Source Paper
Chetan Ahire, Adam Nyul‐Toth, Jordan DelFavero, Rafal Gulej, Janet A. Faakye et al.
Aging Cell • 2023
Abstract Chemotherapy‐induced cognitive impairment (“chemobrain”) is a frequent side‐effect in cancer survivors treated with paclitaxel (PTX). The mechanisms responsible for PTX‐induced cognitive impairment remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that PTX induces endothelial senescence, which impairs microvascular function and contributes to the genesis of cognitive decline. We treated transgenic p16‐3MR mice, which allows the detection and selective elimination of senescent cells, with PTX (5 mg/kg/day, 2 cycles; 5 days/cycle). PTX‐treated and control mice were tested for spatial memory performance, neurovascular coupling (NVC) responses (whisker‐stimulation‐induced increases in cerebral blood flow), microvascular density, blood–brain barrier (BBB) permeability and the presence of senescent endothelial cells (by flow cytometry and single‐cell transcriptomics) at 6 months post‐treatment. PTX induced senescence in endothelial cells, which associated with microvascular rarefaction, NVC dysfunction, BBB disruption, neuroinflammation, and impaired performance on cognitive tasks. To establish a causal relationship between PTX‐induced senescence and impaired microvascular functions, senescent cells were depleted from PTX‐treated animals (at 3 months post‐treatment) by genetic (ganciclovir) or pharmacological (treatment with the senolytic drug ABT263/Navitoclax) means. In PTX treated mice, both treatments effectively eliminated senescent endothelial cells, rescued endothelium‐mediated NVC responses and BBB integrity, increased capillarization and improved cognitive performance. Our findings suggest that senolytic treatments can be a promising strategy for preventing chemotherapy‐induced cognitive impairment.
Objective: Assessment of spatial memory performance in mice following paclitaxel treatment or control conditions using Morris Water Maze and related cognitive tests
This is a Morris Water Maze protocol using mouse as the model organism. The procedure involves 19 procedural steps, 10 equipment items, 5 materials. Extracted from a 2023 paper published in Aging Cell.
Model and subjects
mouse • p16-3MR transgenic mice • male • 3 months old at start of treatment • not specified • 200
Study window
~2 week study window
Core workflow
Paclitaxel treatment initiation • Recovery period after chemotherapy • Senescent cell depletion - Group assignment
Primary readouts
Key equipment and reagents
Verified items
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Three-month-old male p16-3MR mice received intraperitoneal injections of paclitaxel or vehicle control
Note: PTX dose: 5 mg/kg/day; Vehicle: DMSO + saline; n=150 PTX-treated, n=50 vehicle control
“Three-month-old male p16-3MR mice received PTX (5 mg/kg/day, i.p., n = 150) or vehicle (DMSO + saline, n = 50) in 2 cycles (5 days/cycle) with a 7-day interval between cycles”
Mice were left to recover in original environment following PTX treatment completion
Note: After this recovery period, PTX-treated mice were randomly assigned to three groups
“Mice were left to recover for 2 weeks in the original environment”
PTX-treated mice were randomly assigned to three groups: ABT263 treatment, GCV treatment, or vehicle control
Note: Assignment occurred 2 weeks after PTX treatment completion
“PTX treated mice were assigned randomly to three groups. Two groups received the senolytic drug ABT263 or ganciclovir (GCV)”
First group of PTX-treated mice received intraperitoneal injections of senolytic drug ABT263
Note: Dose: 1.5 mg/kg/daily in DMSO/saline; Started 3 months after PTX treatment
“Two groups received the senolytic drug ABT263 (Navitoclax, Chemgood, C-1009, i.p., 1.5 mg/kg/daily in DMSO/saline)”
Second group of PTX-treated mice received intraperitoneal injections of ganciclovir prodrug
Note: Dose: 25 mg/kg/daily; Started 3 months after PTX treatment; Selectively kills p16-positive senescent cells
“ganciclovir (GCV [TSZCHEM, RG001, >99%]; i.p. 25 mg/kg/daily) for 5 days and 2 cycles with a 2 week interval between cycles”
Third group of PTX-treated mice received vehicle control injections
Note: Serves as control for senescent cell depletion treatments
“The third group served as vehicle controls”
Mice tested for spatial memory and long-term memory performance using radial arms water maze
Note: Conducted at 6 months post-chemotherapy; Tests hippocampal-dependent spatial memory
“spatial memory and long term memory were tested by assessing performance in the radial arms water maze at 6 months post-chemotherapy”
Mice tested for hippocampal-dependent contextual memory using Y-maze two-trial delayed alternation task
Note: Conducted at 6 months post-chemotherapy
“Hippocampal-dependent contextual memory was tested with the Y-maze two-trial delayed alternation task”
Measurement of maximal muscle strength of mouse forelimbs as control for pharmacological treatment effects on muscle function
Note: Control test to assess whether treatments affect muscle function
“grip strength test was used to measure the maximal muscle strength of mouse forelimbs”
Assessment of motor coordination using automated four-lane rotarod
Note: Control test to assess motor function
“Motor coordination was assessed using an automated four-lane rotarod tool”
Automated computer-assisted gait analysis to determine impact of PTX treatment on gait coordination
Note: Uses CatWalk system from Noldus Information Technology Inc.
