Intrinsic and spontaneous neurogenesis in the postnatal slice culture of rat hippocampus

Organotypic slice culture preserves the morphological and physiological features of the hippocampus of live animals for a certain time. The hippocampus is one of exceptional regions where neurons are generated intrinsically and spontaneously throughout postnatal life. We investigated the possibility that neurons are generated continuously at the dentate granule cell layer (GCL) in slice culture of the rat hippocampus. Using 5-bromodeoxyuridine (BrdU) labelling and retrovirus vector transduction methods, the phenotypes of the newly generated cells were identified immunohistochemically. At 4 weeks after BrdU exposure, BrdU-labelled cells were found in the GCL and were immunoreactive with a neuronal marker, anti-NeuN. There were fibrils immunoreactive with anti-glial fibrillary acidic protein (GFAP), an astrocyte marker, in the layer covering the GCL and occasionally encapsulated BrdU-labelled nuclei. When the newly divided cells were marked with the enhanced green fluorescent protein (EGFP) using a retrovirus vector, these cells had proliferative abilities throughout the following 4-week cultivation period. Four weeks after the inoculation, the EGFP-expressing cells consisted of various phenotypes of both early and late stages of differentiation; some were NeuN-positive cells with appearances of neurons in the GCL and some were immunoreactive with anti-Tuj1, a marker of immature neurons. Some EGFP-expressing cells were immunoreactive with anti-GFAP or anti-nestin, a marker of neural progenitors. The present study suggests that slice cultures intrinsically retain spontaneous neurogenic abilities for their cultivation period. The combination of slice culture and retrovirus transduction methods enable the newly divided cells to be followed up for a long period.     

Early involvement of synapsin III in neural progenitor cell development in the adult hippocampus

Synapsin III is a synaptic vesicle-associated protein that is expressed in cells of the subgranular layer of the hippocampal dentate gyrus, a brain region known to sustain substantial levels of neurogenesis into adulthood. Here we tested the hypothesis that synapsin III plays a role in adult neurogenesis with synapsin III knockout and wild-type mice. Immunocytochemistry of the adult hippocampal dentate gyrus revealed that synapsin III colocalizes with markers of neural progenitor cell development (nestin, PSA-NCAM, NeuN, and Tuj1) but did not colocalize with markers of mitosis (Ki67 and PCNA). Because neurogenesis consists of a number of stages, the proliferation, survival, and differentiation of neural progenitor cells were systematically quantitated in the hippocampal dentate gyrus of adult synapsin III knockout and wild-type mice. We found a 30% decrease in proliferation and a 55% increase in survival of neural progenitor cells in synapsin III knockout mice. We also observed a 6% increase in the number of neural progenitor cells that differentiated into neurons. No difference in the volume of the dentate gyrus was observed between synapsin III knockout and wild-type mice. Collectively, our results demonstrate a novel role for synapsin III in regulating the proliferation of neural progenitor cells in the adult hippocampal dentate gyrus. These findings suggest a distinct function for this synaptic vesicle protein, in addition to its role in neurotransmission.     

Postnatal neurogenesis in hippocampal slice cultures: early in vitro labeling of neural precursor cells leads to efficient neuronal production

Neurogenesis continues throughout life in the hippocampus. To study postnatal neurogenesis in vitro, hippocampal slices from rats on postnatal day 5 (P5) were cultured on a porous membrane for 14 or 21 days. In the initial experiments, precursor cells were labeled with bromodeoxyuridine (BrdU) after 7 days in culture because hippocampal slices are generally used in experiments after 1-2 weeks in culture. Fourteen days after labeling, however, only about 10% of BrdU-labeled cells expressed neuronal markers, although in living rats, about 80% of cells labeled with BrdU on P5 had become neurons by P19. Next, rats were injected with BrdU 30 min before culture, after which hippocampal slices were cultured for 14 days to examine the capacity of in vivo-labeled neural precursors to differentiate into neurons in vitro. In this case, more than two-thirds of BrdU-labeled cells expressed neuronal markers, such as Hu, NeuN, and PSA-NCAM. Furthermore, precursor cells underwent early in vitro labeling by incubation with BrdU or a modified retrovirus vector carrying EGFP for 30 min from the beginning of the culture. This procedure resulted in a similar high rate of neuronal differentiation and normal development into granule cells. In addition, time-lapse imaging with retrovirus-EGFP revealed migration of neural precursors from the hilus to the granule cell layer. These results indicate that in vivo- and early in vitro-labeled cultures are readily available ex vivo models for studying postnatal neurogenesis and suggest that the capacity of neural precursors to differentiate into neurons is reduced during the culture period.     

Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats

Objective To explore the effects of exercise on dentate gyrus (DG) neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrahippocampal microinjection of kainic acid (KA). Bromodeoxyuridine (BrdU) was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity: lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number (EN) in Y maze test, while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.     

Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats

Objective To explore the effects of exercise on dentate gyrus （DG） neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrabippocampal microinjection of kainic acid （KA）. Bromodeoxyuridine （BrdU） was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity： lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number （EN） in Y maze test, while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.     

Seizure severity‐dependent selective vulnerability of the granule cell layer and aberrant neurogenesis in the rat hippocampus

The pilocarpine‐induced status epilepticus rodent model has been commonly used to analyze the mechanisms of human temporal lobe epilepsy. Recent studies using this model have demonstrated that epileptic seizures lead to increased adult neurogenesis of the dentate granule cells, and cause abnormal cellular organization in dentate neuronal circuits. In this study, we examined these structural changes in rats with seizures of varying severity. In rats with frequent severe seizures, we found a clear loss of Prox1 and NeuN expression in the dentate granule cell layer (GCL), which was confined mainly to the suprapyramidal blade of the GCL at the septal and middle regions of the septotemporal axis of the hippocampus. In the damaged suprapyramidal region, the number of immature neurons in the subgranular zone was markedly reduced. In contrast, in rats with less frequent severe seizures, there was almost no loss of Prox1 and NeuN expression, and the number of immature neurons was increased. In rats with no or slight loss of Prox1 expression in the GCL, ectopic immature neurons were detected in the molecular layer of the suprapyramidal blade in addition to the hilus, and formed chainlike aggregated structures along the blood vessels up to the hippocampal fissure, suggesting that newly generated neurons migrate at least partially along blood vessels to the hippocampal fissure. These results suggest that seizures of different severity cause different effects on GCL damage, neurogenesis, and the migration of new neurons, and that these structural changes are selective to subdivisions of the GCL and the septotemporal axis of the hippocampus.     

Influence of superior cervical ganglionectomy on hippocampal neurogenesis and learning and memory in adult rats

BACKGROUND： Studies have shown that neurogenesis in the dentate gyrus plays an important role in learning and memory. However, studies have not determined whether the superior cervical ganglion or the sympathetic nerve system influences hippocampal neurogenesis or learning and memory in adult rats. OBJECTIVE： To observe differences in dentate gyrus neurogenesis, as well as learning and memory, in adult rats following superior cervical ganglionectomy. DESIGN, TIME AND SETTING： A randomized, controlled, animal study was performed at the Immunohistochemistry Laboratory of the School of Life Sciences in Lanzhou University from July 2006 to July 2007. MATERIALS： Doublecortin polyclonal antibody was provided by Santa Cruz Biotechnology, USA; avidin-biotin-peroxidase complex was purchased from Zhongshan Goldenbride Biotechnology, China; Morris water maze was bought from Taimeng Technology, China. METHODS： A total of 20 adult, male, Wistar rats were randomly divided into surgery and control groups, with 10 rats in each group. In the surgery group, the bilateral superior cervical ganglions were transected. In the control group, the superior cervical ganglions were only exposed, but no ganglionectomy was performed. MAIN OUTCOME MEASURES： To examine distribution, morphology, and number of newborn neurons in the dentate gyrus using doublecortin immunohistochemistry at 36 days following surgical procedures. To examine ability of learning and memory in adult rats using the Morris water maze at 30 days following surgical procedures. RESULTS： Doublecortin immunohistochemical results showed that a reduction in the number of doublecortin-positive neurons in the surgery group compared to the control group （P 〈 0.05）, while the distribution of doublecortin-positive neurons was identical in the two groups. The surgery group exhibited significantly worse performance in learning and spatial memory tasks compared to the control group （P 〈 0.05）. CONCLUSION： Superior cervical ganglienectomy inhibited neurogenesis in the dentate gyrus and decreased learning and memory abilities in adult rats.     

Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods

Methacrylate-embedded sections and short-survival thymidine radiograms of the hippocampal dentate gyrus were examined in perinatal and postnatal rats in order to trace the site of origin and migration of the precursors of granule cells and study the morphogenesis of the granular layer. The densely packed, spindle-shaped cells of the secondary dentate matrix (a derivative of the primary dentate neuroepithelium) stream in a subpial position towards the granular layer of the internal dentate limb during the perinatal and early postnatal periods. By an accretionary process, the crest of the granular layer forms on day E21 and on the subsequent days the granular layer of the internal dentate limb expands progressively in a lateral direction. Granule cells differentiation, as judged by the transformation of polymorph, darkly staining small cells into rounder, lightly staining larger granule cells, follows the same gradient from the external dentate limb to the internal dentate limb. The secondary dentate matrix is in a process of dissolution by day P5. This matrix is the source of what will later become the outer shell of the granular layer composed of early generated granule cells. The thicker inner shell of the granular layer, formed during the infantile and juvenile periods, derives from an intrinsic, tertiary germinal matrix. On day E22, the dentate migration of the secondary dentate matrix becomes partitioned into two components: a) the subpial component of extradentate origin, referred to in this context as the first dentate migration, and b) the second dentate migration. The latter is distributed in the basal polymorph layer throughout the entire dentate gyrus and is henceforth recognized as the tertiary dentate matrix. The tertiary dentate matrix is prominent between days P3 and P10. It is postulated that the great increase in granule cell population during the infantile period is principally due to cells derived from this intrinsic matrix of the dentate gyrus. Between days P20 and P30 the tertiary dentate matrix disappears in the basal polymorph layer and henceforth proliferative cells become largely confined to the subgranular zone at the base of the granular layer. The subgranular zone is the source of granule cells produced during the juvenile and adult periods.     

Consolidation of memory for odour-reward association requires transient polysialylation of the neural cell adhesion molecule in the rat hippocampal dentate gyrus

Cell adhesion molecule function is involved in hippocampal synaptic plasticity and is associated with memory consolidation. At the infragranular zone of the dentate gyrus, neurons expressing the polysialylated form of the neural cell adhesion molecule (NCAM PSA) transiently increase their frequency at the 12-hr posttraining time in behaviours elicited by stressful stimuli, such as those associated with conditioned avoidance, water maze, and fear conditioning paradigms. To determine whether learning-induced modulation of NCAM polysialylation is limited to stressful paradigms, we employed a reward-based odour discrimination task. Animals show a rapid acquisition and recall of this task in terms of latency to identify the food-associated odour and the number of choice errors. Immunohistochemical procedures were employed to determine the change in NCAM PSA expression following task acquisition. NCAM PSA immunoreactivity in the hippocampal formation was most intense on the granule-like neurons in the infragranular zone of the dentate gyrus, and their frequency transiently increased in the 12-hr posttraining period. The nature of the transient increase in NCAM PSA-immunoreactive neurons was indistinguishable from that observed following avoidance conditioning or spatial learning, in that it occurred at the same time. The transient increase in NCAM PSA expression is suggested to facilitate dendritic elaboration in response to the acquisition of novel behavioural repertoires.     

The effects of running and of inhibiting adult neurogenesis on learning and memory in rats

The presence of ongoing adult neurogenesis within the highly plastic hippocampal circuitry poses questions as to the relevance of new neurons to learning and memory. Correlational and causal evidence suggests that some, but not all, hippocampal tasks involve the new neurons. The evidence with regard to spatial learning in the water maze, one of the most commonly used hippocampal tasks, is contradictory. In this study we examined the effects of irradiation-induced reduction in neurogenesis on spatial learning and another standard hippocampal task, contextual fear conditioning, in rats that experienced normal cage conditions or voluntary running. The results indicate that reduced neurogenesis had little effect on spatial learning but severely impaired contextual fear conditioning. It was suggested that compensatory mechanisms within the hippocampus may have contributed selectively to sparing of spatial function. Performance on the fear conditioning task was weakly related to enhanced neurogenesis or running. The results improve our understanding of the functional role of adult neurogenesis in behaving animals.     

