08-P004 PAR-tial to a few neurons? PAR-1 and neurogenesis

Evidence for the generation of young neurons out of precursor cells in the adult brain, i.e. adult neurogenesis, exists for at least two brain regions. New nerve cells are generated in the subventricular zone of the olfactory bulb and in the subgranular zone of hippocampal dentate gyrus. Young neurons of the subgranular zone migrate along the rostral migratory stream to the olfactory bulb, where they functionally integrate and contribute to the discrimination of odors. In the hippocampus the function of newly formed granule cells is still a matter of debate, yet it is thought that adult neurogenesis functionally contributes to hippocampal functions. Over the last twenty years of extensive research it became clear that adult hippocampal neurogenesis (AHN) in laboratory rodents can be up-and down regulated by different internal and external stimuli. Physical exercise in a running wheel being among the factors that have been most investigated. Since voluntary exercise not only increases adult neurogenesis in the hippocampus but also beneficially affects learning and memory in laboratory mice and rats, a widespread assumption holds a direct relationship between AHN and cognitive brain health also in higher order species, including humans. However, translating findings in laboratory rodents to the human condition faces difficulties. Enormous differences in basal rates of adult neurogenesis have been reported between mammalian species. The low level of AHN in primates and the complete lack of adult neurogenesis in bat species indicate species-specific differences in adult neurogenesis not only on a regulatory but also on a functional level. For a better understanding of species-specific differences in the regulation of AHN, we investigated basal rates of adult neurogenesis in laboratory mice and closely related wild mouse strains as well as the reaction of AHN to motivationally different running conditions. Testing different wild- and laboratory mice in the same environment allowed the identification of species-specific differences as well as possible domestication effects. Basal rates of adult hippocampal neurogenesis in equally-aged and genetically identical laboratory C57BL/6 mice show individual differences possibly reflecting epigenetic factors. However, the initial level of adult neurogenesis does not influence the response to wheel-exercise. Voluntary physical exercise in laboratory mice always increases AHN but this positive effect cannot be additively stimulated by enhanced running and is even lost as soon as the mice are forced to run. Rewarding the mice for their performance leads to an increase in wheel activity but does not translate into a corresponding additive increase in adult neurogenesis. Likewise, a more naturalistic situation, in which laboratory mice must run to obtain their daily food does not lead to an increase in cell proliferation and entails only a small increase in the number of young neurons, far below the one in voluntary running mice. Wild wood mice (Apodemus sylvaticus) and wild-derived western house mice (Mus musculus domesticus), both close relatives of the common laboratory mouse strains, were tested in the same running situations as laboratory C57BL/6 mice. Besides species-differences in basal neurogenesis rate, we find adult neurogenesis in wild mice remaining relatively constant in response to external influences. None of the factors that normally affect AHN in laboratory animals, such as stress, environmental changes or physical exercise, have an effect on adult neurogenesis in these animals. In wood mice, neither voluntary wheel running nor stress or an impoverished cage environment affect the number of newly generated neurons. House mice also show a stable adult neurogenesis, which shows no significant change after voluntary running or running for food. Adult neurogenesis in the dentate gyrus is thus regulated differently in laboratory and wild mice. However, even in laboratory mice it is not as plastic as initially suggested: laboratory mice, which are tested in a more naturalistic and complex running situation, show rather weak plasticity of AHN, resembling wild mice. Hence, it seems that the regulatory difference in adult neurogenesis between laboratory- and wild mice is, that laboratory animals react to a single stimulus in absence of other inputs. We believe that the constant exposure to different stimuli potentially affecting AHN has led to a natural selection that stabilizes adult neurogenesis in the wild. In contrast, during domestication - including inbreeding - much of the homeostatic capacity in regulating adult neurogenesis might have been lost. Taken together, our data imply that genetic (species-specific differences as well as within-species variation) play an important role in determining basal rates of adult neurogenesis, while motivational-contextual factors modulate the response of AHN to physical exercise, albeit chiefly in domesticated laboratory strains . As such differences appear already between phylogenetically closely related species, extrapolating findings in laboratory mice to distantly related taxonomic groups, such as humans, obviously requires much caution.

