Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus

Kim, D.H.; Lee, H.E.; Kwon, Kyoung Ja; Park, S.J.; Heo, Hwon; Lee, Y.; Choi, Ji Woong; Shin, Chan Young; Ryu, Jong Hoon

doi:10.1016/j.neuroscience.2014.09.074

Cited by 35 publications

(20 citation statements)

References 55 publications

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“…Accordingly, our 11-month-old sham-operated animals exhibited a low basal level of hippocampal neurogenesis, and we found significantly enhanced neurogenesis in all ischemic groups as compared to shamoperated animals at five weeks post-ischemia. Proper inflammatory response is thought to be necessary for the induction of neurogenesis by ischemic episode [11,16,17,33]. Indeed, we observed that the correlation between the number of neuronal precursors and hippocampal inflammation expressed as total CD45 immunoreactivity followed an inverted U-shape, suggesting that while moderate neuroinflammation may promote compensatory neurogenesis, excessive inflammation may inhibit it.…”

Section: Discussionmentioning

confidence: 78%

“…However, there have been several reports that even after back-crossing to the C57BL/6J strain for six generations, there can still be a certain amount of genetic material from the 129 substrain remaining, which can affect mouse performance in behavioral tests [55,56]. Increase in the hippocampal neurogenesis is well documented in the post-ischemic brain [27,[32][33][34][57][58][59][60]. Enhanced neurogenesis is believed to aim at tissue regeneration, and can be modulated by both NF-κB activity and inflammatory mediators.…”

Section: Discussionmentioning

confidence: 99%

“…Since ischemia-induced inflammation [32][33][34] and hippocampal astrocytic activation [35] have the ability to modulate adult neurogenesis, and we clearly detected increased astrogliosis within the dentate gyrus region of ischemic mice, we further evaluated DCX immunoreactivity in our BCCAo mice at five weeks postinsult. DCX is transiently expressed in proliferating progenitor cells and newly generated neuroblasts for about two weeks before they differentiate into mature neurons [36].…”

Section: Nfkb1 Deficiency Slightly But Significantly Inhibited Bccamentioning

confidence: 99%

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Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage

et al. 2016

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Transient forebrain ischemia induces delayed death of the hippocampal pyramidal neurons, particularly in the CA2 and medial CA1 area. Early pharmacological inhibition of inflammatory response can ameliorate neuronal death, but it also inhibits processes leading to tissue regeneration. Therefore, research efforts are now directed to modulation of post-ischemic inflammation, with the aim to promote beneficial effects of inflammation and limit adverse effects. Transcription factor NF-κB plays a key role in the inflammation and cell survival/apoptosis pathways. In the brain, NF-κB is predominantly found in the form of a heterodimer of p65 (RelA) and p50 subunit, where p65 has a transactivation domain while p50 is chiefly involved in DNA binding. In this study, we subjected middle-aged Nfkb1 knockout mice (lacking p50 subunit) and wild-type controls of both sexs to 17 min of transient forebrain ischemia and assessed mouse performance in a panel of behavioral tests after two weeks of post-operative recovery. We found that ischemia failed to induce clear memory and motor deficits, but affected spontaneous locomotion in genotype-and sex-specific way. We also show that both the lack of the NF-κB p50 subunit and female sex independently protected CA2 hippocampal neurons from ischemia-induced cell death. Additionally, the NF-κB p50 subunit deficiency significantly reduced ischemia-induced microgliosis, astrogliosis, and neurogenesis. Lower levels of hippocampal microgliosis significantly correlated with faster spatial learning. We conclude that NF-κB regulates the outcome of transient forebrain ischemia in middle-aged subjects in a sex-specific way, having an impact not only on neuronal death but also specific inflammatory responses and neurogenesis.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Nfkb1 Deficiency Slightly But Significantly Inhibited Bccamentioning

confidence: 99%

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Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage

et al. 2016

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“…IGF-1 expressing microglia have been proposed to be neuroprotective and to limit inflammatory responses (25, 26). We speculated that the reduction in IGF-1-expressing microglia in Hdc -KO mice would lead to a dysregulated response to pro-inflammatory stimulation.…”

