Neurogenesis In Subgranular Zone Research Articles

Thyroxine restores hippocampal neurogenesis and synaptogenesis in a male rat model of carbimazole-induced hypothyroidism: a histological study

BackgroundAdult-onset hypothyroidism has a deleterious effect on hippocampal cognitive and memory functions. This study was performed to evaluate the possible therapeutic effect of thyroxine on hippocampus degeneration in an adult male rat model of carbimazole-induced hypothyroidism and the potentiality of spontaneous recovery. Thirty-two adult male albino rats were divided equally into four groups, as follows: I (control group), II (hypothyroidism group) received carbimazole (20 mg/kg) orally once daily for 4 weeks; III (recovery group) rats were managed as in group II, then left untreated for an additional 4 weeks to assess spontaneous recovery; and IV (thyroxine-treated group): hypothyroidism was induced as in group II, then rats received levothyroxine (20 µg/kg/day) orally for 4 weeks. Rats and their corresponding controls were sacrificed after 4 weeks in group II and after 8 weeks in groups III and IV. The levels of T3, T4, and TSH were measured. Hematoxylin and Eosin staining of thyroid and hippocampal sections was performed. Additionally, toluidine blue staining and immunohistochemical staining for PCNA, GFAP, and synaptophysin were applied to hippocampus sections. Both morphometric measurements and statistical analysis were performed.ResultsComparison of thyroxine-treated group with hypothyroidism and recovery groups revealed a significant reduction in TSH level and an increase in T3 and T4 levels, as well as improved histological architecture in both the thyroid and hippocampal sections. Hippocampal sections revealed a significant decrease in the mean area percent of GFAP, a significant increase in the mean number of PCNA-positive cells in the subgranular zone (SGZ); a niche for the adult neural stem cells (NSCs) in the hippocampus; and a significant increase in the mean area percent as well as the mean optical density of synaptophysin.ConclusionHippocampal degeneration is induced by hypothyroidism and can be restored by thyroxine replacement therapy, probably through neuronal cell preservation, synaptogenesis, and stimulation of neurogenesis in SGZ. On the other hand, spontaneous recovery from this degeneration was inadequate.

Impaired neurogenesis with reactive astrocytosis in the hippocampus in a porcine model of acquired hydrocephalus

BackgroundHydrocephalus is a neurological disease with an incidence of 0.3–0.7 per 1000 live births in the United States. Ventriculomegaly, periventricular white matter alterations, inflammation, and gliosis are among the neuropathologies associated with this disease. We hypothesized that hippocampus structure and subgranular zone neurogenesis are altered in untreated hydrocephalus and correlate with recognition memory deficits. MethodsHydrocephalus was induced by intracisternal kaolin injections in domestic juvenile pigs (43.6 ± 9.8 days). Age-matched sham controls received similar saline injections. MRI was performed to measure ventricular volume, and/or hippocampal and perirhinal sizes at 14 ± 4 days and 36 ± 8 days post-induction. Recognition memory was assessed one week before and after kaolin induction. Histology and immunohistochemistry in the hippocampus were performed at sacrifice. ResultsThe hippocampal width and the perirhinal cortex thickness were decreased (p < 0.05) in hydrocephalic pigs 14 ± 4 days post-induction. At sacrifice (36 ± 8 days post-induction), significant expansion of the cerebral ventricles was detected (p = 0.005) in hydrocephalic pigs compared with sham controls. The area of the dorsal hippocampus exhibited a reduction (p = 0.035) of 23.4% in the hydrocephalic pigs at sacrifice. Likewise, in hydrocephalic pigs, the percentages of neuronal precursor cells (doublecortin+ cells) and neurons decreased (p < 0.01) by 32.35%, and 19.74%, respectively, in the subgranular zone of the dorsal hippocampus. The percentage of reactive astrocytes (vimentin+) was increased (p = 0.041) by 48.7%. In contrast, microglial cells were found to decrease (p = 0.014) by 55.74% in the dorsal hippocampus in hydrocephalic pigs. There was no difference in the recognition index, a summative measure of learning and memory, one week before and after the induction of hydrocephalus. ConclusionIn untreated juvenile pigs, acquired hydrocephalus caused morphological alterations, reduced neurogenesis, and increased reactive astrocytosis in the hippocampus and perirhinal cortex.

