and electron microscopy [55]. Recent and more quantitative studies revealed the extent of the aging-related decline in neuronal production in each neurogenic region and provide a foundation for ongoing studies of the mechanisms of regulation of aging-related changes.

1. Hippocampus

Since the mid-1990s, several laboratories have demonstrated that the level of hippo-campal neurogenesis in aging and aged animals is only a fraction of that seen in young adults. Experiments using a variety of BrdU labeling paradigms, supplemented with immunolabeling for markers of immature neurons, have revealed the extent and time course of aging-related changes in rats and mice (e.g., [12, 13, 56–59]. The reduction in production of new neurons is profound, consistently on the order of 80% or more, and occurs relatively early in the aging process, with the greatest decline occurring by middle age and only a modest, if any, additional decline during later senescence [13, 58, 60]. Although detailed quantitative studies are limited to rodent models, limited data indicate that the effects of aging on hippocampal neurogenesis are similar in primates. The temporal pattern may differ, however, because one study of macaques revealed a large (approximately 70%) decrease in neurogenesis between young adulthood and middle age, as well as a substantial and additional decrease between middle and old age [14]. Comparisons across species must be made carefully, of course, given the limited sampling in most primate studies and the challenge of determining comparable life stages in species with very different lifespans.

2. SVZ/RMS

The aging SVZ has not been studied as extensively or quantitatively as the aging hippocampus but undergoes a similar decline in proliferation. In mice, the number of BrdU-labeled cells present in the SVZ a few hours after labeling is lower by about a factor of 2 in 20- to 25-month-old vs. 2- to 4-month-old mice [61, 62] and in 24-month-old vs. 3-month-old Fisher-344 rats [63]. As in the hippocampus, the greatest reduction in cell genesis within the SVZ occurs between young adulthood and middle age, with a more modest additional decline with further aging [64]. The aging-related reduction in the appearance of newborn neurons in the OB is somewhat greater than the decline in proliferation within the SVZ; at 1 month after labeling, only 30% as many BrdU-labeled cells are apparent in the OB of older animals [61]. Thus, it appears that the aging-related decrease in progenitor proliferation in the SVZ is compounded by an additional deficit in the division of neuroblasts as they migrate through the RMS, and/or by decreased survival of migrating neuroblasts in older animals. Detailed light and electron microscopic studies indicate that, with aging, neurogenesis in the SVZ becomes restricted to the dorsolateral aspect of the lateral ventricle and increased numbers of astrocytes become interposed among the ependymal cells [64]. Thus, in the case of the SVZ, both the size and cellular makeup of the neurogenic environment are reduced during aging. Notably, the aging-related decline in the neurogenic activity of the SVZ/RMS is not limited to rodents; both the size of the SVZ and the number of migrating neuroblasts are reduced in old macaques compared to young adults [65].

3. Olfactory Epithelium

Data on aging-related changes in the genesis of olfactory receptor neurons are limited and analysis of changes is complicated by the fact that the olfactory epithelium, by virtue of its exposed location within the nasal cavity, is uniquely vulnerable to damage from a variety of insults. There are substantial aging-related changes in the organization of the olfactory epithelium, including a decrease in the number of ORNs and patchy replacement of the sensory epithelium by respiratory epithelium (e.g., [66, 67]. It cannot be assumed, however, that loss of ORNs is the result of decreased genesis. A short report that noted decreased generation of ORNs in the olfactory epithelium of aged mice [68] was followed by a detailed study of Fisher-344 × Brown Norway rats from 7 to 32 months of age [69]. Significantly, in the latter study, the animals were maintained in a barrier facility to minimize the possible impact of rhinitis and other disease on the olfactory epithelium. Although the anterior olfactory epithelium exhibited evidence of degeneration and gross morphological changes, the posterior region was well preserved, and BrdU labeling demonstrated that progenitor cells were dividing and new ORNs were produced even in the oldest animals. The generation of new neurons in the olfactory epithelium still was significantly reduced in older individuals; the number of BrdU-labeled basal cells and immature (GAP43-positive) neurons was approximately 40% lower in 32-month-old rats compared to 7-month-old young adults. Other investigators demonstrated a similar decrease between young adulthood and middle age in Sprague Dawley rats [70]. In addition to such evidence for decreased proliferation of progenitor cells, expression of NeuroD, a basic helix-loop-helix transcription factor that is thought to function in neuronal differentiation, is reduced in the aged olfactory epithelium [71].

B. Mechanisms of Aging-Related Changes

Although the aging-related decline in neurogenesis is profound, the neurobiological changes that contribute to that change are not yet understood. To understand how and why neurogenesis changes in the aging brain, one must consider several processes that influence the rate of neuronal turnover and establish which processes change with aging. The control of adult neurogenesis involves multiple points of regulation, including the size of the progenitor cell population and the rate of division of progenitors cells, the survival of daughter cells, the commitment of daughter cells to a specific (neuronal or glial) lineage, and the rate of neuronal growth and differentiation. In principle, alterations in the regulation of any or all of these processes might contribute to aging-related changes in neuronal replacement. Recent studies have begun to reveal the specificity of aging effects, despite still limited data and occasionally conflicting results.