Section: Resultsmentioning

confidence: 99%

“…IGF-1 is upregulated in neuroprotective microglia induced by T H 2 cytokines such as IL-4 (22). Support by IGF-1 expressing neurotrophic microglia is required for survival of cortical neurons during postnatal development (22), for neurogenesis induced by environmental enrichment and exercise in the adult (23, 24), and for neuroprotection after ischemic injury (25, 26). IGF-1-positive microglia also serve a neuroprotective role in animal models of neurodegenerative diseases such as amyotrophic lateral sclerosis (27) and retinitis pigmentosum (28).…”

Section: Introductionmentioning

confidence: 99%

Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation

Frick

Rapanelli

Abbasi

et al. 2016

Brain, Behavior, and Immunity

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Microglia mediate neuroinflammation and regulate brain development and homeostasis. Microglial abnormalities are implicated in a range of neuropsychiatric pathology, including Tourette syndrome (TS) and autism. Histamine (HA) is both a neurotransmitter and an immune modulator. HA deficiency has been implicated as a rare cause of TS and may contribute to other neuropsychiatric conditions. In vitro studies suggest that HA can regulate microglia, but this has never been explored in vivo. We used immunohistochemistry to examine the effects of HA deficiency in histidine decarboxylase (Hdc) knockout mice and of HA receptor stimulation in wild-type animals. We find HA to regulate microglia in vivo, via the H4 receptor. Chronic HA deficiency in Hdc knockout mice reduces ramifications of microglia in the striatum and (at trend level) in the hypothalamus, but not elsewhere in the brain. Depletion of histaminergic neurons in the hypothalamus has a similar effect. Microglia expressing IGF-1 are particularly reduced, However, the microglial response to challenge with lipopolysacchariade (LPS) is potentiated in Hdc knockout mice. Genetic abnormalities in histaminergic signaling may produce a vulnerability to inflammatory challenge, setting the state for pathogenically dysregulated neuroimmune responses.

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Microglia‐mediated phagocytosis of apoptotic nuclei is impaired in the adult murine hippocampus after stroke

Rudolph

Schmeer

Günther

et al. 2021

Glia

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Following stroke, neuronal death takes place both in the infarct region and in brain areas distal to the lesion site including the hippocampus. The hippocampus is critically involved in learning and memory processes and continuously generates new neurons. Dysregulation of adult neurogenesis may be associated with cognitive decline after a stroke lesion. In particular, proliferation of precursor cells and the formation of new neurons are increased after lesion. Within the first week, many new precursor cells die during development. How dying precursors are removed from the hippocampus and to what extent phagocytosis takes place after stroke is still not clear. Here, we evaluated the effect of a prefrontal stroke lesion on the phagocytic activity of microglia in the dentate gyrus (DG) of the hippocampus. Three‐months‐old C57BL/6J mice were injected once with the proliferation marker BrdU (250 mg/kg) 6 hr after a middle cerebral artery occlusion or sham surgery. The number of apoptotic cells and the phagocytic capacity of the microglia were evaluated by means of immunohistochemistry, confocal microscopy, and 3D‐reconstructions. We found a transient but significant increase in the number of apoptotic cells in the DG early after stroke, associated with impaired removal by microglia. Interestingly, phagocytosis of newly generated precursor cells was not affected. Our study shows that a prefrontal stroke lesion affects phagocytosis of apoptotic cells in the DG, a region distal to the lesion core. Whether disturbed phagocytosis might contribute to inflammatory‐ and maladaptive processes including cognitive impairment following stroke needs to be further investigated.

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Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus

Cited by 35 publications

References 55 publications

Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage

Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage

Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation

Microglia‐mediated phagocytosis of apoptotic nuclei is impaired in the adult murine hippocampus after stroke

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