As the proportion of senior citizens gradually increases, the behavioral changes that occur with normal aging and as a consequence of Alzheimer’s disease (AD) will afflict many of us in the future. Aging is the major risk factor for AD, and pathological changes that occur in AD are superimposed upon normal aging alterations. Thus, to understand etiologies and mechanisms of AD it is important to distinguish normal aging from disease processes. In search of structural parameters, which could correlate with the behavioral changes during normal aging and AD, the discovery of neural progenitor cells and neurogenesis in the adult mammalian brain has received much attention. Furthermore, advances in stem cell techniques have raised the possibility for neuronal replacement strategies in neurodegenerative diseases such as AD. With progresses in mouse genetics and the identification of genes linked to AD it has become possible to generate transgenic mouse models that mimic key aspects of AD pathology. Studies involving such mouse models have identified beta-amyloid peptide (Aβ), the main component of amyloid plaques, as an important factor in the pathophysiology of AD. However, no general consensus exists about the mechanism by which Aβ exerts its detrimental effects. The research described herein addresses key questions regarding (i) neurogenesis and its modulation in the aging mouse brain, (ii) the impact of cerebral amyloidosis on neurodegeneration and neurogenesis in a transgenic mouse model of AD, and (iii) the application of a promising anti-Aβ immunotherapy in this transgenic mouse model. In a first study, we have examined the effect of aging on neurogenesis in the dentate gyrus of C57BL/6 (B6) mice. We used the B6 line because it is one of the best characterized mouse strains in neuroscience, and because it was shown to be relatively resistant to age-related structural brain changes. Our results revealed a striking decrease in neurogenesis due to an age-related reduction in neuronal proliferation. Interestingly, this decrease was observed until late adulthood with no further decline with aging. Stimulated by recent findings that caloric restriction (CR) might increase neurogenesis in young rodents, the potential of CR to postpone the age-related decrease in neurogenesis was tested. However, results revealed no impact of CR on hippocampal neurogenesis. Instead, a survival-promoting effect of CR on newborn glial cells in the hilar region was observed. In a second study, the impact of cerebral amyloidosis on neurodegeneration was studied using a recently generated murine model of AD, the APP23 mouse. This transgenic line overexpresses a mutated human form of the amyloid precursor protein (APP), develops amyloid plaques, and shows cognitive impairments with aging. Stereological estimation revealed a modest but significant age-related neuron loss in the neocortex of APP23 mice. This observation is consistent with the appearance of plaque-associated apoptotic and necrotic neurons in aged APP23 mice. Encouraged by recent reports that demonstrated neocortical neurogenesis after targeted apoptosis, we examined neurogenesis in the neocortex of APP23 mice with a high amyloid burden. However, no evidence for neocortical neurogenesis, both in young and aged APP23 mice, was found. In contrast, we found a fivefold increase in gliogenesis in aged transgenic mice when compared to littermate controls. During the last few years several therapeutic strategies have been proposed for treating AD, and some of them have entered clinical trials. For example, it has been suggested that vaccination with Aβ reduces cerebral amyloidosis and protects against cognitive deficits in different mouse models of AD. Thus, in a third study, we investigated the effect of passive immunization in the APP23 mouse, a model that exhibits amyloid plaques as well as cerebral amyloid angiopathy (CAA), similar to that observed in the human AD brain. Our results showed significant clearance of diffuse amyloid and reductions in the levels of the highly fibrillogenic Aβ42. However, immunized mice exhibited a robust increase in the frequency and severity of CAA-associated cerebral hemorrhages compared to non-vaccinated APP23 controls. Together with the neuroinflammatory side effects recently observed in human trials, our results further stress the need for a better understanding of the basic mechanisms involved in antibody-mediated Aβ clearance.

The Role of SGZ Neurogenesis in Hippocampal Dependent Learning and Memory Brittany Potz Advances in technology have allowed for the discovery of adult neurogenesis inthe human brain. Adult neurogenesis is found only in the subventricular zone (SVZ) and subgranular zone (SGZ) in the dentate gyrus region of the hippocampal formation. There are two types of progenitors found in the SGZ and their growth is thought to be influenced by their immediate environment called the neurogenic niche. Research suggests that new neurons generated in the brain are integrated into existing brain circuitry. This paper will focus on neurogenesis in the SGZ and provide evidence supporting its influence on the hippocampal functions of learning and memory. It appears that some forms of hippocampal dependent learning influence levels of neurogenesis and that the number of adult born neurons influences learning and memory. SGZ neurogenesis is thought to be regulated by factors such as genetics, environment, and age. These factors regulate some forms of hippocampal dependent tasks in a correlative manner. Research on the function of SGZ neurogenesis in hippocampal dependent learning and memory comes to varying conclusions that are caused by differences in procedures. Research indicates that the relationship between adult neurogenesis in the SGZ and hippocampal dependent learning and memory may be dependent on: the age of the neurons, the age of the subjects and the type of learning that is occurring. More work needs to be done before a comprehensive understanding of the functionality of adult neurogenesis can be made.