Adult human neurogenesis: early studies clarify recent controversies and go further.

Evidence on adult mammalian neurogenesis and scarce studies with human brains led to the idea that adult human neurogenesis occurs in the subgranular zone (SGZ) of the dentate gyrus and in the subventricular zone (SVZ). However, findings published from 2018 rekindled controversies on adult human SGZ neurogenesis. We systematically reviewed studies published during the first decade of characterization of adult human neurogenesis (1994-2004) - when the two-neurogenic-niche concept in humans was consolidated - and compared with further studies. The synthesis of both periods is that adult human neurogenesis occurs in an intensity ranging from practically zero to a level comparable to adult mammalian neurogenesis in general, which is the prevailing conclusion. Nonetheless, Bernier and colleagues showed in 2000 intriguing indications of adult human neurogenesis in a broad area including the limbic system. Likewise, we later showed evidence that limbic and hypothalamic structures surrounding the circumventricular organs form a continuous zone expressing neurogenesis markers encompassing the SGZ and SVZ. The conclusion is that publications from 2018 on adult human neurogenesis did not bring novel findings on location of neurogenic niches. Rather, we expect that the search of neurogenesis beyond the canonical adult mammalian neurogenic niches will confirm our indications that adult human neurogenesis is orchestrated in a broad brain area. We predict that this approach may, for example, clarify that human hippocampal neurogenesis occurs mostly in the CA1-subiculum zone and that the previously identified human rostral migratory stream arising from the SVZ is indeed the column of the fornix expressing neurogenesis markers.

Post-stroke Neurogenesis: Friend or Foe?

The substantial clinical burden and disability after stroke injury urges the need to explore therapeutic solutions. Recent compelling evidence supports that neurogenesis persists in the adult mammalian brain and is amenable to regulation in both physiological and pathological situations. Its ability to generate new neurons implies a potential to contribute to recovery after brain injury. However, post-stroke neurogenic response may have different functional consequences. On the one hand, the capacity of newborn neurons to replenish the damaged tissue may be limited. In addition, aberrant forms of neurogenesis have been identified in several insult settings. All these data suggest that adult neurogenesis is at a crossroads between the physiological and the pathological regulation of the neurological function in the injured central nervous system (CNS). Given the complexity of the CNS together with its interaction with the periphery, we ultimately lack in-depth understanding of the key cell types, cell–cell interactions, and molecular pathways involved in the neurogenic response after brain damage and their positive or otherwise deleterious impact. Here we will review the evidence on the stroke-induced neurogenic response and on its potential repercussions on functional outcome. First, we will briefly describe subventricular zone (SVZ) neurogenesis after stroke beside the main evidence supporting its positive role on functional restoration after stroke. Then, we will focus on hippocampal subgranular zone (SGZ) neurogenesis due to the relevance of hippocampus in cognitive functions; we will outline compelling evidence that supports that, after stroke, SGZ neurogenesis may adopt a maladaptive plasticity response further contributing to the development of post-stroke cognitive impairment and dementia. Finally, we will discuss the therapeutic potential of specific steps in the neurogenic cascade that might ameliorate brain malfunctioning and the development of post-stroke cognitive impairment in the chronic phase.

