scholarly journals The sphingosine-1-phosphate analogue, FTY-720, promotes the proliferation of embryonic neural stem cells, enhances hippocampal neurogenesis and learning and memory abilities in adult mice

2016 ◽  
Vol 173 (18) ◽  
pp. 2793-2807 ◽  
Author(s):  
Yili Sun ◽  
Feng Hong ◽  
Lei Zhang ◽  
Linyin Feng
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Learning And Memory ◽  
Hippocampal Neurogenesis ◽  
Fty 720 ◽  
Adult Mice ◽  
Sphingosine 1 Phosphate

scholarly journals IL-1β and HMGB1 are anti-neurogenic to endogenous neural stem cells in the sclerotic epileptic human hippocampus

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Malik Zaben ◽  
Niels Haan ◽  
Feras Sharouf ◽  
Aminul Ahmed ◽  
Lars E. Sundstrom ◽  
...  
Keyword(s):  
Stem Cells ◽  
Animal Models ◽  
Neural Stem Cells ◽  
Temporal Lobe Epilepsy ◽  
Learning And Memory ◽  
Temporal Lobe ◽  
Hippocampal Neurogenesis ◽  
Human Hippocampus ◽  
Dependent Learning ◽  
Endogenous Neural Stem Cells

Abstract Background The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility. Methods We isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it. Results 3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1β. IL-1β and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture. Conclusion Our results demonstrate a HMGB1 and IL-1β-mediated environmental anti-neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.

scholarly journals Nestin Null Mice Show Improved Reversal Place Learning

2019 ◽  
Vol 45 (1) ◽  
pp. 215-220 ◽  
Author(s):  
Ulrika Wilhelmsson ◽  
Marie Kalm ◽  
Marcela Pekna ◽  
Milos Pekny
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Learning And Memory ◽  
Hippocampal Neurogenesis ◽  
Place Learning ◽  
Adult Hippocampal Neurogenesis ◽  
Intermediate Filament Protein ◽  
Nose Poke ◽  
Memory Extinction ◽  
Over Time

Abstract The intermediate filament protein nestin is expressed by neural stem cells, but also by some astrocytes in the neurogenic niche of the hippocampus in the adult rodent brain. We recently reported that nestin-deficient (Nes−/−) mice showed increased adult hippocampal neurogenesis, reduced Notch signaling from Nes−/− astrocytes to the neural stem cells, and impaired long-term memory. Here we assessed learning and memory of Nes−/− mice in a home cage set up using the IntelliCage system, in which the mice learn in which cage corner a nose poke earns access to drinking water. Nes−/− and wildtype mice showed comparable place learning assessed as the incorrect corner visit ratio and the incorrect nose poke ratio. However, during reversal place learning, a more challenging task, Nes−/− mice, compared to wildtype mice, showed improved learning over time demonstrated by the incorrect visit ratio and improved memory extinction over time assessed as nose pokes per visit to the previous drinking corner. In addition, Nes−/− mice showed increased explorative activity as judged by the increased total numbers of corner visits and nose pokes. We conclude that Nes−/− mice exhibit improved reversal place learning and memory extinction, a finding which together with the previous results supports the concept of the dual role of hippocampal neurogenesis in cognitive functions.

scholarly journals IL-1β and HMGB1 are anti-neurogenic to endogenous neural stem cells in the sclerotic epileptic human hippocampus

2021 ◽  
Author(s):  
Malik Zaben ◽  
Niels Haan ◽  
Feras Sharouf ◽  
Aminul Ahmed ◽  
Lars Sundstrom ◽  
...  
Keyword(s):  
Stem Cells ◽  
Animal Models ◽  
Neural Stem Cells ◽  
Temporal Lobe Epilepsy ◽  
Learning And Memory ◽  
Temporal Lobe ◽  
Hippocampal Neurogenesis ◽  
Human Hippocampus ◽  
Dependent Learning ◽  
Endogenous Neural Stem Cells

Abstract Background: The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility.Methods: We isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it.Results: 3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1β. IL-1β and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture. Conclusion: Our results demonstrate a HMGB1 and IL-1β-mediated environmental anti- neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.

scholarly journals Systematic Review of Nicotine Exposure’s Effects on Neural Stem and Progenitor Cells

2021 ◽  
Vol 11 (2) ◽  
pp. 172
Author(s):  
Arrin C. Brooks ◽  
Brandon J. Henderson
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Inverse Correlation ◽  
Hippocampal Neurogenesis ◽  
Nicotine Exposure ◽  
Negative Consequences ◽  
Postnatal Neurogenesis ◽  
Cognitive Behaviors ◽  
Chronic Nicotine ◽  
Stem And Progenitor Cells