As noted previously in this volume, adult neurogenesis is a process, not an event. Adult neurogenesis comprises a series of sequential developmental events that are all necessary for the generation of new neurons under the conditions of the adult brain. In the original publications on adult neurogenesis, the precursor cell population from which neurogenesis originates was identified only by the detection of proliferative activity and the absence of mature neuronal markers (Altman and Das 1965; Kaplan and Hinds 1977; Cameron et al. 1993; Kuhn et al. 1996). The new neurons, in contrast, were identified by the presence of mature neuronal markers in cells that had been birthmarked with the thymidineoder BrdU (bromodeoxyuridine) method (see Chapters 2 and 3) a couple of weeks earlier. The expression of the polysialilated neural cell adhesion molecule (PSA-NCAM) with neurogenesis has been noted early but could not be clearly linked to either proliferation or mature stage (Seki and Arai 1993a,b). PSA-NCAM expression was the first indication of the developmental events that take place, filling the gaps between the start and endpoint of development. Today, we have quite detailed knowledge about the course of neuronal development in the adult hippocampus, and although many detailed questions remain open, a clear overall picture has emerged (Kempermann et al. 2004; Abrous et al. 2005; Ming and Song 2005; Lledo et al. 2006). Although we coarsely talk about neurogenesis in the hippocampus, it should be noted that neurogenesis occurs only in the dentate gyrus (DG), not other regions; in an...

Olfactory neurons arise from the division of a stem cell in the basal area of the epithelium. After dividing asymmetrically and symmetrically, the stem cell gives rise to many immature olfactory receptor neurons that gradually differentiate into mature neurons as they migrate away from the basement membrane. The neurogenesis in the olfactory epithelium takes place throughout adult life, which makes the olfactory epithelium system a useful model with which to study the mechanisms that direct neural development. Olfactory neurogenesis is highly regulated for the need of maintaining the equilibrium between the basal cell mitosis, cell death and cell survival in olfactory epithelium, for which many growth factors have been reported to play roles in regulating olfactory neurogenesis. Many reports observed the proliferative role of TGF and EGF in the olfactory neurogenesis and the expression of their receptors in horizontal basal cells, suggesting their signaling pathways for proliferation were mediated by a common receptor on the horizontal basal cells. FGF2 was reported to induce proliferation in a mouse embryo explant, a basal cell line, and in our laboratory, a basal cell culture. However, the target cells of FGF2 in the olfactory epithelium were not clear at the time of the research. TGF -2 was observed to stimulate differentiation in semi-dissociated olfactory tissues, in basal cell cultures and a basal cell line. Some of the receptors for TGF growth factors were found to be expressed in the olfactory epithelium but the identity of the target cells of TGF growth factors and the cells expressing them remained largely unknown. PDGF was observed in our laboratory to promote survival of immature neurons but there was no evidence to show the existence of its receptors on the immature neurons or to locate its source in the olfactory epithelium. This project aimed to identify and characterize the cells expressing TGF -2, PDGF and FGF growth factors and receptors in the olfactory epithelium using techniques of RT-PCR, immunohistochemistry, and in situ hybridisation. Our results have shown most members of TGF -2 superfamily were expressed in the olfactory epithelium in that TGF growth factors 1, 2, 3 and TGF receptor type 1, 2 and 3 were expressed extensively in superficially located basal cells, immature and mature neurons. FGF1 was expressed in olfactory epithelium. FGF2 and FGFr-1 were expressed by neurons and presumed globose basal cells. The supporting cells were like to express FGF2 mRNA. PDGF A and PDGF receptor had similar expression patterns in the olfactory epithelium. In support of previous studies, this project has provided in vivo evidence for the cells expressing the growth factors of importance and for the target cells these growth factors might act on. In addition to these, this project also investigated an unknown gene, 16b5, which was previously found to be unregulated by differentiation of an olfactory cell line, and has provided the in vivo evidence to support the finding.

