A Novel Animal Model of Hippocampal Cognitive Deficits, Slow Neurodegeneration, and Neuroregeneration

Spanswick, Simon C.; Lehmann, Hugo; Sutherland, Robert J.

doi:10.1155/2011/527201

Cited by 10 publications

(5 citation statements)

References 73 publications

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“…An intrinsic mechanism to cope with neuronal damage is of particular significance in the case of the DG given its exceptional vulnerability to many insults, such as virus-induced encephalitis (Wu et al, 2013), exposure to chemicals (Bruccoleri et al, 1998;Choi et al, 2014Choi et al, , 2017, adrenalectomy/adrenal insufficiency (Spanswick et al, 2007(Spanswick et al, , 2011Izumida et al, 2017), and Alzheimer's disease and frontotemporal lobe degeneration (Small et al, 2011;Armstrong et al, 2012;Adler et al, 2018). Our study adds yet another example for a selective DG vulnerability, namely, selective apoptosis of DG neurons following prolonged exposure to ectopic VEGF (a situation that can be physiologically relevant in the case of CNS tumors).…”

Section: Discussionmentioning

confidence: 99%

“…The exceptional vulnerability of the DG is also evidenced in other human pathologies, such as frontotemporal lobe degeneration, Alzheimer's disease, and adrenal insufficiency (Maehlen and Torvik, 1990;Armstrong et al, 2012;Collins et al, 2012;Kovacs et al, 2013;Takeda and Tamano, 2018) and in rodent models of these and other pathologies that are often associated with enhanced neurogenesis (Spanswick et al, 2007(Spanswick et al, , 2011Watanabe et al, 2016;Choi et al, 2017;Tu et al, 2018;F. Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells

et al. 2020

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Multiple insults to the brain lead to neuronal cell death, thus raising the question to what extent can lost neurons be replenished by adult neurogenesis. Here we focused on the hippocampus and especially the dentate gyrus (DG), a vulnerable brain region and one of the two sites where adult neuronal stem cells (NSCs) reside. While adult hippocampal neurogenesis was extensively studied with regard to its contribution to cognitive enhancement, we focused on their underestimated capability to repair a massively injured, nonfunctional DG. To address this issue, we inflicted substantial DG-specific damage in mice of either sex either by diphtheria toxin-based ablation of Ͼ50% of mature DG granule cells (GCs) or by prolonged brain-specific VEGF overexpression culminating in extensive, highly selective loss of DG GCs (thereby also reinforcing the notion of selective DG vulnerability). The neurogenic system promoted effective regeneration by increasing NSCs proliferation/survival rates, restoring a nearly original DG mass, promoting proper rewiring of regenerated neurons to their afferent and efferent partners, and regaining of lost spatial memory. Notably, concomitantly with the natural age-related decline in the levels of neurogenesis, the regenerative capacity of the hippocampus also subsided with age. The study thus revealed an unappreciated regenerative potential of the young DG and suggests hippocampal NSCs as a critical reservoir enabling recovery from catastrophic DG damage.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells

et al. 2020

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“…Such decrease persists over the course of time of the experiment (0.5, 2, 4, 12 hours, and 1, 3, 7, 14 days). The adrenal gland is known as the major producer of corticosterone in the body and the signi cant depletion that was observed in the ADX rats is attributed to its removal 6,[35][36][37][38] .…”

Section: Discussionmentioning

confidence: 99%

Stereological Evidence of Non-Selective Hippocampal Neurodegeneration, Growth Factors Depletion, and Behavioral Deficit Following Short-Term Bilateral Adrenalectomy in Wistar Rats 

Hamadi

Deniz

Issa

et al. 2021

Preprint

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In the current study we investigated the impact of short-term adrenalectomy on hippocampal neurons of Wistar rats. In addition, the underlying mechanism(s) of degeneration in these neurons was investigated by measuring the levels of insulin-like growth factor-1 and β-nerve growth factor. Moreover, we investigated the cognitive behavior in these rats. The stereological counting in the hippocampus revealed a significant neuronal death in the dentate gyrus and CA3, but not in the CA2 and CA1, area 7 and 14 days post adrenalectomy. The ultrastructural examinations revealed degenerated and degenerating neurons only in the dentate as well as CA4, and CA3 areas over the course of 3, 7 and 14 days. The levels of IGF-1 were significantly decreased in the hippocampus of ADX rats 12 h post adrenalectomy and lasted over the course of two weeks. However, β-NGF was significantly reduced in ADX rats only at 14 days postoperatively. Using passive avoidance test we found a cognitive deficit in the ADX compared to the sham operated rats over time. In conclusion, both granule and pyramidal cells were degenerated in the hippocampus following short-term adrenalectomy. The early depletion of IGF-1 might play a role in the hippocampal neuronal degeneration. Consequently, the loss of the hippocampal neurons after adrenalectomy leads to cognitive deficits.

