Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice

Rola, Radosław; Raber, Jacob; Rizk, Angela; Otsuka, Shinji; VandenBerg, Scott R.; Morhardt, Duncan R.; Fike, John R.

doi:10.1016/j.expneurol.2004.05.005

Cited by 606 publications

(520 citation statements)

References 84 publications

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“…Our finding that the basal density of microglia in the SGZ did not change with age is consistent with previous studies of the murine hippocampus (57). We suspected that the transient increase in proliferation observed one week after WBI was due to increased microgliogenesis, since others have shown that the production of new cells by proliferating cells in the SGZ is altered following WBI and results in increased genesis of oligodendrocytes and microglia (10,13): BrdU labeling of three week old and two month old mice several weeks after WBI revealed an increased percentage of BrdU + cells labeled for CD68 (8,12). We did not quantify microglial proliferation in the current study but qualitative assessment of sections double-labeled for Ki-67 and Iba1 indicated that the majority of Ki-67 + cells in the SGZ at one week after WBI were Iba1 + microglia and that the percentage of Iba1 + cells in the DG that were Ki-67 + increased from less than 1% in control animals to approximately 20% in irradiated rats (data not shown).…”

Section: Discussionmentioning

confidence: 55%

“…WBI-induced deficits in hippocampal function have been associated with decreased neurogenesis (11,12,43), which potentially could arise from changes in cell proliferation, commitment, and/or survival. We examined both the density of proliferating, Ki67 + cells in the SGZ of the rodent hippocampus and, more specifically, the density of immature, DCX + neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Surviving progenitor cells then are chronically suppressed, possibly by increased inflammation (10). These changes have been associated with cognitive deficits in young rodents, suggesting that in the young brain neurogenesis is important in some learning and memory pathways that are vulnerable to WBI (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we irradiated rats 8 (young adult), 18 (middle-age), and 28 (old) months of age to test whether aging alters radiation-induced changes in proliferation and the production of immature neurons in the SGZ of the hippocampus, neurobiological changes thought to contribute to the development of cognitive dysfunction (11,12). In addition, we tested whether old animals show a greater inflammatory response to a single 10Gy dose of WBI by assessing the total number and activation state of the microglia at one and ten weeks post-irradiation.…”

Section: Introductionmentioning

confidence: 99%

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Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

Schindler¹,

Forbes²,

Robbins³

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To assess the impact of aging on the radiation response in the adult rat brain.Methods and Materials-Male rats 8, 18, or 28 months of age received a single 10Gy dose of whole brain irradiation (WBI). The hippocampal dentate gyrus (DG) was analyzed one and ten weeks later for sensitive neurobiological markers associated with radiation-induced damage: changes in the density of proliferating cells, immature neurons, total microglia, and activated microglia.Results-A significant reduction in basal levels of proliferating cells and immature neurons and increased microglial activation occurred with normal aging. WBI induced a transient increase in proliferation that was greater in older animals. This proliferation response did not increase the number of immature neurons, which decreased following WBI in young rats but not in old rats. Total microglial number decreased following WBI at all ages but microglial activation increased markedly, particularly in older animals.Conclusions-Age is an important factor to consider when investigating the radiation response of the brain. In contrast to young adults, older rats show no sustained decrease in the number of immature neurons following WBI but have a greater inflammatory response. The latter may play an enhanced role in the development of radiation-induced cognitive dysfunction in older individuals.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

Schindler¹,

Forbes²,

Robbins³

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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“…While control experiments suggested that irradiation did not disrupt hippocampal function beyond limiting proliferation, the possibility remains that unknown molecular factors important to antidepressant efficacy and/or hippocampal function were affected by the procedure. X-ray irradiation of the hippocampus has been shown to cause cognitive deficits in mice (Rola et al, 2004), and may increase apoptosis, produce changes in genes associated with DNA damage and stress response, alter the morphology or functionality of mature neurons, and alter blood flow to irradiated regions (Gobbel et al, 1998;Shirai et al, 2006). Therefore, there remains a need for less invasive methods to test the link between neurogenesis and antidepressant efficacy.…”

Section: Discussionmentioning

confidence: 99%

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

Miller

Schultz

Gulati

et al. 2007

Neuropsychopharmacol

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Despite widespread use of antidepressants, the factors underlying the behavioral response to antidepressants are unknown. It has been shown that antidepressant treatment promotes the proliferation and survival of neurons in the adult hippocampus via enhanced serotonergic signaling, but it is unclear whether hippocampal neurogenesis is responsible for the behavioral response to antidepressants. Furthermore, a large subpopulation of patients fails to respond to antidepressant treatment due to presumed underlying genetic factors. In the present study, we have used the phenotypic and genotypic variability of inbred mouse strains to show that there is a genetic component to both the behavioral and neuronal effects of chronic fluoxetine treatment, and that this antidepressant induces an increase in hippocampal cell proliferation only in the strains that also show a positive behavioral response to treatment. Furthermore, the behavioral and neuronal responses are associated with an upregulation of genes known to promote neuronal proliferation and survival. These results suggest that inherent genetic predisposition to increased serotonin-induced neurogenesis may be a determinant of antidepressant efficacy.

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Adult hippocampal neurogenesis in aging and Alzheimer's disease

Varela-Nallar

Aranguiz

Abbott

et al. 2010

Birth Defects Research Pt C

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Adult neurogenesis occurs in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles. This process is highly regulated by intrinsic and extrinsic factors, which may control the proliferation and/or maturation of neural progenitor cells. Adult-born neurons are integrated in preexisting networks and may have functional implications for adult brain. Here we attempt to summarize relevant findings concerning the physiological role of adult neurogenesis mainly focused on the subgranular zone, and to discuss the reduced neurogenesis observed during aging and the factors that have been involved in this phenomenon. Finally, we focus on hippocampal neurogenesis in Alzheimer's disease, reviewing animal models of the disease used for the study of this process and the conclusions that have been drawn in this context.

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Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice

Cited by 606 publications

References 84 publications

Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

Adult hippocampal neurogenesis in aging and Alzheimer's disease

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