“automated computer assisted method (CatWalk; Noldus Information Technology Inc.)”
Surgical implantation of chronic cranial window for intravital imaging
Note: Required for two-photon microscopy and OCT imaging
“mice were equipped with a chronic cranial window and intravital two-photon microscopy-based and optical coherence tomography (OCT) based imaging methods were used”
Intravital two-photon microscopy and OCT imaging to assess blood-brain barrier permeability and cerebromicrovascular density
Note: Conducted at 6 months post-chemotherapy
“To assess BBB permeability and cerebromicrovascular density, mice were equipped with a chronic cranial window and intravital two-photon microscopy-based and optical coherence tomography (OCT) based imaging methods were used”
Mice anesthetized with isoflurane, endotracheally intubated, and ventilated for NVC measurements
Note: Isoflurane: 2% induction and 1% maintenance
“mice in each group were anesthetized with isoflurane (2% induction and 1% maintenance), endotracheally intubated, and ventilated”
Assessment of cerebral blood flow changes in response to mechanical whisker stimulation
Note: Skull thinned; CBF measured above left somatosensory whisker barrel cortex in response to right whisker stimulation
“The skull was thinned and changes in cerebral blood flow (CBF) were assessed above the left somatosensory whisker barrel cortex in response to mechanical stimulation of the right whiskers”
CBF responses to whisker stimulation repeated after administrating nitric oxide synthase inhibitor to assess NO mediation
Note: Assesses role of nitric oxide in NVC responses
“CBF responses to whisker stimulation were repeated after administrating the nitric oxide synthase inhibitor N ω-Nitro-L-arginine methyl ester”
Detection and analysis of senescent endothelial cells from brain tissue using flow cytometry
Note: Detects RFP+/CD-31+ senescent endothelial cells; Conducted at 6 months post-chemotherapy
“Flow cytometric detection of RFP+/CD-31+ senescent endothelial cells, RFP-/CD-31+ non-senescent endothelial cells”
Single-cell RNA sequencing to identify senescent cells and characterize cell types in brain tissue
Note: Identifies senescent endothelial cells, microglia, pericytes, vascular smooth muscle cells, and oligodendrocytes
“single-cell transcriptomics”
Mice euthanized and tissues collected for analysis
Note: Conducted at 6 months post-chemotherapy after all behavioral and imaging assessments
“At the end of 6 months after the PTX protocol, mice were tested for cognitive functions, NVC responses, and microvascular density and BBB integrity, and then were euthanized for tissue collection”
This section explains what the experiment is doing, which readouts matter, what the data artifacts usually look like, and how the analysis should flow from raw capture to reported result.
