强制运动促进成年大鼠海马齿状回神经发生并提高学习能力

为了探讨强制运动对成年大鼠海马齿状回（dentate gyrus,DG）神经发生的影响,强制大鼠在马达驱动的转轮中跑步,用5-溴-2-脱氧尿苷（5-bromo-2-deoxyuridine,BrdU）标记增殖细胞,巢蛋白（neuroepthelial stem cell protein,nestin）标记神经干细胞／前体细胞,然后用免疫细胞化学技术检测大鼠DG中BrdU及nestin阳性细胞。为了解强制运动后DG增殖细胞的功能意义,采用Y-迷宫检测大鼠的学习能力。结果表明,强制运动组DG中BrdU及nestin阳性细胞数均日月显多于对照组（P〈0．05）：强制运动对DG神经发生的效应有强度依赖性。Y-迷宫检测结果显示,强制运动能明显改善大鼠的学习能力。结果提示,在转轮中进行强制跑步能促进成年火鼠DG的神经发生,并改善学习能力。     

Transient suppression of progenitor cell proliferation through NMDA receptors in hippocampal dentate gyrus of mice with traumatic stress experience

Post-traumatic stress disorder is a long-lasting psychiatric disease after the traumatic experience of severe fatal stress with the consequence of hippocampal atrophy. Freezing behaviors were more than quintupled on the fear-conditioning test in mice previously subjected to water immersion restrain stress (WIRS) with metronome tones when determined 1–28 days after WIRS, while these mice exhibited the increased immobility time on the forced swimming test with the increased spontaneous locomotion. Prior experience of WIRS led to a transient decrease in subsequent 5-bromo-2'-deoxyuridine (BrdU) incorporation into proliferating cells in the hippocampal dentate gyrus. These behavioral and neurochemical alterations were significantly prevented by the daily injection of the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluvoxamine, respectively. Moreover, WIRS significantly decreased the number of cells holding BrdU without affecting the differentiation ratio to astroglial and neuronal lineages 28 days later. Prior administration of an NMDA receptor antagonist significantly prevented the aforementioned changes by WIRS. These results suggest that NMDA receptors may play a role in mechanisms underlying the crisis of a variety of psychiatric symptoms relevant to post-traumatic stress disorder through transient suppression of neural progenitor cell proliferation in the murine hippocampal dentate gyrus.     

Multipotent progenitor cells in the adult dentate gyrus

Neurogenesis persists in the adult dentate gyrus of rodents throughout the life of the organism. The factors regulating proliferation, survival, migration, and differentiation of neuronal progenitors are now being elucidated. Cells from the adult hippocampus can be propagated, cloned in vitro, and induced to differentiate into neurons and glial cells. Cells cultured from the adult rodent hippocampus can be genetically marked and transplanted back to the adult brain, where they survive and differentiate into mature neurons and glial cells. Although multipotent stem cells exist in the adult rodent dentate gyrus, their biological significance remains elusive. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 249–266, 1998.     

Temporally regulated expression of Cre recombinase in neural stem cells

The use of mouse gene targeting to study molecules important in neural development is oftentimes impaired by early embryonic lethality. In order to address later roles for such molecules, specifically in neural stem cells, we generated transgenic mice that express both the tetracycline-inducible molecule rtTA-M2 and GFP under the control of the neural precursor specific form of nestin. Developmental analysis of these mice demonstrates that GFP expression is exclusive to the neural tube. Adult expression of GFP is seen only in known areas of adult neurogenesis, namely, the subventricular zone and the dentate gyrus. When crossed with a second transgenic mouse (TetOp-Cre) that expresses the Cre recombinase under the control of the tetracycline responsive promotor, we demonstrate temporal induction of Cre in bigenic animals exposed to doxycycline. We further demonstrate the feasibility of this approach by using the ROSA-26 reporter mouse to mediate recombination in neural precursor cells.     

