Microglia are implicated in the development of paclitaxel chemotherapy-associated cognitive impairment in female mice

Grant, Corena V.; Sullivan, Kyle A.; Wentworth, Kylie; Otto, Lauren; Strehle, Lindsay D.; Otero, José; Pyter, Leah M.

doi:10.1016/j.bbi.2022.12.004

Cited by 8 publications

(11 citation statements)

References 53 publications

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“…Free‐floating sections were stored in a cryoprotectant solution (30% ethylene glycol in phosphate buffer) at −20°C until immunolabeling. Brain sections containing regions of interest because of their contribution in regulation of affective‐like and cognitive behaviors (amygdala, hippocampus) were processed as previously described 35 . Briefly, wells were blocked in 5% normal donkey serum (NDS) in immunohistochemistry (IHC) buffer (5% bovine serum albumin/0.1% Triton X‐100/PBS) for 1 h at room temperature while rocking.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were stored at −80°C until RNA was isolated. We have previously determined that >80% of cells are CD11b + /CD45 lo via flow cytometry using this protocol 35 …”

Section: Methodsmentioning

confidence: 99%

“…Brain sections containing regions of interest because of their contribution in regulation of affective-like and cognitive behaviors (amygdala, hippocampus) were processed as previously described. 35 Briefly, wells were blocked in 5% normal donkey serum (NDS) in immunohistochemistry (IHC) buffer (5% bovine serum albumin/0.1% Triton X-100/PBS) for 1 h at room temperature while rocking. Sections were incubated overnight at 4°C in 5% NDS IHC buffer with the following dilutions of primary antibodies: rabbit anti-IBA1 (1:2000; Wako Chemicals, Richmond, VA, USA, cat.…”

Section: Brain Sectioning and Immunolabelingmentioning

confidence: 99%

“…Brain tissues from Experiment 2 were immediately processed following tissue collection to isolate microglia using a Percoll gradient with freshly prepared stock isotonic Percoll (SIP; in 10× PBS) as previously described. 35 Briefly, whole brains were manually homogenized and the suspended cell solution was centrifuged (900× g, 6 min at 4°C). Supernatant was removed and the pellet was resuspended in 70% SIP, followed by careful layering of 50% SIP, 35% SIP, then 1× PBS.…”

Section: Microglia Enrichmentmentioning

confidence: 99%

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Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Strehle,

Otto‐Dobos,

Grant

et al. 2024

The FASEB Journal

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Following diagnosis but before treatment, up to 30% of breast cancer patients report behavioral side effects (e.g., anxiety, depression, memory impairment). Our rodent mammary tumor model recapitulates aspects of these behavioral sequelae, as well as elevated circulating and brain inflammatory mediators. Neuroinflammation is a proposed mechanism underlying the etiology of mood disorders and cognitive deficits, and therefore may be contributing to tumor‐associated behavioral side effects. The cellular mechanisms by which tumor‐induced neuroinflammation occurs remain unknown, making targeted treatment approaches inaccessible. Here, we tested the hypotheses that microglia are the primary cells driving tumor‐induced neuroinflammation and behavioral side effects. Young adult female BALB/c mice were induced with a 67NR mammary tumor; tumor‐free controls underwent a sham surgery. Mammary tumors increased IBA1+ and GFAP+ staining in the amygdala and hippocampus relative to tumor‐free controls. However, tumors did not alter gene expression of Percoll‐enriched microglia isolated from the whole brain. While cognitive, social, and anhedonia‐like behaviors were not altered in tumor‐bearing mice, tumors increased central tendency in the open‐field test; microglia depletion did not reverse this effect. Brain region RT‐qPCR data indicated that microglia depletion attenuated tumor‐induced elevations of neuroinflammatory gene expression in a region‐ and mediator‐specific manner. These results indicate a causal role of microglia in tumor‐induced neuroinflammation. This research advances our understanding of the cellular mechanisms underlying tumor‐induced neuroinflammation in order to understand how brain responses (e.g., behavior) may be altered with subsequent cancer‐related immune challenges.

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Section: Methodsmentioning

confidence: 99%

“…Cells were stored at −80°C until RNA was isolated. We have previously determined that >80% of cells are CD11b + /CD45 lo via flow cytometry using this protocol 35 …”

Section: Methodsmentioning

confidence: 99%

Section: Brain Sectioning and Immunolabelingmentioning

confidence: 99%

Section: Microglia Enrichmentmentioning

confidence: 99%

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Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Strehle,

Otto‐Dobos,

Grant

et al. 2024

The FASEB Journal

Self Cite

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“…Similarly, a study investigating paclitaxel chemotherapy administration in C57BL/6 mice found that hippocampal microglia was significantly increased after 5-days of recovery (24). To date, while the role of microglia in CICI has been well-characterised (25), less is known about the function that astrocytes serve in this process.…”

Section: Introductionmentioning

confidence: 99%

Changes in cognition and neuroinflammation in a rodent model of chemotherapy-induced cognitive impairment are variable both acutely and chronically

Haller,

Semendric,

Collins-Praino

et al. 2024

Preprint

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Chemotherapy-induced cognitive impairment (CICI) affects up to 75% of cancer survivors between 6-months and 20-years post-treatment. Impairments include memory loss, learning difficulties, inability to concentrate and a decrease in processing speed, all of which can negatively impact quality of life. Several mechanisms are proposed to drive these impairments, with evidence implicating neuroinflammation as a key contributor. However, the time course over which impairments occur is less well-established. Several preclinical studies have focused on acute (0-7 days) and sub-acute (8-days to 12-weeks) time-points following chemotherapy, but few have investigated more longer-term time-points. This study therefore aimed to understand the evolution of cognitive changes following methotrexate (MTX) or 5-flurouracil (5-FU) chemotherapy treatment, assessing three time-points: acute (96-hour), sub-acute (31-days) and chronic (93-days). Further, we investigated whether alterations in cognition were associated with concomitant changes in neuroinflammation, assessed via astrocytic reactivity. Female Sprague Dawley rats received two intraperitoneal injections of MTX, 5-FU or saline and were assessed on the novel object recognition, 5-choice serial reaction time task and Barnes maze. Hippocampal (HIPP) and pre-frontal cortex (PFC) tissue was examined for GFAP expression. Results indicate that both MTX and 5-FU exposure were associated with impairments in spatial memory, task acquisition, and processing speed at 31-days, with impairment ameliorated by 93-days post-treatment. While MTX and 5-FU increased GFAP expression across all time-points, with the largest changes at 96-hours and 31-days, drug-specific and region-specific variations were noted. These results provide valuable insight into the complexity of the neuroinflammatory response in CICI. While neuroinflammation may be a promising therapeutic target, further work is required to fully understand this response, including which aspects to target and at what time-points, to ensure optimal outcomes for cancer patients treated with chemotherapy.

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Effects of mammary cancer and chemotherapy on neuroimmunological markers and memory function in a preclinical mouse model

Netherby-Winslow,

Thompson,

Lotta

et al. 2023

Brain, Behavior, & Immunity - Health

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Microglia are implicated in the development of paclitaxel chemotherapy-associated cognitive impairment in female mice

Cited by 8 publications

References 53 publications

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Changes in cognition and neuroinflammation in a rodent model of chemotherapy-induced cognitive impairment are variable both acutely and chronically

Effects of mammary cancer and chemotherapy on neuroimmunological markers and memory function in a preclinical mouse model

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