Neurogenesis and Oligodendrogenesis in a Mouse Model of Blast-Induced Traumatic Brain Injury

Neurological manifestations of blast-induced Post Traumatic Stress Disorder (PTSD) extend long after the initial injury indicating lasting changes in brain function. In this study, we characterized brain injury, changes in neurogenesis and oligodendrogenesis in an adult murine blast model following a short (5 days) and long (21 days) post-blast recovery. Acoustic blasts led to an initial, activation of microglia and astrogliosis and a widespread cortical and subcortical apoptosis. The loss of myelinated cortical axons at 5 days was followed by the reappearance of abnormal misdirected fibers at 21 days. At 21 days post-blast, we observed increases in doublecortin-positive (DCX+ ) neuroblasts in the subventricular zone (SVZ) and hippocampal subgranular zone (SGZ) indicating increased neurogenesis. No changes in DCX+ cells were found in the brain cortex. In the cortex, the early disappearance of myelinated neuronal fibers was accompanied by a loss of O4+ oligodendrocytes and their Ki67-expreasing (Ki67+ ) oligodendrocyte precursor cells (OPC). However, at 5 days we observed a robust appearance of cells expressing Olig2 (O2+ ), an early determinant of oligodendrocyte lineage. At 21 days post-blast, the population of OPC increased and the mature O4+ oligodendrocytes were restored to control levels. In contrast, in the SVZ and SGZ, O4+ cells were not affected by the blast suggesting a local cortical origin for cortical oligodendrogenesis. These results suggest that blast-induced activation of SVZ and SGZ neurogenesis and cortical oligodendrogenesis could have long-lasting impact on brain function including memory disorders observed in both animal models and human’s PTSD.

Immunoexpression of c-Kit in the Mice Hippocampal Subgranular Zone, a Possible Role of Hematopoietic Stem Cells in the Subgranular Zone Neurogenesis

Mammalian hippocampus hosts neural stem cells in the subgranular zone. Here, the neural stem cells are the source of neurogenesis, that happens throughout the lifetime. However, studies show that undifferentiated cells from varied lineage also shape the environment. In the present study, the expression of c-Kit, a marker for hematopoietic stem cells was studied in the mice hippocampal subgranular zone. Immunohistochemistry and reverse transcription-polymerase chain reaction were performed on 12 week-old mice hippocampal tissues. The data shows that c-Kit is present in the mice hippocampus and in the subgranular zone. Therefore, suggesting a possible role of hematopoietic stem cells in the subgranular zone neurogenesis.

Nippostrongylus brasiliensis infection inhibits hippocampal neurogenesis in mice.

The brain has long been considered a site of "immune privilege"; however, recent evidence indicates the presence of brain-immune interactions in physiological and pathological conditions. Neurogenesis, a process of generating functionally integrated neurons, occurs in the adult brain of mammals. The adult neurogenesis predominantly takes place in the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ). Several studies have shown that an immune reaction or alteration could affect adult neurogenesis activity, suggesting a link between the immune system and adult neurogenesis. Helminth infection is one of the activators of Th2 immune response. However, the influence of this type of immune reaction on adult neurogenesis is not well studied. In this study, we evaluated adult neurogenesis in mice infected with the helminth Nippostrongylus brasiliensis (Nb). Immunohistochemically, the number of both doublecortin-positive cells and doublecortin/5-bromodeoxyuridine (BrdU)-double-positive cells was decreased in the SGZ of Nb-infected mice by day 9 after infection. However, the total number of BrdU-positive newborn cells in the SGZ did not change. In no significant alterations were detected in the SVZ of infected mice. In addition, using reverse transcription-quantitative polymerase chain reaction, we observed no significant changes in the expression levels of neurotropic factors important for neurogenesis in the hippocampus. In conclusion, our results indicate that adult neurogenesis in SGZ, but not in SVZ, is inhibited by Nb infection. Th2 immune response might have a suppressive effect on hippocampal neurogenesis.