1. Number and Proliferation Rate of Progenitor Cells

Much of the aging-related decline in neurogenesis in both the DG and SVZ is the result of a dramatic decline in the division of progenitor cells. Quantitative analyses of cell division in the SGZ and SVZ of young adult and older animals, utilizing S-phase labeling with BrdU, have consistently demonstrated 50 to 90% declines in the number of BrdU-labeled cells present in the neurogenic regions immediately or shortly after BrdU injection (e.g., [12, 13, 57, 58, 60–62,72–74]). Stem cells divide so slowly that changes in their rate of division are unlikely to contribute detectably to in vivo measurements of proliferation in adults; thus, the reported changes likely reflect a decrease in the division of more restricted and more rapidly dividing progenitor populations. Although many studies used BrdU labeling protocols that included injections over several days and survival periods of up to a week, which may conflate changes in cell division with changes in survival, recent studies using discrete labeling periods and short survival times (1 hour or less) leave no doubt that there is less cell division in older animals. Consistent with the analysis of more general measures of neurogenesis, most of the aging-related decline in the division of progenitor cells occurs by middle age, with only modest additional declines during later senescence [64]. Both the temporal pattern and the magnitudes of decline are similar in mice and rats, the only species for which there are extensive quantitative data. When examined in the same individuals, the magnitude of the decline is greater in the SGZ than in the SVZ (90 and 50% declines, respectively, comparing 3-month-old and 20-month-old mice [62]).

In principle, the decrease in BrdU labeling could reflect a smaller population of progenitor cells, slower and/or less frequent division of a constant population of progenitors, and/or changes in cell cycle kinetics. At least two studies of the SVZ indicate that the cell cycle of progenitors in the SVZ lengthens in older animals [61, 64]. It should be noted, however, that the change in cell cycle length appears to occur between middle and old age, later than most of the decline in proliferation [64]. In addition to lengthening of the cell cycle, more progenitor cells leave the cell cycle in older animals [64], raising the possibility that the age-related change in cell division includes deviations from steady-state kinetics (which are assumed by most analytical methods). Testing empirically for changes in the length of the S-phase or other components of the cell cycle and for changes in check-point regulation is critical [75, 76], but these difficult and resource-intensive experiments have not been completed for aging animals.

Determining whether the size of the population of stem and progenitor cells declines with aging is as challenging as quantifying cell cycle changes, and recent attempts to answer the question have provided intriguing but somewhat conflicting results. Tropepe et al. [61] reported that progenitor cells isolated from young adult and aged mice formed comparable numbers of, and similarly sized, neurospheres in vitro, leading the authors to conclude that both the number and proliferative potential of progenitor cells is maintained during aging, and that the aging-related decline in proliferation in vivo is due solely to changes in the microenvironment in which progenitor cells proliferate. A more recent study, however, demonstrated a twofold reduction in the number of neurospheres recovered in culture from old relative to young adult mice [77]. Consistent with that study, Luo and colleagues [64] combined BrdU labeling, immunolabeling for Ki-67 (a nuclear protein expressed by dividing cells), and ultrastructural analysis to analyze the number of neuroblasts and TAP cells and reported that both decrease by middle age. Quantifying the population of slowly cycling stem cells is more difficult than analyzing the “later” progenitor cells, but there also is evidence for an aging-related decrease in the number of neural stem cells in the SVZ, based on labeling for the G1-phase cell cycle marker Mcm2 and labeling with nucleoside analogs [77, 78]. The magnitude of the reported declines in stem cells, neuroblasts, and TAP cells is similar to the decline in BrdU labeling (approximately 50%) and, like the decline in cell division, most of the decrease in progenitor cell number occurs by middle age. In considering these and similar studies, it is important to remember that there are no definitive, state-independent markers for neural progenitor cells, and that a “loss” of cells based on immunolabeling or morphological criteria could simply reflect loss of expression of specific phenotypic traits. The ability of progenitor cells in aged animals to respond to a variety of stimuli and return neurogenesis to levels at or near that seen in young adults [56–58, 62, 72, 79–82] demonstrates that even in the aged brain there is a population of neural progenitor cells that is adequate to maintain neurogenesis at a youthful level, given the proper conditions.

2. Cell Survival

Because, at all ages, many of the newborn cells in the adult DG and SVZ/RMS die before reaching full maturity, changes in cell survival could contribute to the aging-related decline in neurogenesis. In young adult rats, 50% of newborn (BrdU-labeled) cells in the DG die within 28 days after labeling; those that survive past the first month live for at least 5 additional months and replace granule cells that were born during development or earlier in adulthood [83]. It has proved difficult to assess directly the survival of newborn neurons in the neurogenic regions. Common markers of apoptosis (e.g., terminal transferase-mediated dUTP nick-end-labeling, TUNEL) generally do not reveal a large enough population of dying cells in the adult DG to account for the extent of cell birth and the fact that the total number of dentate granule cells remains stable throughout adulthood, suggesting either the window during which dying cells can be detected is too short to permit accurate assessment of their number or many cells are dying by a mechanism that is not recognized by current detection methods. Studies using BrdU labeling support the conclusion that aging does not diminish the survival of newborn cells, and that most of the decline in neurogenesis is accounted for by decreased proliferation (e.g., [13, 56, 58]). Using the ratio of the number of BrdU-labeled cells present at 4 weeks after labeling to the number present immediately after labeling as an index of survival, studies of aging mice [56] and rats [58] revealed no decrease in the survival of newborn cells in young adult, middle-aged, and old animals. Aging may, however, alter the balance of cell death among undifferentiated, differentiating, and mature cells in a manner that is not apparent with currently available methods.

