Enhancement Of Neurogenesis Research Articles

Multiparity-induced enhancement of hippocampal neurogenesis and spatial memory depends on ovarian hormone status in middle age

Menopause is associated with cognitive decline, and previous parity can increase or delay the trajectory of cognitive aging. Furthermore, parity enables the hippocampus to respond to estrogens in middle age. The present study investigated how previous parity and estrogens influence cognition, neurogenesis, and neuronal activation in response to memory retrieval in the hippocampus of middle-aged females. Multiparous and nulliparous rats were ovariectomized (OVX) or received sham surgery and were treated with vehicle, 17β-estradiol, 17α-estradiol, or estrone. Rats were trained on the spatial working and reference memory versions of the Morris water maze. Multiparous rats had a significantly greater density of immature neurons in the hippocampus, enhanced acquisition of working memory, but poorer reference memory compared with nulliparous rats. Furthermore, OVX increased, while treatment with estrogens reduced, the density of immature neurons, regardless of parity. OVX improved reference memory only in nulliparous rats. Thus, motherhood has long-lasting effects on the neuroplasticity and function of the hippocampus. These findings have wide-ranging implications for the treatment of age-associated decline in women.

Extremely low frequency electromagnetic fields enhance neuronal differentiation of human mesenchymal stem cells on graphene-based substrates

Graphene is a non-cytotoxic and biocompatible material which serves as a powerful platform for cell growth, differentiation, and fate conversion. The unique features of this nanomaterial are exploited in regenerative medicine and tissue engineering as a scaffold for biological tissues. Graphene-based substrates support neuronal differentiation of stem cells and hence can potentially be applied in nerve regeneration. Since the exact differentiation mechanism mediated by graphene substrate is not fully understood, the efficiency of the process remains to be improved. Herein, the extremely low frequency electromagnetic fields (ELF-EMF; 50 Hz, 1 mT) exposure synergistically increased biological efficacy of neuronal differentiation in bone marrow-derived human mesenchymal stem cells (hMSCs) grown on graphene-coated substrate. We show that such enhancement in neurogenesis is achieved by altering global gene expression profile thereby up-regulating cell adhesion through intracellular calcium influx and activated focal adhesion kinase signaling pathway, which is stimulated by extracellular matrix production. Our findings may provide the framework for a useful therapeutic strategy in regenerative medicine.

The neural stem cell fate determinant TRIM32 regulates complex behavioral traits.

In mammals, new neurons are generated throughout the entire lifespan in two restricted areas of the brain, the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ)—olfactory bulb (OB) system. In both regions newborn neurons display unique properties that clearly distinguish them from mature neurons. Enhanced excitability and increased synaptic plasticity enables them to add specific properties to information processing by modulating the existing local circuitry of already established mature neurons. Hippocampal neurogenesis has been suggested to play a role in spatial-navigation learning, spatial memory, and spatial pattern separation. Cumulative evidences implicate that adult-born OB neurons contribute to learning processes and odor memory. We recently demonstrated that the cell fate determinant TRIM32 is upregulated in differentiating neuroblasts of the SVZ-OB system in the adult mouse brain. The absence of TRIM32 leads to increased progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated OB neurons. Here, we present novel data from behavioral studies showing that such an enhancement of OB neurogenesis not necessarily leads to increased olfactory performance but in contrast even results in impaired olfactory capabilities. In addition, we show at the cellular level that TRIM32 protein levels increase during differentiation of neural stem cells (NSCs). At the molecular level, several metabolic intermediates that are connected to glycolysis, glycine, or cysteine metabolism are deregulated in TRIM32 knockout mice brain tissue. These metabolomics pathways are directly or indirectly linked to anxiety or depression like behavior. In summary, our study provides comprehensive data on how the impairment of neurogenesis caused by the loss of the cell fate determinant TRIM32 causes a decrease of olfactory performance as well as a deregulation of metabolomic pathways that are linked to mood disorders.

Microglia regulate hippocampal neurogenesis during chronic neurodegeneration

Microglia regulate hippocampal neurogenesis during chronic neurodegeneration

Fat cell-secreted adiponectin mediates physical exercise-induced hippocampal neurogenesis: an alternative anti-depressive treatment?