BSCI-18. ABLATION OF Csf2 MITIGATES RADIATION-INDUCED NEUROCOGNITIVE DECLINE INDEPENDENT OF HIPPOCAMPAL NEUROGENESIS

PURPOSE: The results of the RTOG 0933 and NRG CC001 clinical trials have shown that physical sparing of the hippocampus during cranial irradiation (CI) is associated with preservation of memory functions at 4- and 6-months following therapy. Whereas the putative roles of protection of neural stem cells (NSCs) residing within the subgranular zone (SGZ) of the dentate gyrus are presently poorly defined, suppression of inflammation may be involved because ablation of microglia (MG) through blockade of the CSF-1R or selective targeting of CCR2+ macrophages using an appropriate CCR2 inhibitor leads to the retention of hippocampal-dependent cognitive abilities following CI. Inhibition of Colony stimulating factor 2 (CSF-2), a proinflammatory cytokine causing the proliferation and activation of microglia, may be a suitable alternative strategy to alleviate inflammation. METHODS: Our studies have evaluated the effects of ablation of Csf2 and also the inducible ablation of MG on the properties of neuroinflammation, neurogenesis and CI-associated cognitive impairments employing the requisite mouse models. RESULTS: We demonstrate that preservation of cognitive functions following CI does not require ablation of MG. In addition, the reduction in neuroinflammation following Csf2ablation was sufficient to prevent CI-induced cognitive decline. Moreover, Csf2 ablation did not prevent the deficit in neurogenesis, thereby suggesting that NSC-mediated SGZ neurogenesis is not required for the prevention of radiation-induced cognitive dysfunction. CONCLUSION: We have previously shown that MG play seminal roles in neural development and adult homeostasis and plasticity. Our present study demonstrates that selective modulation of MG-associated neuroinflammatory signaling without MG ablation is a novel therapeutic strategy to preserve cognitive functions following CI. These experimental observations have seminal implications for patients undergoing radiation therapy for tumors of the brain or head and neck in which the hippocampus inevitably exposed to a high dose of radiation leading to potentially debilitating and possibly avoidable cognitive deficits.

Histone Deacetylase Inhibitor Alleviates the Neurodegenerative Phenotypes and Histone Dysregulation in Presenilins-Deficient Mice.

Histone acetylation has been shown to play a crucial role in memory formation, and histone deacetylase (HDAC) inhibitor sodium butyrate (NaB) has been demonstrated to improve memory performance and rescue the neurodegeneration of several Alzheimer’s Disease (AD) mouse models. The forebrain presenilin-1 and presenilin-2 conditional double knockout (cDKO) mice showed memory impairment, forebrain degeneration, tau hyperphosphorylation and inflammation that closely mimics AD-like phenotypes. In this article, we have investigated the effects of systemic administration of NaB on neurodegenerative phenotypes in cDKO mice. We found that chronic NaB treatment significantly restored contextual memory but did not alter cued memory in cDKO mice while such an effect was not permanent after treatment withdrawal. We further revealed that NaB treatment did not rescue reduced synaptic numbers and cortical shrinkage in cDKO mice, but significantly increased the neurogenesis in subgranular zone of dentate gyrus (DG). We also observed that tau hyperphosphorylation and inflammation related protein glial fibrillary acidic protein (GFAP) level were decreased in cDKO mice by NaB. Furthermore, GO and pathway analysis for the RNA-Seq data demonstrated that NaB treatment induced enrichment of transcripts associated with inflammation/immune processes and cytokine-cytokine receptor interactions. RT-PCR confirmed that NaB treatment inhibited the expression of inflammation related genes such as S100a9 and Ccl4 found upregulated in the brain of cDKO mice. Surprisingly, the level of brain histone acetylation in cDKO mice was dramatically increased and was decreased by the administration of NaB, which may reflect dysregulation of histone acetylation underlying memory impairment in cDKO mice. These results shed some lights on the possible molecular mechanisms of HDAC inhibitor in alleviating the neurodegenerative phenotypes of cDKO mice and provide a promising target for treating AD.

Radioprotective effect of ursolic acid in radiation-induced impairment of neurogenesis, learning and memory in adolescent BALB/c mouse

