脑缺血后大鼠血管内皮生长因子与神经发生的形态学研究

目的观察缺血性脑损伤后大鼠海马内源性血管内皮生长因子(VEGF)表达与海马齿状回神经发生的相关性。方法将24只雄性SD鼠随机分为脑缺血组(21只)和假手术组(3只),脑缺血组大鼠通过改良的4血管闭塞法建立缺血性脑损伤模型,于6、12、24 h和3、6、12和24天,用免疫组织化学及荧光双标记染色法观察不同时间点大鼠海马内源性VEGF表达及神经发生水平。结果脑缺血组大鼠海马区内源性VEGF表达主要集中于海马齿状回和门区,亚颗粒增生带可见丛集VEGF表达阳性细胞;海马齿状回神经发生水平于缺血后第3天时较假手术组升高,于6天时达到峰值(P<0.01)。缺血后早期海马VEGF表达多见于神经元细胞质,在缺血后期则主要见于胶质细胞质。结论大鼠脑缺血后,来源于海马齿状回神经元的VEGF表达可能是缺血诱导的齿状回神经发生水平上调的一个重要始动信号,胶质细胞表达的内源性VEGF表达可能参与了齿状回神经发生的后续过程。     

Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model

22q11 deletion syndrome (22q11DS) frequently accompanies psychiatric conditions, some of which are classified as schizophrenia and bipolar disorder in the current diagnostic categorization. However, it remains elusive how the chromosomal microdeletion leads to the mental manifestation at the mechanistic level. Here we show that a 22q11DS mouse model with a deletion of 18 orthologous genes of human 22q11 (Df1/+ mice) has deficits in migration of cortical interneurons and hippocampal dentate precursor cells. Furthermore, Df1/+ mice show functional defects in Chemokine receptor 4/Chemokine ligand 12 (Cxcr4/Cxcl12; Sdf1) signaling, which reportedly underlie interneuron migration. Notably, the defects in interneuron progenitors are rescued by ectopic expression of Dgcr8, one of the genes in 22q11 microdeletion. Furthermore, heterozygous knockout mice for Dgcr8 show similar neurodevelopmental abnormalities as Df1/+ mice. Thus, Dgcr8-mediated regulation of microRNA is likely to underlie Cxcr4/Cxcl12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases with schizophrenia compared with normal controls. Given the increased risk of 22q11DS in schizophrenia that frequently shows interneuron abnormalities, the overall study suggests that CXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology of schizophrenia and related mental conditions.The 22q11.2 deletion syndrome (22q11DS) is frequently associated with major mental conditions, such as schizophrenia (SZ) (1). Some reports have indicated that 22q11DS might account for up to 1–2% of subjects diagnosed with SZ (2, 3). All of the genes, except one, in the human 22q11.2 locus exist on mouse chromosome 16, although the organization is different (4). This has facilitated the generation of mouse models of 22q11DS, which carry different-size hemizygous deletions of the 22q11-related region (5–8). These mouse models include Df1/+ and LgDel/+ mice: The former has a deletion from Es2 to Ufd1l, whereas the latter has a deletion from Idd to Hira. A recent study using the LgDel/+ mouse model showed that the hemizygous deletion of the 22q11-related region led to delayed migration of interneurons, altered distribution of parvalbumin (PV)-positive interneurons (9), and reduced Chemokine (C-X-C motif) receptor 4 (Cxcr4) expression known to play a role in interneuron migration (10), although it remains to be determined whether Cxcr4 signaling is impaired or not in this model mouse. Given that changes in PV-positive interneurons occur in the pathology of SZ (11, 12), these reports are intriguing. Nonetheless, the mechanism and clinical evidence that link these phenotypic changes are unclear.DiGeorge syndrome critical region gene 8 (Dgcr8) is one of the genes in the 22q11-related region, and has been proposed to be responsible, at least in part, for psychiatric manifestations (13). Dgcr8 heterozygous knockout mice show working memory deficits and sensory information-processing deficits (6, 14), which are also seen in SZ patients. However, it remains elusive how the deficit of this specific molecule can underlie these behavior changes.Here we show that another mouse model of 22q11DS, Df1/+ mice, which have a shorter deletion of the 22q11-related region, also have abnormal interneuron migration. Using Df1/+ and Dgcr8 heterozygous knockout mice, we directly demonstrate that interneuron progenitors show deficits in Cxcr4/Chemokine (C-X-C motif) ligand 12(Cxcl12) signaling, and that Cxcr4-dependent hippocampal dentate gyrus development is also affected. Furthermore, the decreased preference of Df1/+ interneuron progenitors for Cxcl12 could be rescued by overexpression of Dgcr8, suggesting the involvement of Dgcr8-regulated microRNA (miRNA) in this deficit. Finally, we provide evidence that Cxcl12 is down-regulated in the olfactory epithelium from SZ patients.     