3. Neuronal Commitment and Differentiation

Although the survival of newborn cells in neurogenic regions appears to be unaffected by age, the percentage of newborn cells that become neurons is much lower in middle-aged and old animals than in young adults (e.g., [12, 56, 58, 60, 84]). When examined approximately 4 weeks after BrdU labeling, the percentage of newborn cells in the DG that express neuronal markers is reduced by about 60% between young adulthood and middle-age in rats [58, 84], and by 40% or more in mice [56, 60]. Thus, in aged animals, the overall reduction in the proliferation of progenitor cells is compounded by a decrease in the fraction of cells that are produced that become neurons. The aging-related decrease in the development of newborn neurons may not reflect a decrease in initial commitment to a neuronal lineage, however, because a comparable percentage of newborn cells expresses the neuroblast marker doublecortin (Dcx) 24 hours after BrdU labeling [84]. The subsequent development of new neurons is compromised in older animals, however, because both the rate of migration into the granule cell layer and the rate of structural maturation are slowed in middle-aged and old rats, compared to young adults [84].

Just as one might describe the population of many countries as “graying,” with older individuals representing an increasing percentage of the population, there is a significant “graying” of the population of dentate granule neurons and OB interneurons during the transition from young adulthood into middle and old age. As the rate of addition of new neurons declines, the population of young, developing neurons, which are thought to play a unique role in hippocampal and olfactory function (Section IV.A), decreases relative to the population of older, less plastic neurons. Moreover, the differentiation of newborn neurons is slowed in older animals [84], presumably impacting their integration into neural circuits and their influence on the neural processes that depend on neuronal turnover. Given evidence that adult neurogenesis is important for some functions of the hippocampus and OB (Section IV.B), amelioration of the aging-related decline in neurogenesis represents an attractive target for reducing aging-related cognitive dysfunction. Any attempt to prevent or diminish the effects of aging on neurogenesis depends, however, on understanding the molecular mechanisms that control neurogenesis and mediate the aging-related changes.

III. REGULATORS OF NEUROGENESIS IN THE ADULT AND AGING BRAIN

The list of intrinsic factors (e.g., transcription factors and cell cycle regulators) and extracellular growth factors, hormones, and neurotransmitters that influence neurogenesis in the adult neurogenic zones is large, diverse, and ever-growing (see [85, 86] for reviews). Intrinsic cell cycle regulators have been studied primarily in the developing nervous system, only recently in adults [85], and not at all in the aging brain; they are not discussed here. Importantly, many recent studies indicate that the aging-related decline in neurogenesis develops primarily from changes in the neurogenic microenvironment and in the factors that control the division of stem and progenitor cells, not from loss of, or changes intrinsic to, those precursors. Among the most striking recent advances in the understanding of adult neurogenesis was the observation that proliferation does not occur randomly or homogeneously throughout the neurogenic regions, but rather that dividing progenitor cells are found in close association with the microvasculature, in a “vascular niche,” and that neurogenesis is associated with a process of active vasculogenesis and remodeling (e.g., [87–90]). This view provides hope that aging-related changes may be reversed by experimental modulation of the microenvironment if the critical cellular and molecular factors that define that environment can be identified. A complete discussion of the neurogenic niche and of all the extrinsic factors that might influence adult neurogenesis is beyond the scope of this chapter; the discussion here focuses on factors for which there is evidence of an important role in mediating aging-related changes in neurogenesis in the hippocampus and SVZ (see [44] for an excellent review of the regulation of neurogenesis in the OE).

A. Hormones and Growth Factors

1. Stress Hormones

Stress and corticosteroids were among the first studied regulators of adult neurogenesis [91, 92]. The idea that stress and glucocorticoids contribute to the aging-related decline in neurogenesis is particularly attractive, given widespread evidence that stress influences brain aging and cognitive function (e.g., [93–95]; see Chapter 13), and that aging is associated with elevated levels of corticosteroids [96]. Stress-induced depression of proliferation in the DG has been demonstrated in several species (shrews and marmosets, as well as rats and mice) and in response to a wide variety of stressors (reviewed in [97]) but there are, as yet, no studies of stress effects specifically in old animals. The effects of stress on neurogenesis overall are more complex than the effects on proliferation. Some studies indicate that stress-induced depression of proliferation is accompanied by a decrease in neuronal production, as one would predict [98, 99]. Others, however, have shown that the stress-induced reduction in proliferation is followed, after a short period, by an increase in cell survival, such that the overall addition of new neurons remains largely unchanged [100, 101]. Whatever the complexity of stress-induced changes, clearly they are mediated, at least in part, by glucocorticoids. Depletion of glucocorticoids by adrenalectomy increases the number of BrdU-labeled cells in the DG in both young adult and old rats (e.g., [57]), and increasing glucocorticoid activity decreases proliferation [92, 102]. The relationship between glucocorticoid levels and neurogenesis is not simple, however, because physical activity, living in an enriched environment, and training on learning paradigms all increase glucocorticoids but also increase neurogenesis (see [97]). Moreover, despite the profound effects of glucocorticoids on neurogenesis in the DG, proliferation in the SVZ remains unchanged following adrenalectomy [103]. Progress in investigating the expression of glucocorticoid and mineralocorticoid receptors on neural precursor cell populations [104] is beginning to clarify the cellular targets of stress hormones within neurogenic regions and offers promise that the specific role of those factors in aging-related changes in neurogenesis soon will be clearer.