Psychological depression is drawing accumulating attention nowadays, due to the skyrocketing incidence worldwide and the enormous burdens it incurs. Physical exercise has been long recognized for its therapeutic effects on depressive disorders, although knowledge of the underlying mechanisms remains limited. Suppressed hippocampal neurogenesis in adult brains has been regarded, at least partly, contributive to depression, whereas physical exercise that restores neurogenesis accordingly exerts the anti-depressive action. Several recent publications have suggested the potential role of adiponectin, a protein hormone secreted by peripheral mature adipocytes, in mediating physical exercise-triggered enhancement of hippocampal neurogenesis and alleviation of depression. Here, we briefly review these novel findings and discuss the possibility of counteracting depression by modulating adiponectin signaling in the hippocampus with interventions including physical exercise and administration of pharmacological agents.

Ghrelin is required for dietary restriction-induced enhancement of hippocampal neurogenesis: lessons from ghrelin knockout mice.

Neurogenesis occurs in the adult hippocampus and is enhanced by dietary restriction (DR), and neurogenesis enhancement is paralleled by circulating ghrelin level enhancement. We have previously reported that ghrelin modulates adult neurogenesis in the hippocampus. In order to investigate the possible role of ghrelin in DR-induced hippocampal neurogenesis in adult mice, ghrelin knockout (GKO) mice and wild-type (WT) mice were maintained for 3 months on DR or ad libitum (AL) diets. Protein levels of ghrelin in the stomach and the hippocampus were increased by DR in WT mice. One day after BrdU administration, the number of BrdU-labeled cells in the hippocampal dentate gyrus was decreased in GKO mice maintained on the AL diet. DR failed to alter the proliferation of progenitor cells in both WT and GKO mice. Four weeks after BrdU injection, the number of surviving cells in the dentate gyrus was decreased in AL-fed GKO mice. DR increased survival of newborn cells in WT mice, but not in GKO mice. Levels of brain-derived neurotrophic factor protein in the hippocampus were similar between WT and GKO mice, and were increased by DR both in WT and GKO mice. These results suggest that elevated levels of ghrelin during DR may have an important role in the enhancement of neurogenesis induced by DR.

Intravenous immunoglobulin for Alzheimer's disease.

The foundation for using intravenous immunoglobulin (IVIg) to treat Alzheimer's disease (AD) can be traced back to the discovery, in the early 1990s, of naturally occurring anti-amyloid antibodies in human blood. A decade later, a number of independent investigators reported reduced levels of naturally occurring anti-amyloid antibodies in the spinal fluid and blood of AD patients relative to age-matched controls 1–3. Dodel subsequently reported that IVIg contained elevated levels of antibodies against amyloid-β (Aβ) monomers and proposed its use as a potential treatment for AD 4.

Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone.

Major depressive disorder is often linked to stress. Whereas short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1h/day for 7days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-α1(NF-α1) (also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6h/day for 21days) CRS, mice show decreased hippocampal NF-α1 and FGF2 levels and depressive-like responses. In NF-α1-knock out mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior which is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reveal that NF-α1 treatment directly up-regulates FGF2 expression through ERK-Sp1 signaling. Thus, during short-term CRS, hippocampal NF-α1 expression is up-regulated and it plays a key role in preventing the onset of depressive-like behavior through enhanced FGF2-mediated neurogenesis. To evaluate the therapeutic potential of this pathway, we examined, rosiglitazone, a PPARγ agonist, which has been shown to have antidepressant activity in rodents and humans. Rosiglitazone up-regulates FGF2 expression in a NF-α1-dependent manner in hippocampal neurons. Mice fed rosiglitazone show increased hippocampal NF-α1 levels and neurogenesis compared to controls; thereby indicating the antidepressant action of this drug. Development of drugs that activate the NF-α1/FGF2/neurogenesis pathway can offer a new approach to depression therapy.

Enhancement of Neurogenesis and Memory by a Neurotrophic Peptide in Mild to Moderate Traumatic Brain Injury

Traumatic brain injury (TBI) is a risk factor for Alzheimer disease (AD), a neurocognitive disorder with similar cellular abnormalities. We recently discovered a small molecule (Peptide 6) corresponding to an active region of human ciliary neurotrophic factor, with neurogenic and neurotrophic properties in mouse models of AD and Down syndrome. To describe hippocampal abnormalities in a mouse model of mild to moderate TBI and their reversal by Peptide 6. TBI was induced in adult C57Bl6 mice using controlled cortical impact with 1.5 mm of cortical penetration. The animals were treated with 50 nmol/d of Peptide 6 or saline solution for 30 days. Dentate gyrus neurogenesis, dendritic and synaptic density, and AD biomarkers were quantitatively analyzed, and behavioral tests were performed. Ipsilateral neuronal loss in CA1 and the parietal cortex and increase in Alzheimer-type hyperphosphorylated tau and A-β were seen in TBI mice. Compared with saline solution, Peptide 6 treatment increased the number of newborn neurons, but not uncommitted progenitor cells, in dentate gyrus by 80%. Peptide 6 treatment also reversed TBI-induced dendritic and synaptic density loss while increasing activity in tri-synaptic hippocampal circuitry, ultimately leading to improvement in memory recall on behavioral testing. Long-term treatment with Peptide 6 enhances the pool of newborn neurons in the dentate gyrus, prevents neuronal loss in CA1 and parietal cortex, preserves the dendritic and synaptic architecture in the hippocampus, and improves performance on a hippocampus-dependent memory task in TBI mice. These findings necessitate further inquiry into the therapeutic potential of small molecules based on neurotrophic factors.