Sleep deprivation suppresses neurogenesis in the adult hippocampus of rats

We reported previously that 96 h of sleep deprivation (SD) reduced cell proliferation in the dentate gyrus (DG) of the hippocampus in adult rats. We now report that SD reduces the number of new cells expressing a mature neuronal marker, neuronal nuclear antigen (NeuN). Rats were sleep-deprived for 96 h, using an intermittent treadmill system. Total sleep time was reduced to 6.9% by this method in SD animals, but total treadmill movement was equated in SD and treadmill control (CT) groups. Rats were allowed to survive for 3 weeks after 5-bromo-2-deoxyuridine (BrdU) injection. The phenotype of BrdU-positive cells in the DG was assessed by immunofluorescence and confocal microscopy. After 3 weeks the number of BrdU-positive cells was reduced by 39.6% in the SD group compared with the CT. The percentage of cells that co-localized BrdU and NeuN was also lower in the SD group (SD: 46.6 +/- 1.8% vs. CT: 71.9 +/- 2.1, P < 0.001). The percentages of BrdU-labeled cells co-expressing markers of immature neuronal (DCX) or glial (S100-beta) cells were not different in SD and CT groups. Thus, SD reduces neurogenesis in the DG by affecting both total proliferation and the percentage of cells expressing a mature neuronal phenotype. We hypothesize that sleep provides anabolic or signaling support for proliferation and cell fate determination.     

Characterization of the neurogenesis quiescent zone in the rodent brain: Effects of age and exercise

Although it is accepted that new neurons continue to be generated in the hippocampal dentate gyrus (DG) throughout adulthood, it has recently become apparent that this process is not homogeneous, and that a small region of the DG lacks neurogenesis. Here, we show that the relative area of this neurogenesis quiescent zone (NQZ) did not vary after the peak in hippocampal postnatal neurogenesis and until animals reached adulthood, although the ratio between its actual volume and the total volume of the DG doubled during this time. However, we were able to identify a few mitotic cells that reside within this subregion in early adolescent rats. Furthermore, these cells can be activated, and 1 week of voluntary exercise was enough to significantly increase the number of mitotic cells within the NQZ of adolescent rats. There was, however, no corresponding increase in the number of new neurons in this subregion of the DG, suggesting that some factor necessary to allow these cells to develop into a mature phenotype is missing. Moreover, the same intervention was ineffective in increasing either proliferation or neurogenesis in older adult rats. Surprisingly, we found no evidence for the existence of an NQZ in the mouse DG, suggesting that the neurogenic process in these two rodent species is differently regulated. Understanding the molecular mechanisms underlying the existence of the NQZ in the rat DG might shed light on the processes that regulate adult neurogenesis and its modulation by factors such as aging and exercise.     

Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

Environmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long‐term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long‐term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long‐term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum, Lieberman, Briner, Leonardo, & Dranovsky, 2014 ), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.     

Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat,promotes survival of newly formed neurons and prevents corticosterone-induced suppression

Treating adult male rats with subcutaneous pellets of dehydroepiandrosterone (DHEA) increased the number of newly formed cells in the dentate gyrus of the hippocampus, and also antagonized the suppressive of corticosterone (40 mg/kg body weight daily for 5 days). Neither pregnenolone (40 mg/kg/day), a precursor of DHEA, nor androstenediol (40 mg/kg/day), a major metabolite, replicated the effect of DHEA (40 mg/kg/day). Corticosterone reduced the number of cells labelled with a marker for neurons (NeuN) following a 28-day survival period, and this was also prevented by DHEA. DHEA by itself increased the number of newly formed neurons, but only if treatment was continued throughout the period of survival. Subcutaneous DHEA pellets stimulated neurogenesis in a small number of older rats ( approximately 12 months old). These results show that DHEA, a steroid prominent in the blood and cerebral environment of humans, but which decreases markedly with age and during major depressive disorder, regulates neurogenesis in the hippocampus and modulates the inhibitory effect of increased corticoids on both the formation of new neurons and their survival.     