2. Growth Hormone/Insulin-Like Growth Factor-1 Axis

Interest in the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis as a mediator of aging-related changes in the brain and other organ systems developed from the recognition that a substantial decline in serum GH and IGF-1 levels is one of the most robust hallmarks of mammalian aging (reviewed in [105–107]. Given the pleiotropic effects of IGF-1 in the brain and increasing evidence that GH has direct effects in the brain, as well as regulating IGF-1 levels, it is reasonable to expect that the aging-related decline in GH/IGF-1 activity is significant for brain structure and function. There is experimental evidence that restoring GH and/or IGF-1 in older animals ameliorates many aging-related neural changes (105, 107). With respect to neurogenesis, several lines of evidence implicate the GH/IGF-1 axis in aging-related changes. The regulation of adult neurogenesis appears to be linked to the regulation of angiogenesis (e.g., [87, 90, 108]), which is modulated in the aging brain by the GH/IGF-1 axis [109]. In addition, several laboratories have demonstrated that modulating IGF-1 levels in adult rodents alters hippocampal neurogenesis (see [107, 110] for reviews). Neurogenesis is decreased by hypophysectomy (Hx), which decreases levels of GH (and other pituitary hormones) and IGF-1, and neurogenesis in Hx animals is restored by peripheral infusion of IGF-1 [111]. IGF-1 also mediates the ability of physical exercise to increase neurogenesis [112]. Finally, direct intracerebral ventricular (icv) infusion of IGF-1 into aged rats ameliorates the aging-related decline in neurogenesis [58].

Although the evidence that the GH/IGF-1 axis plays some role in the regulation of adult neurogenesis and contributes to aging-related changes is intriguing, the mechanisms of such regulation remain poorly understood, particularly with respect to which endogenous source or sources of IGF-1 are most important for regulating adult neurogenesis and which aspects of neurogenesis are regulated by the GH/IGF-1 axis. IGF-1 is available to cells in the CNS from at least three sources: from the plasma across the blood-brain barrier [113, 114], following production by cells of the cerebral vasculature [115, 116], and from local production by neurons and glia within the brain parenchyma [115–117]. Teasing apart the endocrine, paracrine, and autocrine effects of IGF-1 on neurogenesis remains a significant challenge, but some insight was provided by the initially paradoxical observation that hippocampal neurogenesis increases in Ames dwarf mice, a model of GH/IGF-1 deficiency. Although Ames mice have profound deficits in circulating GH and IGF-1, analysis revealed greatly increased IGF-1 levels in the hippocampus, presumably accounting for the increase in neurogenesis [118]. Thus, at least for the regulation of adult neurogenesis, local production of IGF-1 may be more important than endocrine levels. Quantitative data on levels and production of IGF-1 within the brain parenchyma are limited, but IGF-1 levels within the rat hippocampus decline significantly by middle age and then only slightly, if at all, during later senescence [119], a temporal pattern that correlates with the aging-related change in neurogenesis.

Even as the regional regulation of IGF-1 production and activity becomes clearer, it is not yet established that IGF-1 modulates the same aspects of neurogenesis that are most affected by aging, and one must consider the possibility that changes in neurogenesis in response to experimental modulation of IGF-1 levels reflect a pharmacological effect rather than normal physiological regulation. As discussed, the aging-related changes in neurogenesis include both decreased proliferation and changes in commitment and/or differentiation, whereas effects on survival are less clear. The reported increase in the number of BrdU-labeled cells in the SGZ following restoration of IGF-1 by icv infusion in aged rats appears to involve increased proliferation [58], but because BrdU was injected over several days in that study, one cannot exclude the possibility that IGF-1 affected survival. Significantly, icv infusion of IGF-1 has no effect on the percentage of newborn cells that committed to neuronal differentiation; thus, it is unlikely that decreased GH/IGF-1 activity accounts for the aging-related decline in neuronal commitment in the DG. A recent study of neurogenesis in a model of adult-onset GH/IGF-1 deficiency indicates that IGF-1 modulates the survival of newborn neurons [120] but, as noted above, the effects of aging on survival remain unclear. Taken together, the available data suggest that the aging-related decline in the activity of the GH/IGF-1 axis contributes to, but cannot fully account for, aging-related changes in neurogenesis. Additional factors clearly are involved.

3. Fibroblast Growth Factor

Fibroblast growth factor 2 (FGF-2), also known as basic fibroblast growth factor (bFGF), declines in the aging hippocampus and, like the declines in IGF-1 and in neurogenesis, the decrease in FGF-2 occurs by middle age [119]. The aging-related decline in FGF-2 appears to be due, at least in part, to decreased local production, because both the number of FGF-positive cells and the intensity of immunolabeling is reduced in middle-aged and old mice compared to young adults [119]. There is more than correlative evidence that FGF-2 contributes to the aging-related decline in neurogenesis; infusion (icv) of FGF-2 into old mice partially ameliorates the aging-related decline in BrdU labeling [62]. In the SGZ, the number of BrdU-labeled cells in FGF-2 infused old mice is 20% of that seen in normal, young adults, compared to the 10% seen in control aged mice. The effects of FGF-2 infusion are greater in the SVZ, where the number of BrdU-labeled cells in FGF-treated aged animals approaches the level seen in normal, young adults. The effects of FGF-2 treatment of aged animals, like the effects of IGF-1, not only suggest the factors may mediate (in part) the aging-related decline in neurogenesis, but they also demonstrate that the aged brain retains the capacity to respond to growth factors with increased neurogenesis, an important consideration as one contemplates the therapeutic potential of modulating neurogenesis to ameliorate aging-related cognitive deficits or neurodegeneration.

4. Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) shows the same pattern of aging-related decline in the hippocampus as IGF-1 and FGF-2; levels of VEGF in middle-aged and aged animals are only about half that in young adults [119]. VEGF is of particular interest with respect to aging-dependent regulation of neurogenesis because adult neurogenesis and angiogenesis may be linked (e.g., [87–90]), but there are multiple mechanisms by which VEGF might influence neurogenesis, some of which need not involve the vasculature. Reports that VEGF receptors are expressed by neurons, as well as by vascular endothelial cells (discussed in [121, 122], and that neurogenesis is increased in response to doses of VEGF that are too low to induce endothelial proliferation, indicate that VEGF may influence neurogenesis independently of its ability to promote angiogenesis [123]. Although the ability of VEGF to restore neurogenesis in aged animals has not been tested directly, there is evidence that modulating VEGF activity in young adults alters neurogenesis in both the DG and SVZ/RMS. VEGF knockout mice show reduced neurogenesis in both neurogenic regions and icv infusion of VEGF increases neurogenesis [124]. Significantly, there is accumulating evidence that VEGF mediates some of the effects of stress [125], of exercise [126, 127], and of complex environments and learning on adult neurogenesis [128, 129].

5. Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is expressed at high levels in the adult hippocampus, including the DG [130], and a variety of evidence implicates BDNF as an important mediator of aging-related neural changes in the brain (reviewed in [131]). The effects of aging on hippocampal BDNF levels remain controversial, with some laboratories reporting an aging-related decrease (e.g., [132, 133]) but others finding little or no change [134, 135]. The specific role of BDNF in modulating neurogenesis in the normal adult and aging brain also remains unclear. Consistent with the hypothesis that BDNF is a proneurogenic factor is evidence that neurogenesis decreases in BDNF knockout mice [136] and that increasing BDNF levels in the SVZ by adenovirus [137] or icv infusion [138, 139] increases the number of neuroblasts and new neurons in the SVZ and OB. Direct unilateral intrahippocampal infusion of BDNF increases neurogenesis in the DG, but the effect must be indirect and not by direct stimulation of progenitor cells because increased neurogenesis is evident bilaterally while exogenous BDNF appears to remain restricted to the infused hemisphere [140]. The effects of BDNF on proliferation and neurogenesis also are influenced by other factors. In apparent contrast to the evidence that BDNF promotes neurogenesis in the normal adult brain, infusion of the factor following an ischemic event reduces the increase in neurogenesis that usually follows ischemia [141]. Moreover, reducing endogenous BDNF following ischemia promotes, rather than decreases, neurogenesis [142]. Additional evidence for complex, differential regulation of BDNF and its effects comes from reports that one form of dietary restriction, every-other-day feeding, increases adult neurogenesis by increasing BDNF [143, 144], whereas another form of dietary restriction, 40% calorie reduction, does not affect BDNF levels and does not increase neurogenesis [60, 135].

6. Epidermal Growth Factor Family

Members of the epidermal growth factor (EGF) family of growth factors and receptors have been implicated in the regulation of both embryonic and adult neurogenesis (e.g., [61, 145–148]). Adult TGF-α knockout mice show decreased proliferation in the SVZ and fewer new neurons migrating to the OB [61]. Aged mice show reduced EGF receptor signaling in the SVZ and decreased neuronal replacement in the OB, along with deficits in olfactory discrimination [149]. Infusion of EGF increases proliferation in the SVZ, but also reduces neuronal replacement in the OB [145, 146]. Thus, EGF not only promotes proliferation of precursors but also directs differentiating cells away from differentiation as neurons. The capacity to respond to EGF with increased proliferation in the SVZ is retained in old animals [150], in which increased proliferation is associated with improved performance in a passive avoidance learning task [151]. EGF does not promote proliferation in the adult hippocampus as it does in the SVZ [146], but another family member, heparin-binding EGF (HB-EGF), increases both BrdU labeling and the number of doublecortin-positive cells in the SVZ and the SGZ [62]. As with all the growth factors discussed above, the roles of EGF family members in regulating neurogenesis in the adult and aging brain are only beginning to be elucidated.

7. Transforming Growth Factor-β Family

Members of the Transforming Growth Factor-β family of growth factors, particularly TGF-β and bone morphogenetic proteins (BMPs), are powerful regulators of neural stem cells and of neurogenesis in both developing and adult brains. Much like BDNF, the effects of TGF-β on neurogenesis appear to be context dependent. Intracerebroventricular infusion of TGF-β reduces proliferation of progenitor cells in both the DG and SVZ of adult mice [152], and chronic overexpression of TGF-β in aged transgenic mice virtually eliminates neurogenesis [153], but TGF-β mediates proneurogenic effects of microglia following adrenalectomy (see below). The question of whether changes in TGF-β signaling contribute to changes in neurogenesis in normally aging mice has not yet been addressed. Whether changes in BMP signaling contribute to aging-related changes in neurogenesis similarly is unknown, but BMPs influence adult neural stem cells in much the same way that they influence stem cells in the developing brain. In the adult SVZ, in the absence of other factors, BMPs direct stem cells toward a glial fate, but that gliogenic signal is blocked by the BMP inhibitor noggin, which is expressed by ependymal cells [154, 155]. Thus, a change in the balance of BMP signaling and inhibitors could contribute to the aging-related decrease in the percentage of newborn cells that differentiate as neurons (Section II.B.3).