Cdk5 is essential for adult hippocampal neurogenesis

The molecular factors regulating adult neurogenesis must be understood to harness the therapeutic potential of neuronal stem cells. Although cyclin-dependent kinase 5 (Cdk5) plays a critical role in embryonic corticogenesis, its function in adult neurogenesis is unknown. Here, we assessed the role of Cdk5 in the generation of dentate gyrus (DG) granule cell neurons in adult mice. Cre recombinase-mediated conditional knockout (KO) of Cdk5 from stem cells and their progeny in the DG subgranular zone (SGZ) prevented maturation of new neurons. In addition, selective KO of Cdk5 from mature neurons throughout the hippocampus reduced the number of immature neurons. Furthermore, Cdk5 gene deletion specifically from DG granule neurons via viral-mediated gene transfer also resulted in fewer immature neurons. In each case, the total number of proliferating cells was unaffected, indicating that Cdk5 is necessary for progression of adult-generated neurons to maturity. This role for Cdk5 in neurogenesis was activating-cofactor specific, as p35 KO but not p39 KO mice also had fewer immature neurons. Thus, Cdk5 has an essential role in the survival, but not proliferation, of adult-generated hippocampal neurons through both cell-intrinsic and cell-extrinsic mechanisms.     

Neurogenesis in the aging brain

Neurogenesis, or the birth of new neural cells, was thought to occur only in the developing nervous system and a fixed neuronal population in the adult brain was believed to be necessary to maintain the functional stability of adult brain circuitry. However, recent studies have demonstrated that neurogenesis does indeed continue into and throughout adult life in discrete regions of the central nervous systems (CNS) of all mammals, including humans. Although neurogenesis may contribute to the ability of the adult brain to function normally and be induced in response to cerebral diseases for self-repair, this nevertheless declines with advancing age. Understanding the basic biology of neural stem cells and the molecular and cellular regulation mechanisms of neurogenesis in young and aged brain will allow us to modulate cell replacement processes in the adult brain for the maintenance of healthy brain tissues and for repair of disease states in the elderly.     

Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance

The long-term response to chronic stress is variable, with some individuals developing maladaptive functioning, although other “resilient” individuals do not. Stress reduces neurogenesis in the dentate gyrus subgranular zone (SGZ), but it is unknown if stress-induced changes in neurogenesis contribute to individual vulnerability. Using a chronic social defeat stress model, we explored whether the susceptibility to stress-induced social avoidance was related to changes in SGZ proliferation and neurogenesis. Immediately after social defeat, stress-exposed mice (irrespective of whether they displayed social avoidance) had fewer proliferating SGZ cells labeled with the S-phase marker BrdU. The decrease was transient, because BrdU cell numbers were normalized 24 h later. The survival of BrdU cells labeled before defeat stress was also not altered. However, 4 weeks later, mice that displayed social avoidance had more surviving dentate gyrus neurons. Thus, dentate gyrus neurogenesis is increased after social defeat stress selectively in mice that display persistent social avoidance. Supporting a functional role for adult-generated dentate gyrus neurons, ablation of neurogenesis via cranial ray irradiation robustly inhibited social avoidance. These data show that the time window after cessation of stress is a critical period for the establishment of persistent cellular and behavioral responses to stress and that a compensatory enhancement in neurogenesis is related to the long-term individual differences in maladaptive responses to stress.     