Lithium enhances long-term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus

We measured the temporal and spatial profiles of neural precursor cells, hippocampal long-term potentiation (LTP), and signaling molecules in neurogenesis-induced adult rats. Chronic lithium treatment produced a significant 54% and 40% increase in the numbers of bromodeoxyuridine [BrdU(+)] cells after 12 h and 28 days, respectively, after treatment completion in the dentate gyrus (DG). Both LTP obtained from slices perfused with artificial cerebrospinal fluid (ACSF-LTP) and LTP recorded in the presence of bicuculline (bicuculline-LTP) were significantly greater in the lithium group than in the saline controls. Although the number of BrdU(+) cells, approximately 90% of which were double-labeled with a neural marker neuronal nuclear protein, were markedly increased in the granule cell layer (GCL) 28 days after the completion of the 28-day lithium treatment, the magnitude of LTP observed at this time was similar to that observed 12 h after completing the 28-day lithium treatment. However, protein levels of calcium and calmodulin-dependent protein kinase II, p-Elk and TrkB were highly elevated until 28 days after the 28-day lithium treatment. Acute lithium treatment for 2 days also enhanced LTP, which was accompanied by the elevated expression of p-CREB, but not by neurogenesis. Our results suggest that the enhancement of LTP is independent of the increased number of neurons per se and it is more closely associated with key molecules, which are probably involved in neurogenesis.     

The chemokine BRAK/CXCL14 regulates synaptic transmission in the adult mouse dentate gyrus stem cell niche

The chemokine BRAK/CXCL14 is an ancient member of the chemokine family whose functions in the brain are completely unknown. We examined the distribution of CXCL14 in the nervous system during development and in the adult. Generally speaking, CXCL14 was not expressed in the nervous system prior to birth, but it was expressed in the developing whisker follicles (E14.5) and subsequently in the hair follicles and skin. Postnatally, CXCL14 was also highly expressed in many regions of the brain, including the cortex, basal ganglia, septum and hippocampus. CXCL14 was also highly expressed in the dorsal root ganglia. We observed that in the hippocampal dentate gyrus (DG) CXCL14 was expressed by GABAergic interneurons. We demonstrated that CXCL14 inhibited GABAergic transmission to nestin-EGFP-expressing neural stem/progenitor cells in the adult DG. CXCL14 inhibited both the tonic and phasic effects of synaptically released GABA. In contrast CXCL12 enhanced the effects of GABA at these same synapses. CXCL14 increased [Ca(2+)](i) in neural stem cells cultured from the postnatal brain indicating that they expressed the CXCL14 receptor. These observations are consistent with the view that CXCL12 and CXCL14 may normally act as positive and negative regulators of the effects of GABA in the adult DG stem cell niche.     

Circadian regulation of dentate gyrus excitability mediated by G-protein signaling

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Flexible encoding of objects and space in single cells of the dentate gyrus

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Mitogen‐ and stress‐activated kinases regulate progenitor cell proliferation and neuron development in the adult dentate gyrus

The neurogenic niche within the subgranular zone (SGZ) of the dentate gyrus is a source of new neurons throughout life. Interestingly, SGZ proliferative capacity is regulated by both physiological and pathophysiological conditions. One outstanding question involves the molecular mechanisms that regulate both basal and inducible adult neurogenesis. Here, we examined the role of the MAPK‐regulated kinases, mitogen‐ and stress‐activated kinase (MSK)1 and MSK2. as regulators of dentate gyrus SGZ progenitor cell proliferation and neurogenesis. Under basal conditions, MSK1/2 null mice exhibited significantly reduced progenitor cell proliferation capacity and a corollary reduction in the number of doublecortin (DCX)‐positive immature neurons. Strikingly, seizure‐induced progenitor proliferation was totally blocked in MSK1/2 null mice. This blunting of cell proliferation in MSK1/2 null mice was partially reversed by forskolin infusion, indicating that the inducible proliferative capacity of the progenitor cell population was intact. Furthermore, in MSK1/2 null mice, DCX‐positive immature neurons exhibited reduced neurite arborization. Together, these data reveal a critical role for MSK1/2 as regulators of both basal and activity‐dependent progenitor cell proliferation and morphological maturation in the SGZ.     

An inducible transgenic Cre mouse line for the study of hippocampal development and adult neurogenesis

The hippocampus is crucial for higher brain functions, such as learning, memory, and emotion. Many diseases like epilepsy and Down's syndrome are associated with abnormalities in early hippocampal development. In addition, adult dentate neurogenesis is thought to be defective in several classes of psychiatric disorders. However, the mechanisms regulating hippocampal development and adult neurogenesis remain unclear. One of the limitations to studying these processes is the scarcity of available specific mouse tools. Here, we report an inducible transgenic Cre mouse line, Frizzled 9‐CreER?, in which tamoxifen administration induces Cre recombinant. Our data show that Cre is expressed in the developing hippocampal primordium, confined to the granule cell layer at P20 and further limited to the subgranular zone in the adult dentate gyrus. Cre recombinase shows very high activity in all of these regions. Thus, this transgenic line will be a powerful tool in understanding the mechanisms of hippocampal development, adult neurogenesis, and associated diseases. genesis 49:919–926, 2011. © 2011 Wiley Periodicals, Inc.     