The effect of acute irradiation with 5Gy or fractionated exposure with 0.5Gy continuously for 10days (a total dose of 5Gy) was evaluated in an immature BALB/c mouse model. Radioprotective effect of ursolic acid (at 25mg/kg/daily administered 1h after acute or each of fractionated irradiations, and continuously for 30days) was also investigated. We found that both acute and fractionated irradiation at a total dose of 5Gy did not induce any mortality within 30days after exposure to postnatal day 26 (P26) BALB/c mice, but reduced animal weigh gain in the first few weeks. At 90days after irradiation, the weight of animals with acute irradiation was still significantly lower than the control group; no significant difference though was observed for those fractionatedly exposed mice compared to the control group. Behavioral tests indicated that acute irradiation at 5Gy induced deficits in learning and memory in the contextual fear conditioning test. The memory for novel object recognition was also impaired. Similar changes were not observed in mice with fractionated irradiation. Immunohistochemical study demonstrated clearly that acute and fractionated irradiations induced impairment of neurogenesis in the subgranular zone (SGZ) of the dentate gyrus although fractionated exposure induced much lesser loss of newly generated neurons. Ursolic acid administered at 25mg/kg/daily for 30days after irradiation greatly improved acute irradiation-induced deficits in contextual learning and memory and in novel object recognition memory although it exacerbated radiation-induced reduction of neurogenesis in SGZ.

Absence of neurogenic response following robust predator-induced stress response

Traumatic events contribute to a variety of neuropsychiatric disorders including post-traumatic stress disorder (PTSD). Identifying the neural mechanisms that affect the stress response may improve treatment for stress-related disorders. Neurogenesis, the production of neurons, occurs within the adult brain and disturbances in neurogenesis in the subgranular zone (SGZ) of the hippocampus have been linked to mood and anxiety disorders. Chronic stress models have mainly suggested correlations with stress reducing adult SGZ neurogenesis, whereas acute stress models and those with a naturalistic component that are also associated with long-lasting behavioral changes have produced inconsistent results. Therefore, the goal of the current study was to examine the effects of acute predator stress on adult neurogenesis. Predator stress involved a single 10-min unprotected rat to cat exposure that has previously been shown to produce contextual fear, hyperarousal, and anxiety-like behavior lasting at least 3weeks. As expected, predator stress produced a stress response as detected by elevated corticosterone (CORT) levels immediately after stress. Despite this robust stress response, there was no significant difference between stressed and handled control rats in the number of proliferating or surviving cells as assessed by a 5-bromo-2′-deoxyuridine-immunoreactive (BrdU-IR) labeling 2h or 4weeks post-stress throughout the rostro-caudal axis of the SGZ, respectively. Additionally, 90% of 4-week-old BrdU-IR cells in both conditions expressed NeuN, suggesting no change in cell fate with stress exposure. Overall, these data give caution to the notion that acute predator stress can alter the production or survival of adult-generated cells.

Neurogenesis in the Hippocampus of Patients with Temporal Lobe Epilepsy.

The mobilization of endogenous neural stem cells in order to substitute lost neurons in the adult brain may reduce the negative effects of patients with chronic neurodegenerative diseases. However, abnormal neurogenesis may be harmful and could lead to the worsening of patients' symptoms. In the brains of patients and animal models with temporal lobe epilepsy (TLE), increased newly generated neurons in the subgranular zone (SGZ) at early stages after brain insults have been speculated to be involved in epileptogenesis. However, this argument is unsupported by evidence showing that (1) hippocampal neurogenesis is reduced at chronic stages of intractable TLE, (2) decreased neurogenesis is involved in epileptogenesis, and (3) spontaneous recurrent seizures occur before newly generated neurons are integrated into hippocampal neural pathways. Therefore, the hypothesis of increased neurogenesis in epileptogenesis may need to be re-evaluated. In this paper, we systemically reviewed brain neurogenesis and relevant molecules in the regulation of neurogenesis in SGZ. We aimed to update researchers and epileptologists on current progresses on pathophysiological changes of neurogenesis at different stages of TLE in patients and animal models of TLE. The interactions among neurogenesis, epileptogenesis and cognitive impairment, and molecules' mechanism involved in neurogenesis would also be discussed. Future research directions are proposed at the end of this paper.

NMDA receptor agonists reverse impaired psychomotor and cognitive functions associated with hippocampal Hbegf-deficiency in mice.