Most organisms rely on an olfactory system to detect and analyze chemical cues from the external world in the context of essential behavior. From worms to vertebrates, chemicals are detected by odorant receptors expressed by olfactory sensory neurons, which send an axon to the primary processing center—the olfactory bulb, in vertebrates. Within this relay, sensory neurons form excitatory synapses with projection neurons and with inhibitory interneurons. Thus, due to complex synaptic interactions in the olfactory bulb circuit, the output of a given projection neuron is determined not only by the sensory input, but also by the activity of local inhibitory interneurons that are concerned by adult neurogenesis throughout life. Recent studies have provided clues about how these new neurons incorporate into preexisting networks, how they survive or die once integrated into proper microcircuits, and how basic network functions are maintained despite the continual renewal of a large percentage of neurons. We know that external influences modulate the process of late neurogenesis at various stages. Thus, this process is probably flexible, allowing brain performance to be optimized for its environment. But optimized how? And why? This chapter describes the adaptation of new interneuron production to experience-induced plasticity. In particular, how the survival of newly generated neurons is highly sensitive not only to the level of sensory inputs, but also to the behavioral context is discussed. Also discussed is how neurogenesis may finely tune the functioning of the neural network, optimizing the processing of sensory information. Adult neurogenesis maintains continual turnover...

During the development of the dentate gyrus (DG), both at embryonic and postnatal stages, radial glial cells (RGCs) and neural progenitors proliferate and generate mature granule neurons, the principal neuron of the DG. In an unique way, in the adult DG, a subpopulation of progenitors with a radial morphology are retained in a quiescent state as adult radial glial-like cells (RGLs) in the subgranular zone (SGZ) of the DG and continue to produce new granule neurons throughout adult life. This raises questions about when and how adult RGLs are generated in the DG, which are essential questions to understand how neurogenic niches are generated and maintained in the adult brain. HMG-box transcription factors of Sox family genes could be at the core of those processes, as many of them have essential regulatory functions in both developmental and adult neurogenesis. In this study, we have focused on SoxD transcription factors (Sox5 and Sox6) in DG neurogenesis, as our laboratory has previously shown that they play a critical role in regulating cell cycle progression in progenitor cells and that they are expressed in the SGZ, both during DG development and in adulthood. We describe now that during DG development both Sox5 and Sox6 are persistently expressed in RGCs/RGLs and that their expression gradually turns off along the progression of those cells towards the neuronal lineage. By conditional deletion of Sox5 and Sox6 from early central nervous system development, we have determined that Sox5 is required for RGCs/RGLs to enter the quiescent state during postnatal development. Thus, deleting Sox5 expression during development results first in an increase in hippocampal neurogenesis in young adults and then, in mature adults, leads to an exhaustion of RGLs pool. Furthermore, we have found that BMP signaling target, Id2, could be mediating Sox5-regulated quiescence acquisition during DG development. Furthermore, we have found that Sox6 alone is less required than Sox5 for the development of DG, at least during first three postnatal weeks. Interestingly, selective creERT/tamoxifen-induced deletion of SoxD genes in the adult DG, showed that both Sox5 and Sox6 are required for RGLs to transit from quiescent into active proliferative states, and consequently they are needed for adult neurogenesis. Taken together, our results prove that the transition from developmental RGCs into adult RGLs during DG development is regulated by Sox5. These results set up the basis to further explore Sox5 direct targets to understand the molecular mechanism that involve how adult neurogenesis is specifically generated at certain brain areas and how could we modulate the neurogenic process in pathological and ageing brains.

During development, neurogenesis is a multistep process that includes cell proliferation, cell cycle exit, a choice between survival and death, cell migration, cell differentiation, and cell-fate decisions, including neuron versus glia and neuronal cell class decisions (for review, see Nowakowski et al. 2002). The same multiple steps and associated decisions occur during adult neurogenesis but with several significant differences, the most important being that (1) there are fewer proliferating cells during adult neurogenesis and (2) the selection of neuronal cell classes produced is limited. With respect to the ultimate outcome—the production of functional neurons—each step in this multistep process is, in effect, a possible site of regulation. The complexity of these regulatory steps is described in the other chapters of this book. In this chapter, we deal with the early steps in the process of neurogenesis, i.e., cell proliferation and cell cycle exit. We discuss how the number of cells produced during neurogenesis is regulated by the proliferative capacity of a population of dividing cells. The proliferative capacity, in turn, is determined by the length of the cell cycle, the number of proliferating cells, and the proportion of daughter cells that exit versus reenter the cell cycle. In addition, we review some of the methods for measuring these properties and discuss some of the pitfalls that are commonly encountered. CELL CYCLE CHARACTERIZATION Neurogenesis is driven by cell proliferation, and the core process of cell proliferation is the cell cycle. Conceptually, the cell cycle is simple (Fig. 1A). It...