A golgi study of cell types in the dentate gyrus of the adult human brain

Summary 1. The morphology of neurons in the dentate gyrus of the adult human brain was analyzed with two variants of Golgi technique.2. About 20 neuronal types and subtypes were observed in the dentate gyrus of the adult human, several of which had not previously been described in the human. The human dentate gyrus harbors 4 types of neurons in the molecular layer, 3 types within the granule cell layer, and at least 10 types in the hilus.3. Compared to the granule neurons in the rat brain, human granule neurons show a much greater variability. Many of these human neurons have basal dendrites and/or axonal spines. Also, there are significant differences among these neurons regarding the density of their dendritic trees and dendritic spines. In contrast to the rat, human hilar neurons with complex spines have complex spines not only on their dendrites but also on their cell bodies.4. This study opens the door for further morphological studies involving specific diseases such as Alzheimer's disease and epilepsy.     

Natural fluctuation and gonadal hormone regulation of astrocyte immunoreactivity in dentate gyrus

The number and the surface density of cells immunoreactive for the specific astrocytic marker glial fibrillary acidic protein (GFAP), were evaluated in both the hilus of the dentate gyrus and the granular layer of the vermis of the cerebellar cortex of adult female rats during the different phases of the estrous cycle, after ovariectomy and after the pharmacological administration of estradiol and/or progesterone to overiectomized rats. Although no significant differences were detected in the number of immunoreactive cells among the different experimental groups studied, their surface density showed significant changes in the hilus of the dentate gyrus. The surface density of immunoreactive cells was increased in the afternoon of proestrus and on the morning of estrus compared to the morning of proestrus, diestrus, and metestrus, was decreased after ovariectomy, and showed a dose-dependent increase in ovariectomized rats injected with 17β estradiol (1, 10, or 300 μg/rat), alone or in combination with progesterone (500 μg/rat). In contrast, it was not affected by the administration of 17β estradiol (300 μg/rat). The surface density of immunoreactive cells was significantly increased over control values by 5 h after the injection of 17β estradiol (300 μg/rat) and as early as 1 h after the administration of progesterone. The separate injection of either 17β estradiol or progesterone had smaller effects on the surface density of immunoreactive cells than did the administration of both hormones together. The surface density of GFAP-immunoreactive cells reached maximal values by 24 h after the administration of 17β estradiol and/or progesterone and returned to control levels by 48 h after the combined injection of progesterone and 17β estradiol, while in the rats that were injected with only one of the two hormones, the surface density of immunoreactive cells remained over control values for at least 9 days. No such hormonal effects on GFAP-immunoreactive cells were observed in the cerebellar cortex. © 1993 John Wiley & Sons, Inc.     

Adolescent development of neuron structure in dentate gyrus granule cells of male Syrian hamsters

Hippocampal function, including spatial cognition and stress responses, matures during adolescence. In addition, hippocampal neuron structure is modified by gonadal steroid hormones, which increase dramatically at this time. This study investigated pubertal changes in dendritic complexity of dentate gyrus neurons. Dendrites, spines, and cell bodies of Golgi-impregnated neurons from the granule cell layer were traced in pre-, mid-, and late-pubertal male Syrian hamsters (21, 35, and 49 days of age). Sholl analysis determined the number of intersections and total dendritic length contained in concentric spheres set at 25-microm increments from the soma. Spine densities were quantified separately in proximal and distal segments of a subset of neurons used for the Sholl analysis. We found that the structure of neurons in the lower, but not upper, blade of the dentate gyrus changed during adolescence. The lower, infrapyramidal blade showed pruning of dendrites close to the cell body and increases in distal dendritic spine densities across adolescence. These data demonstrate that dentate gyrus neurons undergo substantial structural remodeling during adolescence and that patterns of maturation are region specific. Furthermore, these changes in dendrite structure, which alter the electrophysiological properties of granule cells, are likely related to the adolescent development of hippocampal-dependent cognitive functions such as learning and memory, as well as hippocampus-mediated stress responsivity.     