8. Retinoic Acid

Retinoic acid (RA), a member of the steroid/thyroid hormone super family, is an essential growth factor and regulates many aspects of embryonic neural development. Recent evidence indicates that RA continues to influence plasticity and regeneration in the adult brain and may influence neurogenesis in the olfactory epithelium, SVZ, and hippocampus, with possible effects on both proliferation of progenitor cells and differentiation of newborn neurons [156, 157]. Changes in RA signaling may be particularly important in the aging olfactory system, with effects in both the OE and the SVZ [45]. RA critically regulates the initial development of the peripheral olfactory system and continues to influence olfactory progenitor cells in the adult [158–160]. In addition to activating basal stem cells in the OE, RA influences a small population of cells in the SVZ that appear to be stem cells (i.e., they are slowly dividing, express GFAP, and form neurospheres when isolated in culture). A variety of studies in humans and animal models suggest that RA promotes recovery of olfactory function in aged individuals and following injury to the peripheral olfactory system [45]. Moreover, RA improves performance on an odor-mediated learning task when administered to senescent mice [161]. Perhaps most intriguingly, because dietary vitamin A is the primary source of retinoids, RA could play the central role in a feed-forward cycle in which a modest aging-related decline in olfactory function contributes to reduced appetite, which leads to reduced food intake and sub-optimal vitamin A levels, resulting in decreased RA signaling and thereby to further deficits in olfactory neurogenesis (discussed in [45]). Further investigation may establish RA as an important therapeutic target for ameliorating the age-related decline in olfactory function.

B. Neurotransmitters

Several neurotransmitters have been implicated in the regulation of adult neurogenesis, consistent with the growing awareness that neurotransmitters can act as trophic factors as well as synaptic messengers and with evidence that activity within the adult hippocampus and olfactory system influences the production and integration of new neurons. In the OB, centrifugal projections of cholinergic, serotonergic, and catecholaminergic inputs each can influence the differentiation and survival of new neurons [155]. Cholinergic neurons in the basal forebrain project to both the DG and the OB, and the number of newborn granule neurons decreases in both regions following lesion of that cholinergic projection [162, 163]. GABA plays a key role in the integration of newborn neurons in the adult brain [164], and additional influences of serotonin may link changes in neurogenesis to the development of depression [165, 166]. Few studies have investigated neurotransmitter-dependent regulation of neurogenesis in aged animals, but loss of dopaminergic projections from the substantia nigra to the SVZ further decreases the number of proliferating progenitors and developing neurons in the SVZ of aged primates [65], and treatment with antagonists to the NMDA type glutamate receptor increases neurogenesis in aged rats [59], the latter suggesting that the decline in neurogenesis may be one of several deficits influenced by aging-related changes in glutamate signaling (see Chapter 8).

C. Inflammatory Mediators

Evidence from many laboratories and studies suggests that aging-related increases in inflammatory processes contribute to the development of neural deficits (e.g., [167–170]). This hypothesis is based on evidence that (1) basal levels of many pro-inflammatory cytokines increase in older brains and (2) those cytokines affect the function, and even the survival, of neurons, glia, and progenitor cells. Although not yet established, it is reasonable to suspect that aging-related activation of microglia suppresses neurogenesis (and thereby cognitive function), because neurogenesis is profoundly affected by changes in the neurogenic microenvironment that are mediated by reactive microglia and inflammatory cytokines. Inducing an inflammatory response by infusion of the bacterial toxin lipopolysaccharide (LPS) virtually eliminates neurogenesis in the adult brain, with the extent of reduction in individuals well correlated with the number of activated microglia [171]. Neurogenesis is restored in LPS-infused animals by treatment with minocycline, a tetracycline derivative that inhibits the activation of microglia. Studies using brain irradiation to induce microglia activation and a sustained inflammatory response demonstrate that inflammatory-induced changes in neurogenesis arise as a result changes in the neurogenic environment, rather than intrinsic changes in progenitor cells. Hippocampal progenitor cells can be cultured from irradiated brains, divide normally, and produce a normal array of cell types in culture, but hippocampal progenitor cells from non-irradiated brains do not divide and produce neurons when transplanted into an irradiated brain, as they do when transplanted into a nonirradiated brain [108]. Significantly, these deleterious changes in the progenitor cell niche arise, at least in part, from the radiation-induced inflammatory response, because treatment with non-steroidal anti-inflammatory drugs (NSAIDs) ameliorates the deleterious effects of whole-brain irradiation on hippocampal neurogenesis [172].

Thus, to the extent that microglial activation and a chronic inflammatory response accompany brain aging (e.g., [168, 173, 174]), one would expect they contribute to the aging-related decline in neurogenesis, and possibly to cognitive deficits. It must be recognized, however, that the “activation” of microglial cells and their relationship to other cell types is significantly more complex than previously appreciated (e.g., [175]), and that activated microglia are not always antineurogenic. Following adrenalectomy, microglia increase neurogenesis via TGF-β [176] and microglia activated by anti-inflammatory cytokines associated with T-helper cells also increase neurogenesis [177, 178], in contrast to endotoxin-activated microglia, which inhibit neurogenesis [179]. The balance of pro- and anti-inflammatory factors produced by microglial cells under specific conditions determines their effect on the neurogenic microenvironment, and clarification of the role of inflammation in aging-related changes in neurogenesis awaits a clearer understanding of aging and aged microglia (see [180] for a recent discussion of aging-related changes in microglia).