Adult neurogenesis in birds offers unique opportunities to study basic questions addressing the birth, migration and differentiation of neurons. Neurons in adult canaries originate from discrete proliferative regions on the walls of the lateral ventricles. They migrate away from their site of birth, initially at high rates, along the processes of radical cells. The rates of dispersal diminish as the young neurons invade regions devoid of radial fibers, probably under the guidance of other cues. The discrete sites of birth in the ventricular zone generate neurons that end up differentiating throughout the telencephalon. New neurons may become interneurons or projection neurons; the latter connect two song control nuclei between neostriatum and archistriatum. Radial cells, that in mammals disappear as neurogenesis comes to an end, persist in the adult avian brain. The presence of radial cells may be key to adult neurogenesis. Not only do they serve as guides for initial dispersal, they also divide and may be the progenitors of new neurons.

For many models of the cerebral cortex, particularly developmental ones, knowledge of cortical structure is essential to a proper understanding of its functional capacities. We have studied the microscopic neuroanatomic changes of the postnatal human cerebral cortex during its development from birth to 72 mo. The microscopic structural changes we have identified to date are complex, yet well organized, and mathematically describable. The discoveries to date arising from analyses of the Conel data include: 1. That the total number of cortical neurons increases by 1/3 from term birth to 3 mo, then decreases back to the birth value by 15 mo, then increases by approximately 70% above the birth value from 15 to 72 mo. 2. Based on 35 cortical areas, the mean number of neurons under 1 mm2 of cortical surface extending the depth of the cortex decreases by 50% from term birth to 15 mo, then from 15 to 72 mo, increases by 70% above the value at 15 mo. Both of the previous findings provided the first evidence for postnatal mammalian (human) neocortical neurogenesis. These findings have received subsequent support from studies demonstrating cortical neurogenesis in adult macaque monkeys. 3. That changes in total cortical neuron number from birth to 72 mo inversely correlate strongly (ρ = −0.73) with the number of new behaviors acquired during this time. The correlation appears strongest when there is a time delay, suggesting that changes in cortical neuron number precede the appearance of newly acquired behaviors. 4. That each of 35 cortical areas analyzed show characteristic increases and decreases in neuron number in a wave-like fashion from birth to 72 mo, suggesting local regulatory control of both neuronal cell death and neurogenesis. The changes in neuron number appear to follow gradients that correspond to functional cortical systems, including frontal (motor, dorsolateral prefrontal, and orbitofrontal, separately), visual (ventral and dorsal streams, separately), and auditory systems. 5. That within any given cortical area from birth to 72 mo, there are functionally related shifts in the relative numbers of neurons in the six cortical layers. Since each of the six cortical layers has a specific function with specific communication to other layers, the neocortex can create 720 variations (6!) in its function just by changing the relative power of the six cortical layers in all possible permutations. The data clearly show that only a few of these permutations are actually used. It appears that the function of secondary association neocortical areas or higher are most developed when layers III and VI have the most neurons, and that the function of primary sensory, 1st order association, or transitional (i.e., cingulate) neocortical areas are most developed when layers III and IV have the most neurons. Layer III is primarily responsible for long distance cortico-cortical communication; layer IV is primarily responsible for receiving thalamic sensory information from the environment plus feedforward cortico-cortical communication; and layer VI is primarily responsible for sending cortical information back to the thalamus and receiving feedback cortico-cortical information. In this chapter, we present the data and studies that formed the basis for the above discoveries in postnatal human cerebral cortex from birth to 72 mo. These data have particular relevance to those interested in building computational models of cortical development and provide a basis for concomitant cortical electrophysiological and behavioral developmental changes. Computational models incorporating such knowledge may provide a mechanistic understanding of how the brain develops and how it functions.