Noradrenaline overflow in mouse dentate gyrus following locus coeruleus and natural stimulation: real-time monitoring by in vivo voltammetry

The pattern of catecholaminergic innervation of the dentate gyrus (DG) of the hippocampus, particularly the relatively dense and selective noradrenergic input, creates favourable conditions for real-time monitoring of noradrenaline (NA) release following stimulation of the locus coeruleus (LC) by in vivo voltammetry. Two electrochemically active species with different temporal characteristics were registered in the DG following electrical stimulation of the LC. Several approaches, including testing of anatomical and pharmacological specificity, coating of microelectrodes with Nafion and use of fast cyclic voltammetry, were used to verify the characteristics of electrochemical responses. The first sharp peak that appeared immediately during stimulation was definitely associated with NA overflow. The second late peak was possibly attributable to ascorbic acid. We examined the characteristics of alpha-2 adrenoceptor regulation of NA release in the DG, and showed for the first time that noradrenergic terminals resemble dopaminergic terminals in their mechanisms of increasing the refilling rate of the readily releasable pool following stimulation repeated at short intervals. Amperometric registration of NA in the DG was complicated by interference with electrical activity of hippocampus. This interference could be used, after appropriate filtration, for simultaneous recording from the same microelectrode of NA release and electrical activity of the hippocampus.     

Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus

Adult dentate neurogenesis is important for certain types of hippocampal-dependent learning and also appears to be important for the maintenance of normal mood and the behavioural effects of antidepressants. Neuropeptide Y (NPY), a peptide neurotransmitter released by interneurons in the dentate gyrus, has important effects on mood, anxiety-related behaviour and learning and memory. We report that adult NPY receptor knock-out mice have significantly reduced cell proliferation and significantly fewer immature doublecortin-positive neurons in the dentate gyrus. We also show that the neuroproliferative effect of NPY is dentate specific, is Y1-receptor mediated and involves extracellular signal-regulated kinase (ERK)1/2 activation. NPY did not exhibit any effect on cell survival in vitro but constitutive loss of the Y1 receptor in vivo resulted in greater survival of newly generated neurons and an unchanged total number of dentate granule cells. These results show that NPY stimulates neuronal precursor proliferation in the dentate gyrus and suggest that NPY-releasing interneurons may modulate dentate neurogenesis.     

Abca7 deletion does not affect adult neurogenesis in the mouse

ATP-binding cassette transporter A7 (ABCA7) is highly expressed in the brain. Recent genome-wide association studies (GWAS) have identified ABCA7 single nucleotide polymorphisms (SNPs) that increase Alzheimer''s disease (AD) risk, however, the mechanisms by which ABCA7 may control AD risk remain to be fully elucidated. Based on previous research suggesting that certain ABC transporters may play a role in the regulation of neurogenesis, we conducted a study of cell proliferation and neurogenic potential using cellular bromodeoxyuridine (BrdU) incorporation and doublecortin (DCX) immunostaining in adult Abca7 deficient mice and wild-type-like (WT) littermates. In the present study counting of BrdU-positive and DCX-positive cells in an established adult neurogenesis site in the dentate gyrus (DG) indicated there were no significant differences when WT and Abca7 deficient mice were compared. We also measured the area occupied by immunohistochemical staining for BrdU and DCX in the DG and the subventricular zone (SVZ) of the same mice and this confirmed that ABCA7 does not play a significant role in the regulation of cell proliferation or neurogenesis in the adult mouse.     

Plasticity of hippocampal stem/progenitor cells to enhance neurogenesis in response to kainate-induced injury is lost by middle age

A remarkable up-regulation of neurogenesis through increased proliferation of neural stem/progenitor cells (NSCs) is a well-known plasticity displayed by the young dentate gyrus (DG) following brain injury. To ascertain whether this plasticity is preserved during aging, we quantified DG neurogenesis in the young adult, middle-aged and aged F344 rats after kainic acid induced hippocampal injury. Measurement of new cells that are added to the dentate granule cell layer (GCL) between post-injury days 4 and 15 using 5'-bromodeoxyuridine labeling revealed an increased addition of new cells in the young DG but not in the middle-aged and aged DG. Quantification of newly born neurons using doublecortin immunostaining also demonstrated a similar trend. Furthermore, the extent of ectopic migration of new neurons into the dentate hilus was dramatically increased in the young DG but was unaltered in the middle-aged and aged DG. However, there was no change in neuronal fate-choice decision of newly born cells following injury in all age groups. Similarly, comparable fractions of new cells that are added to the GCL after injury exhibited 5-month survival and expressed the mature neuronal marker NeuN, regardless of age or injury at the time of their birth. Thus, hippocampal injury does not adequately stimulate NSCs in the middle-aged and aged DG, resulting in no changes in neurogenesis after injury. Interestingly, rates of both neuronal fate-choice decision and long-term survival of newly born cells remain stable with injury in all age groups. These results underscore that the ability of the DG to increase neurogenesis after injury is lost as early as middle age.