成年大鼠脑缺血再灌注损伤后海马齿状回神经发生的实验研究

目的　观察成年大鼠全脑缺血再灌注损伤对海马齿状回神经的影响 ,并探讨缺血性脑损伤后神经发生的相关机制。方法　采用 4支血管闭塞法建立大鼠全脑缺血模型 ,应用 5 溴脱氧尿核苷 (5 bromodeoxyuridine ,BrdU)标记分裂细胞、观察全脑缺血 再灌注损伤后 3、7、14、2 1d时大鼠海马齿状回神经前体细胞的增殖速度。并应用免疫荧光双标记法结合激光共聚焦显微镜观察确定新生细胞的分化特点。结果　全脑缺血 再灌注损伤后齿状回神经前体细胞增殖速度在 7～ 14d时明显增加 ,BrdU免疫阳性细胞数目与相应对照组比较 ,差异有显著性意义 (P <0 .0 1)。 2 1d时恢复正常水平。新生细胞大多迁移入颗粒细胞层 ,并分化为神经元。结论　缺血性脑损伤可增强海马齿状回神经发生 ,其机制可能与缺血引起的激素水平、神经递质、神经营养因子浓度改变以及齿状回局部微环境变化有关     

Feed-forward inhibition as a buffer of the neuronal input-output relation

Neuronal processing depends on the input-output (I/O) relation between the frequency of synaptic stimulation and the resultant axonal firing rate. The all-or-none properties of spike generation and active membrane mechanisms can make the neuronal I/O relation very steep. The ensuing nearly bimodal behavior may severely limit information coding, as minimal input fluctuations within the expected natural variability could cause neuronal output to jump between quiescence and maximum firing rate. Here, using biophysically and anatomically realistic computational models of individual neurons, we demonstrate that feed-forward inhibition, a ubiquitous mechanism in which inhibitory interneurons and their target cells are activated by the same excitatory input, can change a steeply sigmoid I/O curve into a double-sigmoid typical of buffer systems. The addition of an intermediate plateau stabilizes the spiking response over a broad dynamic range of input frequency, ensuring robust integration of noisy synaptic signals. Both the buffered firing rate and its input firing range can be independently and extensively modulated by biologically plausible changes in the weight and number of excitatory synapses on the feed-forward interneuron. By providing a soft switch between essentially digital and analog rate-code, this continuous control of the circuit I/O could dramatically increase the computational power of neuronal integration.     

病毒载体介导血管内皮生长因子基因表达对大鼠脑缺血后齿状回神经发生的影响

目的观察重组腺相关病毒(rAAV)载体介导人源血管内皮生长因子165(hVEGF165)基因转移表达对成年大鼠缺血性脑损伤后,海马齿状回神经前体细胞增殖水平的影响。方法SD大鼠27只,随机分为rAAV2组(18只)和对照组(9只),将携带hVEGF165基因的rAAV颗粒立体定向给药至rAAV2组大鼠右侧海马2周后,全部大鼠采用4血管闭塞方法建立大鼠缺血性脑损伤模型,于缺血后6、24和48天时,各组随机选取1/3的大鼠处死,分别应用RT-PCR和免疫组织化学染色法检测大鼠海马hVEGF165 mRNA的表达水平或齿状回神经前体细胞的增殖水平。结果荧光显微镜下观察,rAAV2组大鼠海马齿状回均可见报告基因增强型绿色荧光蛋白的表达;rAAV2组大鼠缺血后6、24和48天时,均有海马hVEGF165 mRNA表达,3个时间点比较无统计学差异(P>0.05);rAAV2组大鼠缺血后6、24和48天时,齿状回神经前体细胞增殖水平较对照组显著增高(P<0.05)。结论rAAV载体可介导目的基因hVEGF165高效转染海马神经元,并促进缺血诱导的齿状回神经前体细胞增殖。     