BackgroundStructural and functional changes of the hippocampus are correlated with psychiatric disorders and cognitive dysfunctions. Genetic deletion of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is predominantly expressed in cortex and hippocampus, also causes similar psychiatric and cognitive dysfunctions, accompanying down-regulated NMDA receptor signaling. However, little is known of such dysfunctions in hippocampus-specific Hbegf cKO mice.ResultsWe successfully developed hippocampus-specific cKO mice by crossbreeding floxed Hbegf and Gng7-Cre knock-in mice, as Gng7 promoter-driven Cre is highly expressed in hippocampal neurons as well as striatal medium spiny neurons. In mice lacking hippocampus Hbegf gene, there was a decreased neurogenesis in the subgranular zone (SGZ) of the dentate gyrus as well as down-regulation of PSD-95/NMDA-receptor-NR1/NR2B subunits and related NMDA receptor signaling. Psychiatric, social-behavioral and cognitive abnormalities were also observed in hippocampal cKO mice. Interestingly, D-cycloserine and nefiracetam, positive allosteric modulators (PAMs) of NMDA receptor reversed the apparent reduction in NMDA receptor signaling and most behavioral abnormalities. Furthermore, decreased SGZ neurogenesis in hippocampal cKO mice was reversed by nefiracetam.ConclusionsThe present study demonstrates that PAMs of NMDA receptor have pharmacotherapeutic potentials to reverse down-regulated NMDA receptor signaling, neuro-socio-cognitive abnormalities and decreased neurogenesis in hippocampal cKO mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0176-0) contains supplementary material, which is available to authorized users.

Physical activity ameliorates neuron loss and memory deficits in Tg4-42 mice

N-truncated Aβ4–42 is one of the most abundant Aβ peptide species in the brain of sporadic Alzheimerʼs disease (AD) patients. We have recently developed a transgenic mouse model (Tg4–42) expressing Aβ4–42 without mutations under the control of the neuron-specific Thy1-promotor. These mice develop age-dependent deficits in spatial reference memory accompanied by robust CA1 pyramidal neuron loss. Using an enriched environment paradigm, the impact of enhanced physical activity on hippocampal neuron loss and behavioral deficits was assessed. In this study, Tg4–42 mice were housed under standard conditions or in enriched cages equipped with various objects and running wheels. The number of CA1 pyramidal and dentate gyrus (DG) granule cell layer neurons was assessed using design-based stereological methods. In addition, spatial reference memory using the Morris Water Maze task, as well as neurogenesis in the subgranular zone (SGZ) was analyzed. In addition to CA1 neuron loss, homozygous Tg4–42 at 6 months showed a ~ 45% decrease in SGZ neurogenesis, accompanied by a ~ 20% neuron loss in DG. Housing under enrichment conditions maintained both neurogenesis and granule cell neuron loss, while CA1 neuron loss and spatial reference memory deficits were partially rescued. Amelioration of CA1 neuron loss and working memory deficits could be also shown in 12-month-old hemizygous Tg4–42 animals. We provide evidence that enhanced physical activity due to environmental enrichment leads to an amelioration of neuronal loss and behavioral deficits in a transgenic mouse model reflecting the sporadic form of AD. This might indicate the relevance of increased physical activity as a potential strategy in the prevention of dementia.

Developmental profile of neurogenesis in prenatal human hippocampus: An immunohistochemical study

