Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, with a median survival of about one year1. This poor prognosis is due to therapeutic resistance and tumor recurrence following surgical removal. Precisely how recurrence occurs is unknown. Using a genetically-engineered mouse model of glioma, we identify a subset of endogenous tumor cells that are the source of new tumor cells after the drug, temozolomide (TMZ), is administered to transiently arrest tumor growth. A Nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumor cells. Upon arrest of tumor cell proliferation with TMZ, pulse-chase experiments demonstrate a tumor re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumor growth and combined TMZ-ganciclovir treatment impeded tumor development. These data indicate the existence of a relatively quiescent subset of endogenous glioma cells that are responsible for sustaining long-term tumor growth through the production of transient populations of highly proliferative cells.
It is becoming increasingly clear that brain injuries from a variety of causes stimulate neurogenesis within the hippocampus. It remains unclear, however, how robust this response may be and what primary cell types are involved. Here, using a controlled cortical impact model of traumatic brain injury on a previously characterized transgenic mouse line that expresses enhanced green fluorescent protein (eGFP) under the control of the nestin promoter, we demonstrate that it is the earliest type-1 quiescent progenitor cells that are induced to proliferate and migrate outside the subgranular layer of the dentate gyrus. This type-1 cell activation occurs at the same time that we observe adjacent but more differentiated doublecortin-expressing progenitors (type-2 cells) being eliminated. Also, although type-2 cells remain intact in the contralateral (uninjured) dentate gyrus, the type-1 cells there are also activated and result in increased numbers of the doublecortin-expressing type-2 cells. In addition, we have generated a novel mouse transgenic that expresses a modified version of the herpes simplex virus thymidine kinase along with eGFP that allows for the visualization and inducible ablation of early dividing progenitors by exposing them to ganciclovir. Using this transgenic in the context of traumatic brain injury, we demonstrate that these early progenitors are required for injury-induced remodeling to occur. This work suggests that injury-induced hippocampal remodeling following brain injury likely requires sustained activation of quiescent early progenitors.
Significant spontaneous recovery occurs following essentially all forms of serious brain injury, though the mechanisms underlying this recovery are unknown. Given that many forms of brain injury such as traumatic brain injury (TBI) induce hippocampal neurogenesis, we investigated whether these newly generated neurons might play a role in recovery. By modeling TBI in transgenic mice, we determined that injury-induced newly generated neurons persisted over time and elaborated extensive dendritic trees that stably incorporated themselves throughout all neuronal layers of the dentate gyrus. When we selectively ablated dividing stem/progenitors at the time of injury with ganciclovir in a nestin-HSV-TK transgenic model, we eliminated injury-induced neurogenesis and subsequently diminished the progenitor pool. Moreover, using hippocampal-specific behavioral tests, we demonstrated that only injured animals with neurogenesis ablated at the time of injury lost the ability to learn spatial memory tasks. These data demonstrate a functional role for adult neurogenesis following brain injury and offer compelling and testable therapeutic options that might enhance recovery.
Different places may share common features, but are coded by distinct populations of CA3 neurons in the hippocampus. Here we show that chemical or genetic suppression of adult neurogenesis in the hippocampus impairs this population-based coding of similar (but not dissimilar) contexts. These data provide a neural basis for impaired spatial discrimination following ablation of adult neurogenesis, and support the proposal that adult neurogenesis regulates the efficiency of a pattern separation process in the hippocampus.
BackgroundThe molecular mechanism underlying progressive memory loss in Alzheimer’s disease is poorly understood. Neurogenesis in the adult hippocampus is a dynamic process that continuously changes the dentate gyrus and is important for hippocampal plasticity, learning and memory. However, whether impairments in neurogenesis affect the hippocampal circuitry in a way that leads to memory deficits characteristic of Alzheimer’s disease is unknown. Controversial results in that regard were reported in transgenic mouse models of amyloidosis.MethodsHere, we conditionally ablated adult neurogenesis in APPswe/PS1ΔE9 mice by crossing these with mice expressing nestin-driven thymidine kinase (δ-HSV-TK).ResultsThese animals show impairment in performance in contextual conditioning and pattern separation tasks following depletion of neurogenesis. Importantly, these deficits were not observed in age-matched APPswe/PS1ΔE9 or δ-HSV-TK mice alone. Furthermore, we show that cognitive deficits were accompanied by the upregulation of hyperphosphorylated tau in the hippocampus and in immature neurons specifically. Interestingly, we observed upregulation of the immediate early gene Zif268 (Egr-1) in the dentate gyrus, CA1 and CA3 regions of the hippocampus following learning in the neurogenesis-depleted δ-HSV-TK mice. This may suggest overactivation of hippocampal neurons in these areas following depletion of neurogenesis.ConclusionsThese results imply that neurogenesis plays an important role in the regulation of inhibitory circuitry of the hippocampus. This study suggests that deficits in adult neurogenesis may contribute to cognitive impairments, tau hyperphosphorylation in new neurons and compromised hippocampal circuitry in Alzheimer’s disease.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0207-7) contains supplementary material, which is available to authorized users.
The use of mouse gene targeting to study molecules important in neural development is oftentimes impaired by early embryonic lethality. In order to address later roles for such molecules, specifically in neural stem cells, we generated transgenic mice that express both the tetracycline-inducible molecule rtTA-M2 and GFP under the control of the neural precursor specific form of nestin. Developmental analysis of these mice demonstrates that GFP expression is exclusive to the neural tube. Adult expression of GFP is seen only in known areas of adult neurogenesis, namely, the subventricular zone and the dentate gyrus. When crossed with a second transgenic mouse (TetOp-Cre) that expresses the Cre recombinase under the control of the tetracycline responsive promotor, we demonstrate temporal induction of Cre in bigenic animals exposed to doxycycline. We further demonstrate the feasibility of this approach by using the ROSA-26 reporter mouse to mediate recombination in neural precursor cells.
Highlights d Adult-born neuron (ABN) activity during sleep can be seen using Ca 2+ imaging d ABNs active after learning reactivate in subsequent rapid eye movement (REM) sleep d Optogenetic manipulation of ABN activity in REM sleep impairs memory consolidation d This effect may be mediated by ABN synaptic plasticity
Adult hippocampal neurogenesis occurs throughout life and is believed to participate in cognitive functions such as learning and memory. A number of genes that regulate adult hippocampal neurogenesis have been identified, although most of these have been implicated in progenitor proliferation and survival, but not in the development into fully differentiated neurons. Among these genes, apolipoprotein E (ApoE) is particularly compelling because the human ApoE isoform E4 is a risk factor for the development of Alzheimer’s disease, where hippocampal neurogenesis is reported to be dysfunctional. To investigate the effects of ApoE and its human isoforms on adult hippocampal neurogenesis and neuronal development, retroviruses carrying a GFP-expressing vector were injected into wild-type (WT), ApoE-deficient, and human targeted replacement (ApoE3 and ApoE4) mice to infect progenitors in the dentate gyrus and analyze the morphology of fully developed GFP-expressing neurons. Analysis of these adult-born neurons revealed significant decreases in the complexity of dendritic arborizations and spine density in ApoE-deficient mice compared with WT mice, as well as in ApoE4 mice compared with ApoE3. These findings demonstrate that ApoE deficiency and the ApoE4 human isoform both impair hippocampal neurogenesis and give insight into how ApoE may influence hippocampal-related neurological diseases.
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