离子型谷氨酸受体拮抗剂对大鼠脑缺血再灌注后海马齿状回5-溴脱氧尿核苷表达的影响

目的　观察选择性离子型谷氨酸受体 (iGluRs)拮抗剂对大鼠全脑缺血再灌注损伤后齿状回神经发生的调控作用 ,探讨谷氨酸 离子型谷氨酸受体通路在神经发生中的作用。方法　采用 5 溴脱氧尿核苷 (BrdU)标记分裂细胞 ,比较大鼠全脑缺血再灌注损伤后 7d和 14d时各iGluRs拮抗剂处理组与相应对照组之间海马齿状回神经前体细胞的增殖速度。结果　腹腔注射N 甲基 D 天门冬氨酸 (NMDA)受体阻滞剂 5 甲基二氢二苯丙环庚烯亚胺后显著抑制了大鼠全脑缺血后 7d和 14d时齿状回神经发生水平的升高 ,BrdU免疫阳性细胞数较缺血再灌注 +生理盐水组各时间点明显减少 ;而α 氨基羟甲基恶唑丙酸和 (或 )红藻氨酸受体阻滞剂二硝基喹喔啉对全脑缺血后不同时间点齿状回神经发生的增强基本没有影响。结论　全脑缺血再灌注损伤后NMDA受体通路的激活可能促进了齿状回神经发生。     

Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo

The perforant path (PP) undergoes synaptic changes in the course of aging and dementia. Previous studies attempting to assess the integrity of the PP in humans using diffusion tensor imaging (DTI) were limited by low resolution and the inability to identify PP fibers specifically. Here we present an application of DTI at ultrahigh submillimeter resolution that has allowed us to successfully identify diffusion signals unique to the PP and compare the intensity of these signals in a sample of young adults and older adults. We report direct evidence of age-related PP degradation in humans in vivo. We find no evidence of such loss in a control pathway, the alveus, suggesting that these findings are not evidence for a global decline. We also find no evidence for specific entorhinal gray matter atrophy. The extent of PP degradation correlated with performance on a word-list learning task sensitive to hippocampal deficits. We also show evidence for gray matter diffusion signals consistent with pyramidal dendrite orientation in the hippocampus and cerebral cortex. Ultrahigh-resolution microstructural DTI is a unique biomarker that can be used in combination with traditional structural and functional neuroimaging methods to enhance detection of Alzheimer disease in its earliest stages, test the effectiveness of new therapies, and monitor disease progression.     

Stress coping stimulates hippocampal neurogenesis in adult monkeys

Coping with intermittent social stress is an essential aspect of living in complex social environments. Coping tends to counteract the deleterious effects of stress and is thought to induce neuroadaptations in corticolimbic brain systems. Here we test this hypothesis in adult squirrel monkey males exposed to intermittent social separations and new pair formations. These manipulations simulate conditions that typically occur in male social associations because of competition for limited access to residency in mixed-sex groups. As evidence of coping, we previously confirmed that cortisol levels initially increase and then are restored to prestress levels within several days of each separation and new pair formation. Follow-up studies with exogenous cortisol further established that feedback regulation of the hypothalamic-pituitary-adrenal axis is not impaired. Now we report that exposure to intermittent social separations and new pair formations increased hippocampal neurogenesis in squirrel monkey males. Hippocampal neurogenesis in rodents contributes to spatial learning performance, and in monkeys we found that spatial learning was enhanced in conditions that increased hippocampal neurogenesis. Corresponding changes were discerned in the expression of genes involved in survival and integration of adult-born granule cells into hippocampal neural circuits. These findings support recent indications that stress coping stimulates hippocampal neurogenesis in adult rodents. Psychotherapies designed to promote stress coping potentially have similar effects in humans with major depression.     

Performance level modulates adult age differences in brain activation during spatial working memory

Working memory (WM) shows pronounced age-related decline. Functional magnetic resonance imaging (fMRI) studies have revealed age differences in task-related brain activation. Evidence based primarily on episodic memory studies suggests that brain activation patterns can be modulated by task difficulty in both younger and older adults. In most fMRI aging studies on WM, however, performance level has not been considered, so that age differences in activation patterns are confounded with age differences in performance level. Here, we address this issue by comparing younger and older low and high performers in an event-related fMRI study. Thirty younger (20–30 years) and 30 older (60–70 years) healthy adults were tested with a spatial WM task with three load levels. A region-of-interest analysis revealed marked differences in the activation patterns between high and low performers in both age groups. Critically, among the older adults, a more “youth-like” load-dependent modulation of the blood oxygen level-dependent signal was associated with higher levels of spatial WM performance. These findings underscore the need of taking performance level into account when studying changes in functional brain activation patterns from early to late adulthood.     