Adrenalectomy-induced granule cell degeneration in the hippocampus causes spatial memory deficits that are not reversed by chronic treatment with corticosterone or fluoxetine

Long-term adrenalectomy (ADX) causes a nearly complete and selective loss of granule cells in the dentate gyrus (DG) of the hippocampus. Previously, learning and memory deficits have been observed following ADX-induced granule cell degeneration for tasks that require the hippocampus. Our objective here was to determine whether corticosterone (CORT) replacement and treatment with the neurogenic compound fluoxetine could reverse behavioral deficits after ADX. We trained ADX and control rats in a moving, hidden platform version of the Morris water task before chronic administration (6 weeks) of CORT and either fluoxetine or vehicle. After treatment, all rats were retested in the Morris water task. Brains were labeled for the endogenous neurogenic markers Ki67 and doublecortin. Here we provide evidence that neurogenesis persists at a normal rate in the hippocampus after long-term ADX. After 8 weeks of CORT and fluoxetine administration, ADX-fluoxetine rats did not differ significantly compared to ADX-vehicle rats receiving CORT or compared to control rats in the number of Ki67 or doublecortin labeled cells. ADX-fluoxetine rats also did not significantly differ from ADX-vehicle rats in regards to granule cell layer thickness. Our results indicate that long-term ADX is associated with impaired spatial ability in the Morris water task and that neither chronic treatment with CORT, nor with CORT and fluoxetine are capable of altering the Morris water task deficit.     

Adult neurogenesis alters response to an aversive distractor in a labyrinth maze without affecting spatial learning or memory

Adult neurogenesis has been implicated in learning and memory of complex spatial environments. However, new neurons also play a role in nonmnemonic behavior, including the stress response and attention shifting. Many commonly used spatial tasks are very simple, and unsuitable for detecting neurogenesis effects, or are aversively motivated, making it difficult to dissociate effects on spatial learning and memory from effects on stress. We have therefore created a novel complex spatial environment, the flex maze, to enable reward‐mediated testing of spatial learning in a flexibly configurable labyrinth. Using a pharmacogenetic method to completely inhibit neurogenesis in adulthood, we found that rats lacking new neurons (TK rats) and wild type controls completed and remembered most mazes equally well. However, control rats were slower to complete peppermint‐scented mazes than other mazes, while neurogenesis‐deficient rats showed no effect of mint on maze behavior, completing these mazes significantly faster than control rats. Additional testing found that wild type and TK rats showed similar detection of, avoidance of, and glucocorticoid response to the mint odor. These results suggest that spatial learning and memory in a labyrinth task is unaffected by the loss of new neurons, but that these cells affect the ability of an aversive stimulus to distract rats from completing the maze.     

Attractive action of FGF‐signaling contributes to the postnatal developing hippocampus

During brain development neural cell migration is a crucial, well‐orchestrated, process, which leads to the proper whole brain structural organization. As development proceeds, new neurons are continuously produced, and this protracted neurogenesis is maintained throughout life in specialized germinative areas inside the telencephalon: the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. In the anterior SVZ, newly generated neurons migrate through long distances, along the rostral migratory stream (RMS), before reaching their final destinations in the olfactory bulb (OB). Intriguingly, recent observations pointed out the existence of other postnatal tangential routes of migration alternative to the RMS but still starting from the SVZ. The presence of such dynamic and heterogeneous cell movements contributes to important features in the postnatal brain such as neural cell replacement and plasticity in cortical regions. In this work, we asked whether a caudal migratory pathway starting from the caudal SVZ continues through life. Strikingly, in vivo analysis of this caudal migration revealed the presence of a postnatal contribution of SVZ to the hippocampus. In vitro studies of the caudal migratory stream revealed the role of FGF signaling in attracting caudally the migrating neuroblasts during postnatal stages. Our findings demonstrate a postnatal neuronal contribution from the caudal ganglionic eminence (CGE) CGE‐SVZ to the hippocampus through an FGF‐dependent migrating mechanism. All together our data emphasizes the emerging idea that a developmental program is still operating in discrete domains of the postnatal brain and may contribute to the regulation of neural cell replacement processes in physiological plasticity and/or pathological circumstances. © 2014 Wiley Periodicals, Inc.     

Identification of a sustained neurogenic zone at the dorsal surface of the adult mouse hippocampus and its regulation by the chemokine SDF‐1

We identified a previously unknown neurogenic region at the dorsal surface of the hippocampus; (the “subhippocampal zone,” SHZ) in the adult brain. Using a reporter mouse in which SHZ cells and their progeny could be traced through the expression of EGFP under the control of the CXCR4 chemokine receptor promoter we observed the presence of a pool of EGFP expressing cells migrating in direction of the dentate gyrus (DG), which is maintained throughout adulthood. This population appeared to originate from the SHZ where cells entered a caudal migratory stream (aCMS) that included the fimbria, the meninges and the DG. Deletion of CXCR4 from neural stem cells (NSCs) or neuroinflammation resulted in the appearance of neurons in the DG, which were the result of migration of NSCs from the SHZ. Some of these neurons were ectopically placed. Our observations indicate that the SHZ is a neurogenic zone in the adult brain through migration of NSCs in the aCMS. Regulation of CXCR4 signaling in these cells may be involved in repair of the DG and may also give rise to ectopic granule cells in the DG in the context of neuropathology. © 2015 Wiley Periodicals, Inc.     

Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats

Objectives –  Adult neurogenesis in dentate gyrus (DG) is an evolutionarily preserved trait in most mammals examined thus far. Neuronal proliferation and subsequent integration of new neurons into the hippocampal circuit are regulated processes that can have profound effects on an animal's behaviour. A streptozotocin model of type I diabetes, characterized by low insulin and high plasma glucose levels, affects not only body's overall metabolism but also brain activity.
Materials and methods –  Neurogenesis was measured within the DG of the hippocampus using immunohistochemical markers Ki67, Doublecortin, Calbindin (CaBP) and bromodeoxyuridine (BrdU).
Results –  Cell proliferation, measured with the endogenous marker Ki67, was reduced by 45%, and cell survival, measured with BrdU, was reduced by 64% of the control. Combined effects on proliferation and survival produced dramatically lower neuronal production. Among the surviving cells only 33% matured normally as judged by the co-labelling of BrdU and CaBP.
Conclusion –  Such a reduction lowered the number of surviving cells with neuronal phenotype by over 80% of the control values and this is expected to cause a significant functional impairment of learning and memory in diabetic animals. These results may shed light on causes of diabetic neuropathology and provide an explanation for the memory deficiencies seen in some diabetic patients.     

Blunted neurogenesis and gliosis due to transgenic overexpression of human soluble IL-1ra in the mouse

Interleukin-1 (IL-1) is one of the most important cytokines in neuroinflammation, in acute conditions as well as during natural ageing and neurodegenerative disorders. Using a transgenic mouse strain with brain-directed overexpression of IL-1 receptor antagonist (Tg hsIL-1ra), we show that blocking IL-1 receptor-mediated activity resulted in abolishing the alterations in neurogenesis in response to acute and chronic neuroinflammation. In addition, using a novel approach to quantifying glial activation, we show that expression of the astrocyte cytoskeletal marker glial fibrillary acidic protein (GFAP) following kainic acid (KA)-induced seizures or during ageing did not change in Tg hsIL-1ra animals. Nevertheless, the astrocyte morphology showed major alterations, consisting of fragmentation of the processes in Tg hsIL-1ra mice. Similarly, although there was a higher degree of basal microglial activation in the transgenic mice than wild-type animals, there was no change following KA-induced seizures or with ageing. Taken together, our results indicate that IL-1 is crucial for the adaptability of the brain to acute and chronic neuroinflammation.