Anti-depressant effect of hesperidin in diabetic rats.

This study aimed to investigate the anti-depressant effect of hesperidin (Hsp) in streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of Hsp on hyperglycaemia, oxidative stress, inflammation, brain-derived neurotrophic factor (BDNF), and brain monoamines in diabetic rats was also assessed. The Wistar rats in the experimental groups were rendered hyperglycaemic with a single dose of STZ (52.5 mg·(kg body mass)(-1), by intraperitoneal injection). The normal group received the vehicle only. Hyperglycaemic rats were treated with Hsp (25.0, 50.0, or 100.0 mg·(kg body mass)(-1)·day(-1), per oral) and fluoxetine (Flu) (5.0 mg·(kg body mass)(-1)·day(-1), per oral) 48 h after the STZ injection, for 21 consecutive days. The normal and STZ control groups received the vehicle (distilled water). Behavioral and biochemical parameters were then assessed. When Hsp was administered to the STZ-treated rats, this reversed the STZ-induced increase in immobility duration in the forced swimming test (FST) and attenuated hyperglycaemia, decreased malondialdehyde (MDA), increased reduced glutathione (GSH) decreased interleukin-6 (IL-6), and increased BDNF levels in the brain. Treatment with Hsp attenuated STZ-induced neurochemical alterations, as indicated by increased levels of monoamines in the brain, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT). All of these effects of Hsp were similar to those observed with the established anti-depressant Flu. This study shows that Hsp exerted anti-depressant effect in diabetic rats, which may have been partly mediated by its amelioration of hyperglycaemia as well as its anti-oxidant and anti-inflammatory activities, the enhancement of neurogenesis, and changes in the levels of monoamines in the brain.

Systemic angiotensin II and exercise-induced neurogenesis in adult rat hippocampus

Physical exercise is a robust stimulus that enhances hippocampal neurogenesis via cell proliferation in rodents. We examined the role of systemic angiotensin (Ang) peptides in exercise-dependent enhancement of neurogenesis in the adult rat hippocampus. Plasma angiotensin peptide concentration increased rapidly in response to 30min of treadmill exercise. After undertaking this exercise once daily for a week, the number of proliferating cells in the hippocampus, identified by 5-bromo-2′-deoxyuridine (BrdU) incorporation, had increased compared with controls. To mimic the increase in plasma Ang peptide concentrations brought about by exercise, rats were injected with 10−5M Ang II once daily for a week. The number of BrdU-incorporating cells and of doublecortin (DCX)-expressing immature neurons in the hippocampus rose approximately 1.5 and 1.9-fold compared with controls, respectively. The effects were completely abolished by an Ang II receptor subtype 1 antagonist losartan. These findings, taken together, suggest that an increased concentrations of Ang peptides in the systemic circulation during exercise may promote neurogenesis in the adult rat hippocampus.

Efficacy of the selective progesterone receptor agonist Nestorone for chronic experimental autoimmune encephalomyelitis

Progesterone plays a protective role in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Besides spinal cord neuropathology, MS patients present a dysfunctional hippocampus. In this work we studied the therapeutic effects of the progestin Nestorone in the brain of mice with chronic EAE. Nestorone decreased clinical grade and enhanced motor behavior. In addition, it increased cell proliferation and doublecortin positive neuroblasts in the hippocampus, increased GABAergic interneurons and attenuated the number of Iba1+ microglia/macrophages, events possibly linked to enhancement of neurogenesis. Therefore, Nestorone protected against hippocampus abnormalities and improved functional outcomes of EAE mice, suggesting its potential value for MS.

Pheromone-induced cell proliferation in the murine subventricular zone.