While various modalities of chronic nicotine use have been associated with numerous negative consequences to human health, one possible benefit of nicotine exposure has been uncovered. The discovery of an inverse correlation between smoking and Parkinson’s disease, and later Alzheimer’s disease as well, motivated investigation of nicotine as a neuroprotective agent. Some studies have demonstrated that nicotine elicits improvements in cognitive function. The hippocampus, along with the subventricular zone (SVZ), is a distinct brain region that allow for ongoing postnatal neurogenesis throughout adulthood and plays a major role in certain cognitive behaviors like learning and memory. Therefore, one hypothesis underlying nicotine-induced neuroprotection is possible effects on neural stem cells and neural precursor cells. On the other hand, nicotine withdrawal frequently leads to cognitive impairments, particularly in hippocampal-dependent behaviors, possibly suggesting an impairment of hippocampal neurogenesis with nicotine exposure. This review discusses the current body of evidence on nicotine’s effects on neural stem cells and neural progenitors. Changes in neural stem cell proliferation, survival, intracellular dynamics, and differentiation following acute and chronic nicotine exposure are examined.

scholarly journals GABAB receptor antagonist promotes hippocampal neurogenesis and facilitates cognitive function recovery following acute cerebral ischemia in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dan Song ◽  
Yaohua Chen ◽  
Cheng Chen ◽  
Lili Chen ◽  
Oumei Cheng
Keyword(s):  
Cognitive Function ◽  
Cerebral Ischemia ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Hippocampal Neurogenesis ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
In Vitro Experiments ◽  
Adult Mice

Abstract Purpose and background Previous studies have suggested that promoting endogenous neurogenesis has great significance for the recovery of cognitive dysfunction caused by cerebral ischemia (CI). Pharmacological inhibition of GABAB receptor can enhance neurogenesis in adult healthy and depressed mice. In the study, we intended to investigate the effects of GABAB receptor antagonists on cognitive function and hippocampal neurogenesis in mice following CI. Methods Adult mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min to induce CI and treated with CGP52432 (antagonist of GABAB receptor, CGP, 10 mg/kg intraperitoneal injection) starting 24 h after CI. The Morris water maze test was performed to test spatial learning and memory at day 28. Immunofluorescence was applied to detect neurogenesis in the DG region at day 14 and 28. In in vitro experiments, cell proliferation was detected by CCK8 and immunofluorescence, and the expression of cAMP/CREB signaling pathway-related proteins was detected by ELISA assay and Western blot. Results CGP significantly improved spatial learning and memory disorders caused by CI, and it enhanced the proliferation of neural stem cells (NSCs), the number of immature neurons, and the differentiation from newborn cells to neurons. In vitro experiments further confirmed that CGP dose-dependently enhanced the cell viability of NSCs, and immunofluorescence staining showed that CGP promoted the proliferation of NSCs. In addition, treatment with CGP increased the expression of cAMP, PKA, and pCREB in cultured NSCs. Conclusion Inhibition of GABAB receptor can effectively promote hippocampal neurogenesis and improve spatial learning and memory in adult mice following CI.

Abstract 214: The Vascular Niche in Adult Mouse Brain After Stroke - Confocal Imaging of Whole Mount SVZ

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Rui Lan Zhang ◽  
Michael Chopp ◽  
Cynthia Roberts ◽  
Siamak Nejad-Davarani ◽  
Li Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Neural Stem Cells ◽  
Blood Vessels ◽  
Artery Occlusion ◽  
Confocal Imaging ◽  
Adult Mice ◽  
Cell Niche ◽  
Newborn Neurons ◽  
Whole Mounts

Stroke induces angiogenesis in the peri-infarct region. It is not known whether angiogenesis occurs in the subventricular zone (SVZ) of the lateral ventricle after stroke. The SVZ is a neural stem cell niche containing vascular plexus that supports adult neurogenesis. We characterized longitudinal changes of vascular structures in the SVZ niche after stroke using whole mounts, an organotypic preparation of the SVZ in which the 3D cell-vessel relationships are preserved. Adult mice were subjected to middle cerebral artery occlusion (MCAO). The vascular architectures within the 50 μm thick SVZ of immunostained whole mounts were imaged by 3D confocal microscopy. In non-MCAO mice (n=4), 2±0.2% of endothelial cells were proliferative (BrdU+/CD31+). Blood vessels in this niche constituted 2.6±0.01% of the total volume with 75±17 vascular branches. However, 7 and 14 days after MCAO, proliferated endothelial cells significantly (p<0.05) increased to 12±1% (n=5) and 15±1 % (n=5), respectively, which was followed by substantial increases in vascular volume at 14 (4.2±0.01%, n=3), 30 (4.9±0.05%, n=3), and 90 (5.7±0.01%, n=3) days, but not at 7 days after MCAO. Moreover, vascular branches increased significantly to 156±27 and 216±8 at 30 and 90 days, respectively, but not at 14 days. Interestingly, we detected increases in the number of string-like vessels starting at 14 days (731±79/mm 3 vs 476±41/mm 3 in control) which increased and persisted at 30 (1,824±255/mm 3 ) and 90 (1,748±204/mm 3 ) days after MCAO. These string-like vessels were not perfused by plasma. String vessels increase during embryonic angiogenesis. Collectively, these data indicate that stroke induces angiogenesis in the SVZ, which lasts at least 90 days after stroke. Moreover, stroke significantly increased neural stem cells (BrdU + /GFAP + , 13±3%, 15±3%, and 11±4% at 7, 14, and 90 days, respectively, vs 6±1% in control) and newborn neurons (BrdU + /DCX + , 14±2% and 12±2.0% at 7 and 14 days, respectively, vs 4±1% in control). Neural stem cells at the ventricular surface extended their processes to the blood vessels in the SVZ. Our data indicate that stroke induces angiogenesis in the SVZ, which is associated with stroke-induced neurogenesis.