Persistent impairment of hippocampal neurogenesis in young adult rats following early postnatal alcohol exposure

Background: Prenatal alcohol exposure can cause damage to the developing fetus with outcomes including growth deficiency, facial dysmorphology, brain damage, and cognitive and behavioral deficits. Smaller brains in children with FASD have been linked both with reduced cell proliferation in the developing CNS and with apoptotic cell loss of postmitotic neurons. Prenatal alcohol exposure in rodents during the period of brain development comparable to that of the first and second trimesters of human pregnancy persistently alters adult neurogenesis. Long‐term effects of alcohol exposure during the third trimester equivalent, which occurs postnatally in the rat, on adult neurogenesis have not been previously reported. The goal of this study was to examine the effect of postnatal binge‐like alcohol exposure on cell proliferation and neurogenesis in hippocampal dentate gyrus during adolescence and young adulthood. Methods: Male Long‐Evans rat pups were assigned to 3 groups: alcohol‐exposed (AE), sham‐intubated (SI) or suckle control (SC). AE pups received ethanol in a milk formula in a binge manner (2 feedings, 2 hours apart, total dose 5.25 g/kg/day) on postnatal days (PD) 4–9. BrdU was injected every other day on PD30–50. Animals were perfused either on PD50 to examine cytogenesis and neurogenesis in hippocampal dentate gyrus at the end of BrdU injections or on PD80 to evaluate new cell survival. Dorsal hippocampal sections were immunostained for BrdU, a marker for proliferating cells, Ki67, endogenous marker of proliferation, and NeuN, a marker for mature neurons. Results: Binge‐like alcohol exposure on PD4–9 significantly reduced the number of mature neurons in adult hippocampal dentate gyrus (DG) both on PD50 and PD80, without altering cumulative cytogenesis on PD50. In addition, the number of new neurons, that were generated between PD30 and 50, was further reduced after 30 days of survival in all 3 groups (SC, SI, and AE). Conclusions: These observations suggest that early postnatal binge alcohol exposure results in long‐term deficits of adult hippocampal neurogenesis, providing a potential basis for the deficits of hippocampus‐dependent behaviors reported for this model.     

Multiple types of navigational information are independently encoded in the population activities of the dentate gyrus neurons

The dentate gyrus (DG) plays critical roles in cognitive functions, such as learning, memory, and spatial coding, and its dysfunction is implicated in various neuropsychiatric disorders. However, it remains largely unknown how information is represented in this region. Here, we recorded neuronal activity in the DG using Ca²⁺ imaging in freely moving mice and analyzed this activity using machine learning. The activity patterns of populations of DG neurons enabled us to successfully decode position, speed, and motion direction in an open field, as well as current and future location in a T-maze, and each individual neuron was diversely and independently tuned to these multiple information types. Our data also showed that each type of information is unevenly distributed in groups of DG neurons, and different types of information are independently encoded in overlapping, but different, populations of neurons. In alpha-calcium/calmodulin-dependent kinase II (αCaMKII) heterozygous knockout mice, which present deficits in spatial remote and working memory, the decoding accuracy of position in the open field and future location in the T-maze were selectively reduced. These results suggest that multiple types of information are independently distributed in DG neurons.