Hippocampus has attracted the attention of the neuroscientists for its involvement in a wide spectrum of higher-order brain functions and pathological conditions, especially its persistent neurogenesis in subgranular zone (SGZ). The development of hippocampus was intensively investigated on animals such as rodents. However, in prenatal human hippocampus, little information on the distribution of neural stem/progenitor cells, newly generated neurons and mature neurons is available and the timetable of a series of neurogenesis event is even more obscure. So in the present study, we aim at immunohistochemically providing more information on neurogenesis in prenatal human hippocampus from 9 weeks to 32 weeks of gestation. We found that the ki67-positive cells were always detected in hippocampus from 9 weeks to 32 weeks, with a peak at 9 weeks in cornu ammonis (CA) or 14 weeks in dentate gyrus (DG). At 9 weeks the nestin-expressing cells were distributed throughout the hippocampus, with concentrated immunoreactivity in intermediate zone (IZ), marginal zone (MZ), fimbria, and relatively sparse immunoreactivity in the ventricular zone (VZ) and hippocampal plate (HP). With development, the optical density (OD) and the number of nestin-positive cells decreased gradually. At 32 weeks, there were relatively more nestin-positive cells in DG than that in CA. About DCX-positive cells, they displayed a similar distribution as nestin-positive cells (immunoreactivity concentrated in IZ, MZ, fimbria and HP) and a dramatic decrease of OD or cell number density from 9 weeks on. NeuN-positive cells, with small nuclei, were firstly found in MZ and subplate of hippocampus at 9 weeks. After 14 weeks, many NeuN-positive cells extended from subplate into HP and the density of NeuN-positive cells peaked at 22 weeks. That the immunoreactivity for NeuN was the strongest and the nuclei were the biggest at 32 weeks suggests that the neurons reach maturity gradually. Therefore this study provides an important timetable of neurogenesis in prenatal human hippocampus for the clinicians in neuroscience or pediatrics.

Neurogenesis and progenitor cell distribution in the subgranular zone and subventricular zone of the adult sheep brain

Progenitor cell proliferation is ubiquitous in the subventricular zone (SVZ) and subgranular zone (SGZ) of adult mammalian brains, however, the abundance and distribution of proliferation are surprisingly heterogeneous between species. In rodents, proliferation is high in both the SVZ and SGZ, while in humans proliferation is prominent in the SVZ but limited in the SGZ. To accurately study proliferation and how it changes in human disease, we should focus on animals in which the patterns of proliferation are consistent with the human brain. In this study, we characterized the neurogenic niches of the adult sheep, an animal model with a longer lifespan than rodents and a highly gyrencephalic brain, using 5-bromo-2′-deoxyuridine (BrdU) as a mitotic marker and neuronal nuclear antigen to identify neuronal lineage cells. Our study demonstrates that the sheep SVZ is organized into the same distinct layers that are comparable to what has been described in humans. The rate of maturation of new neurons was slower in sheep than in previous reports in rodents, with only 20% of BrdU-positive cells showing neuronal phenotype after 4 months survival following BrdU administration. Most importantly, as in the human, there was much greater proliferation in the sheep SVZ than in the SGZ. These results suggest that the sheep is a better basis for comparisons with human SVZ and SGZ neurogenesis than rodents.

Intrahippocampal injection of Aβ1-42 inhibits neurogenesis and down-regulates IFN-γ and NF-κB expression in hippocampus of adult mouse brain

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by accumulation of amyloid plaques and neurofibrillary tangles. Amyloid-β (Aβ) is widely recognized as a key factor in the pathogenesis of AD. Aβ1-42, a major component of amyloid plaques, has shown synaptotoxicity associated with impaired long-term potentiation and cognitive deficits. Alteration of neurogenesis in AD patients has been reported, while little is known about how Aβ1-42 affects hippocampal neurogenesis in the adult brain. In this study, we injected human Aβ1-42 peptide into hippocampal CA1 area of adult mouse brain bilaterally and evaluated histological change and neurogenesis in the hippocampus. Hematoxylin and eosin (HE) stain showed that Aβ1-42-injection resulted in an extensive neurodegeneration in the Aβ-accumulated area and CA3 in hippocampus. Immunostaining showed that intrahippocampal Aβ1-42-injection dramatically decreased the number of bromodeoxyuridine (BrdU)-positive cells in the dentate gyrus (DG) compared to the vehicle injection. Moreover, a significant decrease in the number of BrdU/double-cortin double-positive cells in Aβ1-42-injected hippocampus was observed, suggesting that Aβ1-42-injection inhibited progenitor cell proliferation and neurogenesis in subgranular zone of the DG in the adult brain. We also found that the Aβ1-42-mediated decline of neurogenesis was associated with decreased protein levels of cytokines interferon-γ (IFN-γ) and transcription factor nuclear factor-kappa B (NF-κB) in the hippocampus. These results suggest that Aβ1-42 inhibits hippocampal neurogenesis in the adult brain possibly through down-regulation of INF-γ and NF-κB signaling pathway. This study provides a new insight into Aβ1-42-mediated decrease in hippocampal neurogenesis in the adult central nervous system.Abbreviations: Aβ, Amyloid-β; AD, Alzheimer’s disease; AβPP (APP), Amyloid β precursor protein; BrdU, Bromodeoxyuridine; CNS, central nervous system; DCX, doublecortin; DG, dentate gyrus; IFN-γ, interferon-γ; NF-κB, nuclear factor-kappa B; NS, normal saline; RT, room temperature; SGZ, subgranular zone; SVZ, subventricular zone.