IV. FUNCTIONAL SIGNIFICANCE OF ADULT NEUROGENESIS

Since the initial demonstrations that neurogenesis continues in the adult brain, it has been a major challenge to understand the functional significance of the ongoing production of new neurons in the mammalian brain (function is better understood in avian species [6, 181, 182]). It has been demonstrated repeatedly in rodents that adult-born neurons become functional; that is, they develop synaptic and electrophysiological properties characteristic of mature neurons and are integrated into synaptic networks. The current challenge is establishing the importance of neurogenesis at the systems and cognitive levels. There is compelling evidence that newborn neurons have distinct electrophysiological properties that endow them with greater plasticity, which may permit them to play a unique role in hippocampal and olfactory circuits (discussed in [183] and below). Some investigators suggest that ongoing neuronal replacement provides more long-term and adaptive, rather than acute, benefits [182, 184, 185], perhaps permitting the hippocampus and OB to be optimized for particular environments [186]. Such long-term function might explain, in part, the difficulties in linking differences in neurogenesis to differences in cognitive ability. Further complicating the issue, it cannot be assumed that new neurons in the hippocampus have the same or even similar functional roles as new neurons in the OB. Even a cursory summary of the investigations addressing this issue is beyond the scope of this chapter, but many excellent reviews and discussions are available (e.g., [7, 182–193]). It is important here, however, to consider the experimental approaches that have been taken and to consider the limited number of studies that have examined the issue in aging animals.

A. Cell Physiology of Newborn Neurons

Many laboratories are studying adult-born neurons at the cellular level, using electrophysiological methods to compare the membrane and synaptic properties of newborn neurons to those of older neurons and to assess the integration of the new neurons into neural circuits. Such studies are critical to understanding what capacities are added by the constant addition of new neurons. Although the questions of whether and when adult-born neurons send projections into target regions was answered soon after the rediscovery of adult neurogenesis (e.g., [30, 194, 195]), investigations of the electrophysiological development of adult-born neurons and their functional integration required the development of methods for identifying newborn neurons in living tissue. In recent years, adult-born neurons have been labeled with fluorescent proteins controlled by viral vectors or developmentally regulated promoters, so that one can identify and record from the neurons in living preparations (e.g., [32, 33, 196–198]. Such studies have provided detailed descriptions of the development of cell physiological and synaptic properties of dentate granule neurons and granule and periglomerular neurons in the OB, both in normal adults and under a variety of clinically relevant experimental conditions (reviewed in [186]). Evidence that long-term potentiation (LTP) can be induced more readily in newborn dentate granule neurons than in older granule neurons [199, 200] suggests that unique mechanisms for synaptic plasticity may underlie the contributions of newborn neurons to hippocampal and olfactory function. To date, electrophysiological studies of newborn neurons have not been done in aged animals, as most experiments are done using brain slices, which are more difficult to prepare from old animals, and it is unknown whether the functional maturation of new neurons is altered in older individuals. Evidence that the dendritic maturation of newborn dentate granule neurons is slowed in older animals [84] suggests, however, that the development of mature functional properties by newborn neurons also may be altered in senescent animals.

B. Adult Neurogenesis and Cognitive Function

Systems-level studies of the significance of adult neurogenesis have taken three general approaches: (1) experimentally decreasing or stopping neurogenesis and testing for changes in performance in some cognitive task, (2) testing whether training in a cognitive task alters neurogenesis, and (3) testing whether individual performance in a cognitive task correlates with individual differences in ongoing neurogenesis. Numerous such studies have addressed the role of neurogenesis in hippocampal-dependent learning (see [193] for a recent review); investigations of the contributions of neurogenesis to olfactory function are more limited but indicate a strong relationship between the number of newborn neurons and olfactory performance (see, e.g., [198, 201–203]). Several broad conclusions can be drawn from the available literature. First, some, but not all, functions of the hippocampus and OB depend on ongoing neurogenesis. Second, some cognitive functions appear to be linked to newborn cell proliferation, whereas others are linked to survival. Third, demonstrated associations between neurogenesis and performance in a given cognitive task are complex and dependent upon specific stages and aspects of learning and specific stages of maturity of newborn cells (e.g., [204]). Finally, it is difficult to demonstrate direct and causal links between neurogenesis and neural function since manipulations that alter neurogenesis (brain irradiation and treatment with antimitotic agents commonly are used) generally have broader and non-specific effects; moreover, training in cognitive tasks may produce neural changes that influence neurogenesis secondarily (e.g., changes in the vasculature or in the production of growth factors).

C. Neurogenesis and Cognitive Function in Aged Animals

Attempts to link aging-related changes in neurogenesis to aging-related changes in neural and cognitive function are largely limited to correlative analyses. Enwere and colleagues [149] demonstrated that aged (24 months old) mice are less capable than young adult (2 months old) mice in making fine olfactory discriminations, but are not impaired in discriminating more discrete odors. Because the same deficit in fine, but not gross, discrimination was evident in transgenic mice with deficits in olfactory neurogenesis that are similar to those seen in aging, the authors suggested that the impairment in fine olfactory discrimination that is seen with age results from the reduction in neurogenesis. Direct evidence of such a mechanistic link is not, as yet, available.

