Rtrack: a software package for reproducible automated water maze analysis

Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell–cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.

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“…Search strategy use was analyzed using a machine learning classifier package in R called RTrack [ 116 ] (Fig. 2 d).…”

Section: Resultsmentioning

confidence: 99%

“…Raw data from Ethovision (Noldus) was obtained and analyzed using the Rtrack in R, a package for reproducible and automated water maze analysis using a machine learning classifying strategy [ 116 ]. Metrics obtained from this package were latency to platform, time in goal zone, and search strategy classification.…”

Section: Methodsmentioning

confidence: 99%

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Schwab

Hazrati

2021

acta neuropathol commun

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“…Our group recently showed that, in aged mice, assessment of navigational learning strategies revealed important aspects of cognition that would not necessarily be apparent when assessing behavioral performance alone (Berdugo-Vega et al, 2020). Hence, we tested GFP and 4D-injected mice 4 weeks after tamoxifen administration to evaluate their evolution in the use of hippocampus-dependent and spatially-precise strategies over time by using an automated machine learning model that assesses swimming trajectories (Overall et al, 2020).…”

Section: Increased Neurogenesis Promotes Spatial Navigation and Fleximentioning

confidence: 99%

Adult-born neurons promote cognitive flexibility by improving memory precision and indexing

Berdugo-Vega

Lee

Garthe

et al. 2020

Preprint

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The dentate gyrus (DG) of the hippocampus is fundamental for cognitive flexibility and has the extraordinary ability to generate new neurons throughout life. Recent evidence suggested that adult-born neurons differentially modulate input to the DG during the processing of spatial information and novelty. However, how this differential regulation by neurogenesis is translated into different aspects contributing cognitive flexibility is unclear. Here, we increased adult-born neurons by a genetic expansion of neural stem cells and studied their influence during navigational learning. We found that increased neurogenesis improved memory precision, indexing and retention and that each of these gains was associated with a differential activation of specific DG compartments and better separation of memory representations in the DG-CA3 network. Our results highlight the role of adult-born neurons in promoting memory precision in the infrapyramidal and indexing in the suprapyramidal blade of the DG and together contributing to cognitive flexibility.

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“…Finally, we analysed a publicly available dataset with two strains of mice (10-week old female mice C57Bl/6J and DBA/2J) tested in a goal reversal task (Overall et al, 2020). These analyses highlight the power of the current vector field property-based measures in detecting search centers.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, such methods can detect multiple search strategies within a given MWM session (Cooke et al, 2019; Vouros et al, 2018). A parameter free machine learning based algorithm was also developed to classify MWM search strategies (Overall et al, 2020). This approach is automated and uses trajectories to assign performances in individual trials to different classes.…”

Section: Introductionmentioning

confidence: 99%

Novel measures of Morris water maze performance that use vector field maps to assess accuracy, uncertainty, and intention of navigational searches

Kumar

Mehrotra

Nruythyathi

et al. 2021

Preprint

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Most commonly used behavioural measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal s residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal s performance. Here, we describe novel measures of performance in the MWM that use vector fields to capture the motion of mice as well as their search pattern in the maze. Using these vector fields, we develop quantitative measures of performance that are intuitive and more sensitive than classical measures. First, we describe search patterns in terms of vector field properties and use these properties to define three metrics of spatial memory namely Spatial Accuracy, Uncertainty and, Intensity of Search. We demonstrate the usefulness of these measures using four different data sets including comparisons between different strains of mice, an analysis of two mouse models of Noonan syndrome (Ptpn11 D61G and Ptpn11 N308D/+), and a study of goal reversal training. Importantly, besides highlighting novel aspects of performance in this widely used spatial task, our measures were able to uncover previously undetected differences, including in an animal model of Noonan syndrome, which we rescued with the mitogen activated protein kinase kinase (MEK) inhibitor SL327. Thus, our results show that our approach breaks down performance in the Morris water maze into sensitive measurable independent components that highlight differences in spatial learning and memory in the MWM that were undetected by conventional measures.

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Rtrack: a software package for reproducible automated water maze analysis

Cited by 18 publications

References 14 publications

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Adult-born neurons promote cognitive flexibility by improving memory precision and indexing

Novel measures of Morris water maze performance that use vector field maps to assess accuracy, uncertainty, and intention of navigational searches

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