The dentate gyrus (DG) in the hippocampus has been implicated in cognitive functions such as pattern separation (1, 2), contextual encoding (3, 4), and place recognition (3–7), and its dysfunction is suggested to be associated with various neuropsychiatric disorders, such as epilepsy (8), schizophrenia (9, 10), and Alzheimer’s disease (8). The DG receives excitatory input from layer II neurons in the entorhinal cortex (EC) (11, 12) and sends output to Cornu Ammonis 3 (CA3) pyramidal cells (4, 5). The EC receives multimodal sensory information from other brain regions and contains neurons with distinct functional properties, including grid (13), border (14), speed (15, 16), and head-direction cells (17). Likewise, the hippocampal CA regions receive information from the DG and contain neurons that represent place (18), locomotion speed (16), episodic memory (19), time (20), and novel spatial experience (21, 22). Therefore, the DG is thought to be involved in the processing and integration of a variety of information (23).Despite its wide-ranging functions, the DG is unusual among hippocampal regions in that only a small population of principal DG neurons are thought to be active in a given environment (24, 25). In addition, several studies have reported that most DG neurons exhibit poor tuning to position (6) and movement speed (26). This paradox has led to a significant interest in how information is represented in the population activity patterns of DG neurons (7).Here, to unveil important functional characteristics of DG neurons, we performed Ca²⁺ imaging using a microendoscope in freely moving mice, which enables us to record activity from a large population of neurons (27, 28). We recorded neural activity of the dorsal DG (dDG) that is thought to be relatively more involved in the exploratory behavior and contextual memory encoding than in the ventral DG (29, 30). Then, we analyzed how individual DG neurons are involved in encoding position, speed, and motion direction in an open field (OF), as well as current and future location (left or right) in a T-maze. Even if the majority of individual neurons are poorly tuned to these types of information, neurons may encode information by the population activity patterns (7). Therefore, by using machine-learning methods, we also asked if these types of information are encoded in the population activity patterns of DG neurons. We then investigated how these types of information are distributed in the populations of DG neurons. Concurrently, to assess how these neural representations might be altered in a disease model, we carried out the same imaging and analysis in heterozygous alpha-calcium/calmodulin-dependent kinase II knockout (αCaMKII^+/−) mice. The αCaMKII^+/− mice exhibit an array of behavioral abnormalities, including locomotor hyperactivity, impaired working and remote memory, abnormal social/aggressive behavior, and exaggerated infradian rhythms (31–35). We have reported that these mice have an endophenotype called “immature DG (iDG),” in which neurons show properties similar to immature neurons, such as altered expression of maturation-related genes, decreased induction of some of the immediate early genes (cFos and Arc), increased membrane excitability, and weak synaptic plasticity at mossy-fiber–CA3 synapses (31, 34). By studying how neural representation of information is altered in the DG of these mice, we further aimed to gain insight into how multiple types of information are represented in the population activities of dDG neurons in normal and abnormal conditions.     

Gene expression changes in the course of normal brain aging are sexually dimorphic

Gene expression profiles were assessed in the hippocampus, entorhinal cortex, superior-frontal gyrus, and postcentral gyrus across the lifespan of 55 cognitively intact individuals aged 20-99 years. Perspectives on global gene changes that are associated with brain aging emerged, revealing two overarching concepts. First, different regions of the forebrain exhibited substantially different gene profile changes with age. For example, comparing equally powered groups, 5,029 probe sets were significantly altered with age in the superior-frontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the sixth to seventh decades across cortical regions, suggesting that this period is a critical transition point in brain aging, particularly in males. Second, clear gender differences in brain aging were evident, suggesting that the brain undergoes sexually dimorphic changes in gene expression not only in development but also in later life. Globally across all brain regions, males showed more gene change than females. Further, Gene Ontology analysis revealed that different categories of genes were predominantly affected in males vs. females. Notably, the male brain was characterized by global decreased catabolic and anabolic capacity with aging, with down-regulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with proportionally greater activation in the female brain. These data open opportunities to explore age-dependent changes in gene expression that set the balance between neurodegeneration and compensatory mechanisms in the brain and suggest that this balance is set differently in males and females, an intriguing idea.     

Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain

Neurogenesis has recently been observed in the adult human brain, suggesting the possibility of endogenous neural repair. However, the augmentation of neurogenesis in the adult human brain in response to neuronal cell loss has not been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the subependymal layer (SEL) adjacent to the caudate nucleus in the human brain in response to neurodegeneration of the caudate nucleus in Huntington's disease (HD). Postmortem control and HD human brain tissue were examined by using the cell cycle marker proliferating cell nuclear antigen (PCNA), the neuronal marker beta III-tubulin, and the glial cell marker glial fibrillary acidic protein (GFAP). We observed a significant increase in cell proliferation in the SEL in HD compared with control brains. Within the HD group, the degree of cell proliferation increased with pathological severity and increasing CAG repeats in the HD gene. Most importantly, PCNA+ cells were shown to coexpress beta III-tubulin or GFAP, demonstrating the generation of neurons and glial cells in the SEL of the diseased human brain. Our results provide evidence of increased progenitor cell proliferation and neurogenesis in the diseased adult human brain and further indicate the regenerative potential of the human brain.     