There have been several attempts to link changes in neurogenesis and aging-related deficits in hippocampal-dependent functions. A recent study of Fisher-344 × Brown Norway hybrid rats from the aging colony maintained by the National Institute on Aging demonstrated by correlation analysis that two measures of neurogenesis, immunolabeling for proliferating cells and for developing neurons in the DG, were among a subset of structural and histological changes that predict performance on hippocampal-dependent tasks [205]. In addition to such correlational evidence from normal animals, the reductions in aging-related cognitive deficits seen in long-lived Ames dwarf mice [118] and in rats treated with the neurosteroid pregnalone sulfate [206] or maintained on antioxidant-rich diets [79] all are associated with increased neurogenesis in the DG. Other investigations have taken advantage of the recognition that aging-related cognitive deficits are not homogenously represented among populations of aged rats; some individuals exhibit large impairments while others perform at levels comparable to young adults [207]. Critically, such individual variability in cognitive performance is consistent across cognitive domains [208]. Thus, to look for neurobiological changes that may underlie cognitive impairments, one can test for differences in specific anatomical, biochemical or electrophysiological endpoints comparing impaired and unimpaired senescent animals (e.g., [209, 210]. Using this approach, Drapeau and colleagues [211] reported that 20-month-old rats that exhibited better spatial memory performance in the Morris Water Maze (MWM) had higher levels of neurogenesis in the DG, as demonstrated by BrdU labeling and immunolabeling with a marker of dividing cells (anti-Ki-67) 3 weeks after the end of behavioral testing. No such correlation between performance and proliferation was evident in 3-month-old animals. The authors also reported that the commitment of newborn cells to a neuronal lineage (i.e., the percentage of BrdU-labeled cells co-labeled with a neuronal marker) was higher in better performing than poorer performing old rats, and that behavioral performance positively correlated with the survival of newborn neurons. Given the BrdU labeling protocol used in the study, however, it is not clear that the difference in “survival” did not simply reflect the difference in proliferation. A link between aging-related declines in hippocampal function and neuronal turnover also was suggested by a report that decreased survival of newborn cells in the DG of 28-month-old rats is associated with a deficit in contextual fear conditioning ([212], but see also [190] for evidence that trace fear conditioning, but not contextual fear conditioning, is compromised by reduction of neurogenesis in young rats).

Although the idea that decreased cognitive performance in aged rodents is strongly correlated with decreased cognitive performance is intuitively appealing, several studies found no such connection. Merrill and colleagues [213] tested young adult and aged Fisher-344 rats in the MWM and then assessed neurogenesis by BrdU labeling for several days after the completion of behavioral testing. Although the number of BrdU-labeled cells in the SGZ of the DG was reduced in old rats compared to young adults, there was no difference in this measure of proliferation between aged rats that were impaired in the MWM and those that performed at a level comparable to young animals. A similar study of Long-Evans rats, in which proliferation was measured by BrdU labeling 1 week after completion of behavioral testing, also found no correlation between cognitive performance and neurogenesis [214]. Surprisingly, in a subsequent study, the latter investigators examined the survival of newborn neurons approximately 1 month after BrdU labeling (and the completion of testing in the MWM) and found that survival was greater in the aged rats with impaired cognitive function than in aged animals that were not impaired [215]; that is, hippocampal function was worse in those rats in which neurogenesis was greater. At this point, one must conclude that elucidating the functional links between aging-related changes in neurogenesis and aging-related cognitive deficits will require reconsideration of intuitive biases, assessment of a broader array of cognitive tasks, better measures of neurogenesis that differentiate among mechanisms of regulation, and new approaches that move beyond the limitations of correlational studies.

V. CONCLUSIONS

Given that neurogenesis is regionally restricted in the adult brain, the direct contribution of changes in neurogenesis to the development of aging-related cognitive decline is likely limited, perhaps accounting for the difficulty thus far in linking the decline in neurogenesis to specific neural deficits. As investigations of the contributions of adult neurogenesis to neural function continue, however, it is reasonable to expect they will demonstrate that the aging-related loss of the plasticity afforded by the continued addition of new neurons contributes to functional decline in senescence. Moreover, the interest of experimental gerontologists in the regulation of neurogenesis in the adult and aging brain extends beyond direct roles in hippocampal and olfactory function. It is reasonable to expect that the changes in neuronal microenvironment that lead to the decline in neurogenesis in older individuals may contribute to functional changes in established neurons and glial cells as well. In addition, the ability to isolate and expand neural stem cells from healthy brains, along with a rapidly growing capacity to regulate those cells and their progeny, keeps alive a vision of using transplanted stem cells to treat neurodegenerative diseases [216–221]. Even more appealing is that every advance in understanding the regulation of neurogenesis in vivo is a step toward therapeutic manipulation of endogenous progenitors to replace lost neurons or compensate for lost function [222], whether that occurring with normal aging or as a result of neurodegenerative disease. Although neuronal turnover is reduced in every neurogenic region of the aged brain, neuronal precursor cells clearly survive, remain responsive to growth factors and other physiological stimuli (e.g., [56, 58, 72, 81, 223]), and can increase their activity in response to damage (e.g., [63, 80]). Continued exploration of the regulation of neural progenitor cells in the adult and aging brain is critical not only for understanding normal, aging-related cognitive deficits, but also for progress toward the goal of using the brain’s regenerative potential to restore function lost to injury or neurodegenerative disease.

ACKNOWLEDGMENTS

Preparation of this chapter was supported in part by the National Institute on Aging, Grant No. AG11370.

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Copyright © 2007, Taylor & Francis Group, LLC.
Bookshelf ID: NBK3874PMID: 21204350

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