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“…It is one of the first regions damaged in Alzheimer’s disease (AD) [ 1 , 2 ]. Hippocampal neurodegeneration accounts for the cognitive impairments observed in neurodegenerative disorders, such as AD [ 3 ]. There is a clinical association between hippocampal neurogenesis and cognition and microglia are important effectors of hippocampal neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of ex vivo-expanded regulatory T cells on trimethyltin-induced neurodegeneration in mice

Park

Yang

et al. 2022

J Neuroinflammation

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Background Trimethyltin (TMT) is a potent neurotoxicant that leads to hippocampal neurodegeneration. Regulatory T cells (Tregs) play an important role in maintaining the immune balance in the central nervous system (CNS), but their activities are impaired in neurodegenerative diseases. In this study, we aimed to determine whether adoptive transfer of Tregs, as a living drug, ameliorates hippocampal neurodegeneration in TMT-intoxicated mice. Methods CD4+CD25+ Tregs were expanded in vitro and adoptively transferred to TMT-treated mice. First, we explored the effects of Tregs on behavioral deficits using the Morris water maze and elevated plus maze tests. Biomarkers related to memory formation, such as cAMP response element-binding protein (CREB), protein kinase C (PKC), neuronal nuclear protein (NeuN), nerve growth factor (NGF), and ionized calcium binding adaptor molecule 1 (Iba1) in the hippocampus were examined by immunohistochemistry after killing the mouse. To investigate the neuroinflammatory responses, the polarization status of microglia was examined in vivo and in vitro using real-time reverse transcription polymerase chain reaction (rtPCR) and Enzyme-linked immunosorbent assay (ELISA). Additionally, the inhibitory effects of Tregs on TMT-induced microglial activation were examined using time-lapse live imaging in vitro with an activation-specific fluorescence probe, CDr20. Results Adoptive transfer of Tregs improved spatial learning and memory functions and reduced anxiety in TMT-intoxicated mice. Additionally, adoptive transfer of Tregs reduced neuronal loss and recovered the expression of neurogenesis enhancing molecules in the hippocampi of TMT-intoxicated mice. In particular, Tregs inhibited microglial activation and pro-inflammatory cytokine release in the hippocampi of TMT-intoxicated mice. The inhibitory effects of TMT were also confirmed via in vitro live time-lapse imaging in a Treg/microglia co-culture system. Conclusions These data suggest that adoptive transfer of Tregs ameliorates disease progression in TMT-induced neurodegeneration by promoting neurogenesis and modulating microglial activation and polarization.

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A Novel Animal Model of Hippocampal Cognitive Deficits, Slow Neurodegeneration, and Neuroregeneration

Cited by 10 publications

References 73 publications

Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells

Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells

Stereological Evidence of Non-Selective Hippocampal Neurodegeneration, Growth Factors Depletion, and Behavioral Deficit Following Short-Term Bilateral Adrenalectomy in Wistar Rats

Neuroprotective effects of ex vivo-expanded regulatory T cells on trimethyltin-induced neurodegeneration in mice

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A Novel Animal Model of Hippocampal Cognitive Deficits, Slow Neurodegeneration, and Neuroregeneration

Cited by 10 publications

References 73 publications

Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells

Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells

Stereological Evidence of Non-Selective Hippocampal Neurodegeneration, Growth Factors Depletion,&nbsp;and Behavioral Deficit Following Short-Term Bilateral Adrenalectomy in Wistar Rats&nbsp;

Neuroprotective effects of ex vivo-expanded regulatory T cells on trimethyltin-induced neurodegeneration in mice

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Stereological Evidence of Non-Selective Hippocampal Neurodegeneration, Growth Factors Depletion, and Behavioral Deficit Following Short-Term Bilateral Adrenalectomy in Wistar Rats