FGF-2 regulation of neurogenesis in adult hippocampus after brain injury

Fibroblast growth factor-2 (FGF-2) promotes proliferation of neuroprogenitor cells in culture and is up-regulated within brain after injury. Using mice genetically deficient in FGF-2 (FGF-2(-/-) mice), we addressed the importance of endogenously generated FGF-2 on neurogenesis within the hippocampus, a structure involved in spatial, declarative, and contextual memory, after seizures or ischemic injury. BrdUrd incorporation was used to mark dividing neuroprogenitor cells and NeuN expression to monitor their differentiation into neurons. In the wild-type strain, hippocampal FGF-2 increased after either kainic acid injection or middle cerebral artery occlusion, and the numbers of BrdUrd/NeuN-positive cells significantly increased on days 9 and 16 as compared with the controls. In FGF-2(-/-) mice, BrdUrd labeling was attenuated after kainic acid or middle cerebral artery occlusion, as was the number of neural cells colabeled with both BrdUrd and NeuN. After FGF-2(-/-) mice were injected intraventricularly with a herpes simplex virus-1 amplicon vector carrying FGF-2 gene, the number of BrdUrd-labeled cells increased significantly to values equivalent to wild-type littermates after kainate seizures. These results indicate that endogenously synthesized FGF-2 is necessary and sufficient to stimulate proliferation and differentiation of neuroprogenitor cells in the adult hippocampus after brain insult.     

Tooth loss and subsequent disability and mortality in old age

OBJECTIVES: To examine whether tooth loss at age 70 is associated with onset of disability at 5-, 10-, 15-, and 20-year follow-up and to mortality at 21-year follow-up.
SETTING: Community-based population in Copenhagen.
DESIGN: A baseline study of a random sample of 70-year-old people born in 1914 and follow-up 5, 10, 15, and 20 years later.
PARTICIPANTS: A total of 573 nondisabled individuals participated in the study of 70-year-olds in 1984, 460 participated in the 5-year follow-up, 292 in the 10-year follow-up, 150 in the 15-year follow-up, and 78 in the 20-year follow-up.
MEASUREMENTS: Data from interviews and a medical and oral examination. Oral health was measured according to number of teeth (0, 1–9, 10–19, ≥20). Disability was measured using the Avlund Mob-H scale at age 75, 80, 85, and 90. Mortality data were obtained from the National Death Register.
RESULTS: Being edentulous or having one to nine teeth was associated with onset of disability at age 75 and 80. Health-related variables and education attenuated the associations between edentulism and onset of disability, although they remained marginally significant, whereas the association between having one to nine teeth and onset of disability remained unchanged and statistically significant at 10-year follow-up (odds ratio=3.02, 95% confidence interval (CI)=1.26–7.24). Persons who were edentulous at age 70 were at significantly higher risk of mortality 21 years later, also in the adjusted analysis (hazard ratio=1.26, 95% CI=1.03–1.55).
CONCLUSION: Tooth loss is independently associated with onset of disability and mortality in old age. The findings indicate that tooth loss may be an early indicator of accelerated aging.     

CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain

The postnatal forebrain subventricular zone (SVZ) harbors stem cells that give rise to olfactory bulb interneurons throughout life. The identity of stem cells in the adult SVZ has been extensively debated. Although, ependymal cells were once suggested to have stem cell characteristics, subsequent studies have challenged the initial report and postulated that subependymal GFAP(+) cells were the stem cells. Here, we report that, in the adult mouse forebrain, immunoreactivity for a neural stem cell marker, prominin-1/CD133, is exclusively localized to the ependyma, although not all ependymal cells are CD133(+). Using transplantation and genetic lineage tracing approaches, we demonstrate that CD133(+) ependymal cells continuously produce new neurons destined to olfactory bulb. Collectively, our data indicate that, compared with GFAP expressing adult neural stem cells, CD133(+) ependymal cells represent an additional-perhaps more quiescent-stem cell population in the mammalian forebrain.