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

Abstract

Chemotherapy remains a mainstay in the treatment of many types of cancer even though it is associated with debilitating behavioral side effects referred to as “chemobrain,” including difficulty concentrating and memory impairment. The predominant hypothesis in the field is that systemic inflammation drives these cognitive impairments, although the brain mechanisms by which this occurs remain poorly understood. Here, we hypothesized that microglia are activated by chemotherapy and drive chemotherapy-associated cognitive impairments. To test this hypothesis, we treated female C57BL/6 mice with a clinically-relevant regimen of a common chemotherapeutic, paclitaxel (6 i.p. doses at 30 mg/kg), which impairs memory of an aversive stimulus as assessed via a contextual fear conditioning (CFC) paradigm. In this work, paclitaxel increased the percent area of IBA1 staining in the dentate gyrus of the hippocampus. Moreover, using a machine learning random forest classifier we identified immunohistochemical features of reactive microglia in multiple hippocampal subregions that were distinct between vehicle- and paclitaxel-treated mice. Paclitaxel treatment also increased gene expression of inflammatory cytokines in a microglia-enriched population of cells from mice. Lastly, a selective inhibitor of colony stimulating factor 1 receptor, PLX5622, was employed to deplete microglia and then assess CFC performance following paclitaxel treatment. PLX5622 significantly reduced hippocampalmore » gene expression of paclitaxel-induced proinflammatory cytokines and restored memory, suggesting that microglia play a critical role in the development of chemotherapy-associated neuroinflammation and cognitive impairments. This work provides critical evidence that microglia drive paclitaxel-associated cognitive impairments, a key mechanistic detail for determining preventative and intervention strategies for these burdensome side effects.« less

Authors:

Grant, Corena V. ^[1]; Sullivan, Kyle A.  ^[2];

• Search DOE PAGES for author "Sullivan, Kyle A."
• Search DOE PAGES for ORCID "0000-0002-4621-5598"

Wentworth, Kylie M. ^[1]; Otto, Lauren D. ^[1]; Strehle, Lindsay D. ^[1]; Otero, Jose J. ^[3]; Pyter, Leah M. ^[4]

---

+ Show Author Affiliations

1. The Ohio State Univ. Wexner Medical Center, Columbus, OH (United States)
2. The Ohio State Univ. Wexner Medical Center, Columbus, OH (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
3. The Ohio State Univ., Columbus, OH (United States)
4. The Ohio State Univ. Wexner Medical Center, Columbus, OH (United States); The Ohio State Univ., Columbus, OH (United States)

Publication Date:

Tue Dec 06 00:00:00 EST 2022

Research Org.:

Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Org.:

USDOE; National Institutes of Health (NIH)

OSTI Identifier:

1905395

Grant/Contract Number:  

AC05-00OR22725; CA216290

Resource Type:

Accepted Manuscript

Journal Name:

Brain, Behavior, and Immunity

Additional Journal Information:

Journal Volume: 108; Journal Issue: 1; Journal ID: ISSN 0889-1591

Publisher:

Elsevier

Country of Publication:

United States

Language:

English

Subject:

60 APPLIED LIFE SCIENCES; Contextual fear conditioning; Inflammation; PLX5622; Hippocampus; Machine learning