Assessment of spatial memory performance in mice following paclitaxel treatment or control conditions using Morris Water Maze and related cognitive tests
Objective
Assessment of spatial memory performance in mice following paclitaxel treatment or control conditions using Morris Water Maze and related cognitive tests
Subjects
From papermouse • p16-3MR transgenic mice • male • 3 months old at start of treatment • not specified
Sample count
From paper200
Cohort notes
From paperPTX-treated (n=150) or vehicle control (n=50); tested at 6 months post-chemotherapy
Paclitaxel treatment initiation (2 cycles of 5 days each with 7-day interval between cycles)
Recovery period after chemotherapy (2 weeks)
Senescent cell depletion - Group assignment (not specified)
ABT263 (Navitoclax) treatment (5 days per cycle, 2 cycles with 2-week interval between cycles)
Spatial memory performance (radial arms water maze)
From papernot explicitly detailed in provided text; statistical significance indicated by p-values (*** p < 0.001 versus control)
Artifact type
Longitudinal gait metrics and per-animal performance tables
Comparison focus
Compare recovery trajectory across post-injury timepoints and treatment conditions
Long-term memory performance (radial arms water maze)
From papernot explicitly detailed in provided text; statistical significance indicated by p-values (*** p < 0.001 versus control)
Artifact type
Longitudinal gait metrics and per-animal performance tables
Comparison focus
Compare recovery trajectory across post-injury timepoints and treatment conditions
Hippocampal-dependent contextual memory (Y-maze two-trial delayed alternation)
From papernot explicitly detailed in provided text; statistical significance indicated by p-values (*** p < 0.001 versus control)
Artifact type
Longitudinal gait metrics and per-animal performance tables
Comparison focus
Compare recovery trajectory across post-injury timepoints and treatment conditions
Grip strength (forelimb muscle strength)
From papernot explicitly detailed in provided text; statistical significance indicated by p-values (*** p < 0.001 versus control)
Artifact type
Longitudinal gait metrics and per-animal performance tables
Comparison focus
Compare recovery trajectory across post-injury timepoints and treatment conditions
Spatial memory performance (radial arms water maze)
From paperRaw artifact
Per-run gait capture with paw placement, timing, and stride features for each animal
Processed artifact
Cleaned gait metrics table and recovery trend summary across timepoints
Final reported form
Group comparisons of gait indices, stride metrics, or recovery curves
Long-term memory performance (radial arms water maze)
From paperRaw artifact
Per-run gait capture with paw placement, timing, and stride features for each animal
Processed artifact
Cleaned gait metrics table and recovery trend summary across timepoints
Final reported form
Group comparisons of gait indices, stride metrics, or recovery curves
Hippocampal-dependent contextual memory (Y-maze two-trial delayed alternation)
From paperRaw artifact
Per-run gait capture with paw placement, timing, and stride features for each animal
Processed artifact
Cleaned gait metrics table and recovery trend summary across timepoints
Final reported form
Group comparisons of gait indices, stride metrics, or recovery curves
Grip strength (forelimb muscle strength)
From paperRaw artifact
Per-run gait capture with paw placement, timing, and stride features for each animal
Processed artifact
Cleaned gait metrics table and recovery trend summary across timepoints
Final reported form
Group comparisons of gait indices, stride metrics, or recovery curves
Acquisition
Capture run-level gait data for each animal and preserve the timepoint or treatment labeling.
Preprocessing / cleaning
not explicitly detailed in provided text; statistical significance indicated by p-values (*** p < 0.001 versus control)
Scoring or quantification
Quantify the primary readouts for this experiment: Spatial memory performance (radial arms water maze); Long-term memory performance (radial arms water maze); Hippocampal-dependent contextual memory (Y-maze two-trial delayed alternation); Grip strength (forelimb muscle strength).
Statistical comparison
Statistical method not yet structured for this page.
Reporting output
Report representative outputs alongside summary comparisons for Spatial memory performance (radial arms water maze), Long-term memory performance (radial arms water maze), Hippocampal-dependent contextual memory (Y-maze two-trial delayed alternation), Grip strength (forelimb muscle strength).
Source links and direct wording from the methods section for validation and deeper review.
Citation
Chetan Ahire et al. (2023). Accelerated cerebromicrovascular senescence contributes to cognitive decline in a mouse model of paclitaxel (Taxol)‐induced chemobrain. Aging Cell
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