Enhancement of adult neurogenesis in female mice was previously demonstrated through exposure to soiled bedding from males, although the identity of relevant chemosignals has remained unknown. The farnesenes and SBT (2-sec-butyl-4,5-dihydrothiazole) are male murine pheromones that dominant males secrete at higher levels. Previous studies have shown that they induce oestrus in female mice. We have recently shown that these pheromones strongly increase cell proliferation in the SVZ (subventricular zone) of adult female mice. In addition, we found that a female murine pheromone, 2,5-dimethylpyrazine, facilitates similar changes in males. 2,5-dimethylpyrazine is a female pheromone that is secreted when females are housed in large groups and it was originally found to suppress oestrus in females. We found that it does not have suppressive effect on the cell proliferation in the SVZ of females. Similarly, male murine pheromones, SBT and the farnesenes, do not show a suppressive effect on the cell proliferation in the SVZ of males. Our results demonstrated that pheromonal communication between males and females has strong stimulatory effect on both the reproductive physiology and brain cell proliferation, but intrasex pheromonal exchanges do not reduce progenitor proliferation in these brain regions.

Changes in the social environment induce neurogenic plasticity predominantly in niches residing in sensory structures of the zebrafish brain independently of cortisol levels.

The social environment is known to modulate adult neurogenesis. Studies in mammals and birds have shown a strong correlation between social isolation and decreases in neurogenesis, whereas time spent in an enriched environment has been shown to restore these deficits and enhance neurogenesis. These data suggest that there exists a common adaptive response among neurogenic niches to each extreme of the social environment. We sought to further test this hypothesis in zebrafish, a social species with distinct neurogenic niches within primary sensory structures and telencephalic nuclei of the brain. By examining stages of adult neurogenesis, including the proliferating stem/progenitor population, their surviving cohort, and the resulting newly differentiated neuronal population, we show that niches residing in sensory structures are most sensitive to changes in the social context, and that social isolation or novelty are both capable of decreasing the number of proliferating cells while increasing the number of newborn neurons within a single niche. Contrary to observations in rodents, we demonstrate that social novelty, a form of enrichment, does not consistently rescue deficits in cell proliferation following social isolation, and that cortisol levels do not negatively regulate changes in adult neurogenesis, but are correlated with the social context. We propose that enhancement or suppression of adult neurogenesis in the zebrafish brain under different social contexts depends largely on the type of niche (sensory or telencephalic), experience from the preceding social environment, and occurs independently of changes in cortisol levels.

Ginkgo Biloba (EGb 761®) Augments the Repair and Regeneration Process by Enhancing Neurogenesis after Experimental Stroke in Mice

The Journal of Alternative and Complementary MedicineVol. 20, No. 5 Oral Abstract Session 03: Basic ScienceGinkgo Biloba (EGb 761®) Augments the Repair and Regeneration Process by Enhancing Neurogenesis after Experimental Stroke in MiceShadia Nada, Jatin Tulsulkar, and Zahoor ShahShadia NadaSearch for more papers by this author, Jatin TulsulkarSearch for more papers by this author, and Zahoor ShahSearch for more papers by this authorPublished Online:7 May 2014https://doi.org/10.1089/acm.2014.5011.abstractAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Ginkgo Biloba (EGb 761®) Augments the Repair and Regeneration Process by Enhancing Neurogenesis after Experimental Stroke in Mice." The Journal of Alternative and Complementary Medicine, 20(5), p. A6FiguresReferencesRelatedDetails Volume 20Issue 5May 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Shadia Nada, Jatin Tulsulkar, and Zahoor Shah.Ginkgo Biloba (EGb 761®) Augments the Repair and Regeneration Process by Enhancing Neurogenesis after Experimental Stroke in Mice.The Journal of Alternative and Complementary Medicine.May 2014.A6-A6.http://doi.org/10.1089/acm.2014.5011.abstractPublished in Volume: 20 Issue 5: May 7, 2014PDF download

Epigenetic Modulation of Adult Hippocampal Neurogenesis by Extremely Low-Frequency Electromagnetic Fields