Minor neuronal damage and recovered cellular proliferation in the hippocampus after continuous unilateral forelimb restraint in normal rats

Constraint-induced movement therapy (CIMT) involves the restraint of an intact limb to force the dominant use of an affected limb, in an attempt to enhance use-dependent plasticity and reduce dysfunction. To investigate whether forced disuse of an intact forelimb with CIMT causes a loss of limb function and degenerative damage in the brain, a staircase test and a horizontal ladder test were carried out in control rats and forelimb-restrained rats, and then Argyrophil III silver staining, which is capable of detecting subtle neuronal damage, was used to examine histological alterations associated with restraint. No significant changes in forelimb function were observed in restrained rats. However, atypical weak argyrophilic neurons, an indicator of minor neural damage, were found in the bilateral hippocampus of restrained rats. This damage was not found in the cortex, striatum, or spinal cord. Investigation of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) revealed a clear reduction in the number of bromodeoxyuridine-positive cells in bilateral SGZ, but not in the SVZ, in restrained rats compared with controls. This reduction was accompanied by reduced mRNA expression of vascular endothelial growth factor and glial-derived neurotrophic factor. However, reduced cellular proliferation and decreased gene expression were recovered after the removal of the restraint. Our results suggest that forced disuse of the intact forelimb has no significant effect on skilled forelimb function but has a minor effect on neurogenesis in SGZ, suggesting that mild stress may be caused by the restraint.

Time course of morphine's effects on adult hippocampal subgranular zone reveals preferential inhibition of cells in S phase of the cell cycle and a subpopulation of immature neurons

Opiates, such as morphine, decrease neurogenesis in the adult hippocampal subgranular zone (SGZ), raising the possibility that decreased neurogenesis contributes to opiate-induced cognitive deficits. However, there is an incomplete understanding of how alterations in cell cycle progression and progenitor maturation contribute to this decrease. The present study examined how morphine regulates progenitor cell cycle, cell death and immature SGZ neurons (experiment 1) as well as the progression of SGZ progenitors through key stages of maturation (experiment 2). In experiment 1, mice received sham or morphine pellets (s.c., 0 and 48 h) and bromodeoxyuridine (BrdU) 2 h prior to sacrifice (24, 72 or 96 h). Morphine decreased both the number of S phase and total cycling cells, as there were fewer cells immunoreactive (IR) for the S phase marker BrdU and the cell cycle marker Ki67. The percentage of Ki67-IR cells that were BrdU-IR was decreased after 24 but not 96 h of morphine, suggesting a disproportionate effect on S phase cells relative to all cycling cells at this time point. Cell death (activated caspase-3 counts) was increased after 24 but not 96 h. In experiment 2, nestin-green fluorescent protein (GFP) mice given BrdU 1 day prior to morphine or sham surgery (0 and 48 h, sacrifice 96 h) had fewer Ki67-IR cells, but no change in BrdU-IR cell number, suggesting that this population of BrdU-IR cells was less sensitive to morphine. Interestingly, examination of key stages of progenitor cell maturation revealed that morphine increased the percent of BrdU-IR cells that were type 2b and decreased the percent that were immature neurons. These data suggest that chronic morphine decreases SGZ neurogenesis by inhibiting dividing cells, particularly those in S phase, and progenitor cell progression to a more mature neuronal stage.

Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies.