Tetrahydrohyperforin Increases Adult Hippocampal Neurogenesis in Wild-Type and APPswe/PS1ΔE9 Mice

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

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Effect of Soluble Amyloid Precursor Protein-alpha on Adult Hippocampal Neurogenesis in a Mouse Model of Alzheimer’s Disease

10.21203/rs.3.rs-952426/v1 ◽

2021 ◽

Author(s):

Shane M. Ohline ◽

Connie Chan ◽

Lucia Schoderboeck ◽

Hollie E. Wicky ◽

Warren P. Tate ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Precursor Protein ◽

Hippocampal Neurogenesis ◽

Precursor Protein ◽

Adult Hippocampal Neurogenesis ◽

Wild Type ◽

Viral Expression ◽

Model Of Alzheimer’S Disease

Abstract Soluble amyloid precursor protein-alpha (sAPPα) is a regulator of neuronal and memory mechanisms, while also having neurogenic and neuroprotective effects in the brain. As adult hippocampal neurogenesis is impaired in Alzheimer’s disease, we tested the hypothesis that sAPPα delivery would rescue adult hippocampal neurogenesis in an APP/PS1 mouse model of Alzheimer’s disease. An adeno-associated virus-9 (AAV9) encoding murine sAPPα was injected into the hippocampus of 8 month-old wild-type and APP/PS1 mice, and later two different thymidine analogues (XdU) were systemically injected to label adult-born cells at different time points after viral transduction. The proliferation of adult-born cells, cell survival after eight weeks, and cell differentiation into either neurons or astrocytes was studied. Proliferation was impaired in APP/PS1 mice but was restored to wild-type levels by viral expression of sAPPα. In contrast, sAPPα overexpression failed to rescue the survival of XdU+-labelled cells that was impaired in APP/PS1 mice, although it did cause a significant increase in the area density of astrocytes in the granule cell layer across both genotypes. Finally, viral expression of sAPPα reduced amyloid-beta plaque load in APP/PS1 mice in the dentate gyrus and somatosensory cortex. These data add further evidence that increased levels of sAPPα could be therapeutic for the cognitive decline in AD, in part through restoration of the proliferation of neural progenitor cells in adults.

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Effects of social defeat stress and fluoxetine treatment on neurogenesis and behaviour in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc

10.1101/776633 ◽

2019 ◽

Author(s):

Brendan B. McAllister ◽

Angela Pochakom ◽

Selena Fu ◽

Richard H. Dyck

Keyword(s):

Knockout Mice ◽

Selective Serotonin Reuptake Inhibitors ◽

Social Defeat ◽

Zinc Transporter ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Social Avoidance ◽

Wild Type ◽

Social Defeat Stress ◽

Fluoxetine Treatment

ABSTRACTDepression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behaviour and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress-induced behavioural symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression-like effects, including social avoidance and anxiety-like behaviour. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety-like behaviour. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioural benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.

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Effect of soluble amyloid precursor protein-alpha on adult hippocampal neurogenesis in a mouse model of Alzheimer’s disease

Molecular Brain ◽

10.1186/s13041-021-00889-1 ◽

2022 ◽

Vol 15 (1) ◽

Author(s):

Shane M. Ohline ◽

Connie Chan ◽

Lucia Schoderboeck ◽

Hollie E. Wicky ◽

Warren P. Tate ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Precursor Protein ◽

Hippocampal Neurogenesis ◽

Precursor Protein ◽

Adult Hippocampal Neurogenesis ◽

Wild Type ◽

Viral Expression ◽

Model Of Alzheimer’S Disease

AbstractSoluble amyloid precursor protein-alpha (sAPPα) is a regulator of neuronal and memory mechanisms, while also having neurogenic and neuroprotective effects in the brain. As adult hippocampal neurogenesis is impaired in Alzheimer’s disease, we tested the hypothesis that sAPPα delivery would rescue adult hippocampal neurogenesis in an APP/PS1 mouse model of Alzheimer’s disease. An adeno-associated virus-9 (AAV9) encoding murine sAPPα was injected into the hippocampus of 8-month-old wild-type and APP/PS1 mice, and later two different thymidine analogues (XdU) were systemically injected to label adult-born cells at different time points after viral transduction. The proliferation of adult-born cells, cell survival after eight weeks, and cell differentiation into either neurons or astrocytes was studied. Proliferation was impaired in APP/PS1 mice but was restored to wild-type levels by viral expression of sAPPα. In contrast, sAPPα overexpression failed to rescue the survival of XdU+-labelled cells that was impaired in APP/PS1 mice, although it did cause a significant increase in the area density of astrocytes in the granule cell layer across both genotypes. Finally, viral expression of sAPPα reduced amyloid-beta plaque load in APP/PS1 mice in the dentate gyrus and somatosensory cortex. These data add further evidence that increased levels of sAPPα could be therapeutic for the cognitive decline in AD, in part through restoration of the proliferation of neural progenitor cells in adults.

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Disruption of NREM sleep and sleep-related spatial memory consolidation in mice lacking adult hippocampal neurogenesis

Scientific Reports ◽

10.1038/s41598-020-72362-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

D. Sippel ◽

J. Schwabedal ◽

J. C. Snyder ◽

C. N. Oyanedel ◽

S. N. Bernas ◽

...

Keyword(s):

Adult Neurogenesis ◽

Memory Consolidation ◽

Memory Task ◽

Nrem Sleep ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Structural Level ◽

Wild Type ◽

Cyclin D2 ◽

Morris Water Maze Task

Abstract Cellular plasticity at the structural level and sleep at the behavioural level are both essential for memory formation. The link between the two is not well understood. A functional connection between adult neurogenesis and hippocampus-dependent memory consolidation during NREM sleep has been hypothesized but not experimentally shown. Here, we present evidence that during a three-day learning session in the Morris water maze task a genetic knockout model of adult neurogenesis (Cyclin D2−/−) showed changes in sleep macro- and microstructure. Sleep EEG analyses revealed a lower total sleep time and NREM fraction in Cyclin D2−/− mice as well as an impairment of sleep specific neuronal oscillations that are associated with memory consolidation. Better performance in the memory task was associated with specific sleep parameters in wild-type, but not in Cyclin D2−/− mice. In wild-type animals the number of proliferating cells correlated with the amount of NREM sleep. The lack of adult neurogenesis led to changes in sleep architecture and oscillations that represent the dialog between hippocampus and neocortex during sleep. We suggest that adult neurogenesis—as a key event of hippocampal plasticity—might play an important role for sleep-dependent memory consolidation and modulates learning-induced changes of sleep macro- and microstructure.

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