Objective To investigate whether mild hypothermia can promote neurogenesis in the dentate gyrus of hippocampus and cognitive function recovery after traumatic brain injury (TBI) through inhibiting apoptosis of hippocampal neurons. Methods A total of 66 healthy adult Sprague-Dawley rats were randomly divided into sham group, TBI group and TBI+ hypothermia group, with 22 rats in each group. The rat TBI model was established using the fluid percussion device. The rats in TBI+ hypothermia group received 4-hour hypothermia therapy immediately after injury, with the target temperature of 33.5℃. Bromodeoxyuridine (BrdU) was injected into the rats' abdominal cavity to label the mitotic cells. The test of Morris water maze was used to evaluate the rats' spatial learning and memory capabilities. Immunofluorescence staining was used to observe the expression levels of BrdU, doublecortin (DCX), neuron specific nuclear protein (NeuN), cysteinyl aspartate specific proteinase 3 (caspase-3) and cleaved caspase-3 expressions in dentate gyrus of hippocampus at 7 days and 28 days after injury. Expressions apoptosis-related proteins including the factor associated suicide (FAS)/factor associated suicide ligand (FASL), B-cell lymphoma-2 (Bcl-2), caspase-3 and cleaved caspase-3 expressions were detected by Western blot assay. Results The water maze tests at 28 days after injury showed that compared with TBI group, the escape latency in TBI+ hypothermia group was significantly shorter [(24.2±5.9)s∶(18±4.1)s], and both the time in the target quadrant and the number of platform crossing were increased significantly [(24.9±6.5)s∶(31.7±5.2)s; (1.9±0.8) times∶(3.5±1.2)times](P<0.05). Compared with the sham group, in TBI group and TBI+ hypothermia group, the BrdU+ new-born cells in the dentate gyrus of hippocampus were significantly increased at 7 days after injury [(9.4±4.1)∶(33.4±3.8); (9.4±4.1)∶(45.8±5.6)], the BrdU+ /DCX+ new-born neurons were increased at 7 days after injury [(2.0±0.6)∶(9.6±1.6); (2.0±0.6)∶(19.2±3.7)], and the BrdU+ /NeuN+ mature neurons were increased at 28 days after injury [(2.6±1.0)∶(17.2±3.9); (2.6±1.0)∶(33.6±9.1)] (P<0.01). TBI group showed more obvious increase than the TBI+ hypothermia group (P<0.01). Moreover, compared with 7 days after injury, the number of BrdU+ cells at 28 days after injury was further increased in TBI+ hypothermia group but decreased in TBI group [(45.8±5.6)∶(58.8±9.2); (33.4±3.8)∶(22.0±3.5)](P<0.05 or <0.01). Compared with the sham group, the caspase-3+ NeuN+ and caspase-3+ NeuN+ apoptotic neurons were significantly increased at 7 days after injury in TBI group [(2.0±0.9)∶(11.6±2.6); (2.6±1.0)∶(10.2±2.9)] (P<0.05). Compared with the TBI group, the cleaved caspase-3+ NeuN+ apoptotic neurons were decreased in TBI+ hypothermia group [(6.6±2.0)∶(11.6±2.6)](P<0.05). Furthermore, compared with the TBI group, mild hypothermia might down-regulate the expression of FAS, FASL, cleaved caspase-3 and caspase-3 and up-regulate the expression of Bcl-2 in the hippocampus [(1.54±0.15) ∶(1.14±0.12); (1.06±0.04)∶(0.80±0.09); (0.84±0.03)∶(0.62±0.08); (0.93±0.06)∶(0.86±0.09); (0.71±0.01)∶(1.58±0.18)](P<0.05). Conclusions Mild hypothermia might inhibit apoptosis of hippocampal neurons through cleaved caspase-3, FAS/FASL and Bcl-2 pathways, thus improving the neurogenesis and maturation of neurons in the dentate gyrus of hippocampus and facilitating cognitive function recovery in rats. It indicates that the function of hypothermia in anti-apoptosis and neurogenesis and maturity of hippocampal neurons may have a potential role in predicting the prognosis of TBI patients. Key words: Hypothermia; Brain injuries; Hippocampus; Neuve regeneration; Apoptosis