Abstract TP78: Combination of Neuroprotective Drug and Neural Stem Cells Benefits Aged Stroke Mice with Delayed Tissue Plasminogen Activator Treatment

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Auston Eckert ◽  
Milton H Hamblin ◽  
Jean-Pyo Lee
Keyword(s):  
Stem Cells ◽  
Young Adult ◽  
Neural Stem Cells ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Inflammatory Drug ◽  
Aged Mice ◽  
Post Stroke ◽  
Adult Mice ◽  
Tissue Plasminogen

Background: Presently, tissue plasminogen activator (tPA) is the sole FDA-approved antithrombotic treatment available for stroke. However, tPA’s harmful side effects within the central nervous system can exacerbate blood-brain barrier (BBB) damage and increase mortality. Patients should receive tPA less than 4.5 hours post-stroke. Although age alone is not an impediment for tPA treatment, the harmful effects of delayed tPA (>4.5h), particularly on aged stroke animals, have not been well studied. We reported that intracranial transplantation of neural stem cells (hNSCs) ameliorates BBB damage caused by ischemic stroke. In this study, we examined the combined effects of minocycline (a neuroprotective and anti-inflammatory drug) and hNSC transplantation on the mortality of delayed tPA-treated aged mice within 48h post-stroke. Methods and Results: We utilized the middle cerebral artery occlusion stroke mouse model to induce focal cerebral ischemia followed by reperfusion (MCAO/R). 6h post-MCAO, we administered tPA intravenously. Minocycline was administered intraperitoneally at various time points prior to tPA injection. One day post-stroke, we injected hNSCs intracranially. Previously, we reported that hNSCs (both human and mouse) transplanted into the brain 24h post-stroke rapidly improve neurological outcome in young-adult mice (4-5mo). In our current study, tPA administered within 4.5h did not increase mortality in either young-adult or aged mice. However, we found delayed tPA treatment (6h post-stroke) significantly increased the mortality of aged mice (13-18 mo) but not in young-adult mice. Here, we report that by combining minocycline prior to tPA significantly reduced mortality. Furthermore, transplanting hNSCs in minocycline-treated mice further ameliorated the pathophysiology caused by delayed tPA. Conclusions: Our findings implicate that administering the anti-apototic and anti-inflammatory drug prior to tPA injection, and then post-treating with multipotent neuroprotective hNSCs might expand the time window of tPA and reduce reperfusion injury.

scholarly journals Isolation of Neural Stem Cells from Whole Brain Tissues of Adult Mice

2019 ◽  
Vol 49 (1) ◽  
pp. e80
Author(s):  
Krutika Deshpande ◽  
Behnaz Saatian ◽  
Vahan Martirosian ◽  
Michelle Lin ◽  
Alex Julian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Whole Brain ◽  
Adult Mice ◽  
Brain Tissues

scholarly journals Metabolic tuning of inhibition regulates hippocampal neurogenesis in the adult brain

2020 ◽  
Vol 117 (41) ◽  
pp. 25818-25829
Author(s):  
Xinxing Wang ◽  
Hanxiao Liu ◽  
Johannes Morstein ◽  
Alexander J. E. Novak ◽  
Dirk Trauner ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Energy Homeostasis ◽  
Inhibitory Neuron ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Neuron Activity ◽  
Adult Mice ◽  
Sphingosine 1 Phosphate ◽  
Underlying Mechanisms

Hippocampus-engaged behaviors stimulate neurogenesis in the adult dentate gyrus by largely unknown means. To explore the underlying mechanisms, we used tetrode recording to analyze neuronal activity in the dentate gyrus of freely moving adult mice during hippocampus-engaged contextual exploration. We found that exploration induced an overall sustained increase in inhibitory neuron activity that was concomitant with decreased excitatory neuron activity. A mathematical model based on energy homeostasis in the dentate gyrus showed that enhanced inhibition and decreased excitation resulted in a similar increase in neurogenesis to that observed experimentally. To mechanistically investigate this sustained inhibitory regulation, we performed metabolomic and lipidomic profiling of the hippocampus during exploration. We found sustainably increased signaling of sphingosine-1-phosphate, a bioactive metabolite, during exploration. Furthermore, we found that sphingosine-1-phosphate signaling through its receptor 2 increased interneuron activity and thus mediated exploration-induced neurogenesis. Taken together, our findings point to a behavior-metabolism circuit pathway through which experience regulates adult hippocampal neurogenesis.

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