Throughout life, adult neurogenesis generates new neurons in the dentate gyrus of hippocampus that have a critical role in memory formation. Strategies able to stimulate this endogenous process have raised considerable interest because of their potential use to treat neurological disorders entailing cognitive impairment. We previously reported that mice exposed to extremely low-frequency electromagnetic fields (ELFEFs) showed increased hippocampal neurogenesis. Here, we demonstrate that the ELFEF-dependent enhancement of hippocampal neurogenesis improves spatial learning and memory. To gain insights on the molecular mechanisms underlying ELFEFs' effects, we extended our studies to an in vitro model of neural stem cells (NSCs) isolated from the hippocampi of newborn mice. We found that ELFEFs enhanced proliferation and neuronal differentiation of hippocampal NSCs by regulation of epigenetic mechanisms leading to pro-neuronal gene expression. Upon ELFEF stimulation of NSCs, we observed a significant enhancement of expression of the pro-proliferative gene hairy enhancer of split 1 and the neuronal determination genes NeuroD1 and Neurogenin1. These events were preceded by increased acetylation of H3K9 and binding of the phosphorylated transcription factor cAMP response element-binding protein (CREB) on the regulatory sequence of these genes. Such ELFEF-dependent epigenetic modifications were prevented by the Cav1-channel blocker nifedipine, and were associated with increased occupancy of CREB-binding protein (CBP) to the same loci within the analyzed promoters. Our results unravel the molecular mechanisms underlying the ELFEFs' ability to improve endogenous neurogenesis, pointing to histone acetylation-related chromatin remodeling as a critical determinant. These findings could pave the way to the development of novel therapeutic approaches in regenerative medicine.

Microglia Enhance Neurogenesis and Oligodendrogenesis in the Early Postnatal Subventricular Zone

Although microglia have long been considered as brain resident immune cells, increasing evidence suggests that they also have physiological roles in the development of the normal CNS. In this study, we found large numbers of activated microglia in the forebrain subventricular zone (SVZ) of the rat from P1 to P10. Pharmacological suppression of the activation, which produces a decrease in levels of a number of proinflammatory cytokines (i.e., IL-1β, IL-6, TNF-α, and IFN-γ) significantly inhibited neurogenesis and oligodendrogenesis in the SVZ. In vitro neurosphere assays reproduced the enhancement of neurogenesis and oligodendrogenesis by activated microglia and showed that the cytokines revealed the effects complementarily. These results suggest that activated microglia accumulate in the early postnatal SVZ and that they enhance neurogenesis and oligodendrogenesis via released cytokines.

Translational research guided by animal studies in Fragile X Disorders

This special issue on fragile X-associated disorders will open your eyes to the broad spectrum of clinical involvement that occurs with mutations in the FMR1 gene. This gene creates a protein, FMRP, which is a key protein for regulating the translation of hundreds of mRNAs, particularly those involved in synapse formation and plasticity. Fragile X syndrome (FXS) results from the loss or deficiency of FMRP and it is the most common cause of inherited intellectual disability and autism or autism spectrum disorder (ASD). The review of animal models for FXS by Kazdoba-Leach et al. (2014) in this issue, demonstrates how these models have led the way to targeted treatments for FXS and for ASD. One of the more promising new treatments for FXS is the use of low dose sertraline in young children 2 years and older with FXS. The paper by Hansen and Hagerman (in this edition) outlines the benefits of sertraline including the enhancement of serotonin neurotransmission, neurogenesis, and BDNF levels that has the potential to improve language and development for these children. GABA agonists and mGluR5 antagonists have also been studied in FXS but the mouse model is easily rescued with many different targeted treatments, whereas the patients with FXS have only responded well to a few new treatments. There is a great need to improve the participation of minorities in the new clinical trials of targeted treatments for FXS and this is reviewed in detail by Chechi et al. (2014) in this issue.

Shifting balance from neurodegeneration to regeneration of the brain: a novel therapeutic approach to Alzheimer's disease and related neurodegenerative conditions.

Shifting balance from neurodegeneration to regeneration of the brain: a novel therapeutic approach to Alzheimer's disease and related neurodegenerative conditions.

Gypenosides pre-treatment protects the brain against cerebral ischemia and increases neural stem cells/progenitors in the subventricular zone

Gypenosides (GPs) have been reported to have neuroprotective effects in addition to other bioactivities. The protective activity of GPs during stroke and their effects on neural stem cells (NSCs) in the ischemic brain have not been fully elucidated. Here, we test the effects of GPs during stroke and on the NSCs within the subventricular zone (SVZ) of middle cerebral artery occlusion (MCAO) rats. Our results show that pre-treatment with GPs can reduce infarct volume and improve motor function following MCAO. Pre-treatment with GPs significantly increased the number of BrdU-positive cells in the ipsilateral and contralateral SVZ of MCAO rats. The proliferating cells in both sides of the SVZ were glial fibrillary acidic protein (GFAP)/nestin-positive type B cells and doublecortin (DCX)/nestin-positive type A cells. Our data indicate that GPs have neuroprotective effects during stroke which might be mediated through the enhancement of neurogenesis within the SVZ. These findings provide new evidence for a potential therapy involving GPs for the treatment of stroke.