Stroke is caused by occlusion of a cerebral artery, which gives rise to focal ischemia with irreversible injury in a core region and partially reversible damage in the surrounding penumbra zone. In another type of insult, abrupt and near-total interruption of cerebral blood flow as a consequence of cardiac arrest or coronary artery occlusion leads to global ischemia and selective death of certain vulnerable neuronal populations such as the pyramidal neurons of hippocampal CA1. During the last decade, these ischemic insults have been reported to induce the formation of new neurons in the adult rodent brain from neural stem cells (NSCs) located in two regions: the subventricular zone (SVZ), lining the lateral ventricle, and the subgranular zone (SGZ) in the dentate gyrus (DG). Ischemia-induced neurogenesis is triggered both in areas where new neurons are normally formed, such as the DG, and in areas that are nonneurogenic in the intact brain, e.g., the striatum. These findings have raised several important issues: (1) Is the evidence for the formation of new neurons really solid or could there be other interpretations such as aberrant DNA synthesis caused by the ischemic insult in already existing, mature neurons? (2) What are the functional consequences of ischemia-induced neurogenesis? (3) Because the neurogenic response is minor and recovery after stroke incomplete, how can this presumed self-repair mechanism be boosted? In this chapter, we summarize the current status of research on neurogenesis after stroke. We also discuss the basic scientific problems that need to be addressed before this...

Advances in our understanding of the extent and regulation of adult neurogenesis have been dependent on continued improvements in the detection and quantification of critical events in neurogenesis. To date, no specific and exclusive stem cell marker has been described that would allow for prospective studies of neurogenesis. As a result, detection of neurogenic events has depended on a combination of labeling approaches that document the two critical events in neurogenesis: the generation of new cells and their subsequent progression through lineage commitment to a mature neuron. Detection of neurogenesis in vivo requires the ability to image at a cellular resolution. Although advances in noninvasive imaging approaches, such as magnetic resonance imaging (MRI), show promise for longitudinal studies of neurogenesis, the lack of suitable resolution to characterize individual cells limits the information that can be obtained. In vivo microscopy, using deeply penetrating UV illumination with mulitphoton microscopy or by the recently available endoscopic confocal microscopy, may provide new opportunities for longitudinal studies of neurogenesis in the living animal with single-cell resolution. These latter microscopy approaches are particularly compelling when coupled with transgenic mice expressing phenotype-specific fluorescent reporter genes. However, at present, the predominant approach for studies of neurogenesis relies on traditional histological methods of fixation, production of tissue sections, staining, and microscopic analysis. This chapter discusses methodological considerations for in vivo detection of neurogenesis in the adult brain according to our current state of knowledge. First, detection of newly generated cells is evaluated and the strengths of using exogenous or...

Recent experimental evidence obtained mainly in rodents has indicated that the stroke-damaged adult brain makes an attempt to repair itself by producing new neurons from its own neural stem cells. Here, we summarize the current status of this research with an emphasis on how, in the future, optimization of this potential self-repair mechanism could become of therapeutical value to promote functional restoration after stroke. Currently, our knowledge about the mechanisms regulating the different steps of neurogenesis after stroke is incomplete. Despite a lot of circumstantial evidence, we also do not know if stroke-induced neurogenesis contributes to functional improvement and to what extent the new neurons are integrated into existing neural circuitries. It is highly likely that, in order to have a substantial impact on the recovery after stroke, neurogenesis has to be markedly enhanced. Based on available data, this should primarily be achieved by increasing the survival and differentiation of the generated neuroblasts. Moreover, for maximum functional recovery, optimization of neurogenesis most likely needs to be combined with stimulation of other endogenous neuroregenerative responses, e.g., protection and sprouting of remaining mature neurons, and transplantation of stem cell-derived neurons and glia cells.

The term “adult neurogenesis” is used to describe the observation that, in the adult mammalian brain, new neurons are born from stem cells residing in discrete locations and these new neurons migrate, differentiate, and mature into newly integrated, functioning cells. By virtue of this definition, adult neurogenesis is a process, not an event, and as such, can be dissected and examined in evermore discrete components. In general, researchers seek a complete understanding of not only the details of these separate components but also the purpose and function of this process as a whole. Once the tools became available to monitor and measure adult neurogenesis, the interest in this process grew enormously, not the least because the birth and integration of new neurons in the adult brain constitute the most extreme cases of neuroplasticity in the adult brain. While the phenomenon is interesting enough to investigate and understand in the normal, healthy brain, the fact that this process is also disrupted in many disease states adds substantially to the numbers of those studying adult neurogenesis. As a result, a new way of looking at brain therapy has emerged that incorporates the potential of generating new neurons in the context of aging and disease into the search for a strategy for “self-repair.” The idea for this book originated from a meeting on adult neurogenesis in the adult brain held at the Banbury Conference Center at Cold Spring Harbor Laboratory in February 2006. In the secluded and intimate setting of this event, the