Emerging Role of Translational Digital Biomarkers Within Home Cage Monitoring Technologies in Preclinical Drug Discovery and Development

Baran, Szczepan W.; Bratcher, Natalie A; Dennis, John U.; Gaburro, Stefano; Karlsson, Eleanor M.; Maguire, Sean; Makidon, Paul E.; Noldus, L.P.J.J.; Potier, Yohann; Rosati, Giorgio; Ruiter, Matt; Schaevitz, Laura; Sweeney, Patrick J.; LaFollette, Megan R.

doi:10.3389/fnbeh.2021.758274

Cited by 29 publications

(33 citation statements)

References 74 publications

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“…It will likely be refined and augmented in the future, to provide greater sensitivity and nuance to the detection of animal frailty. Nonetheless, even in its current state, it serves as a proof of principle for the aspirational concept of an operationally efficient and humane digital vivarium (Baran et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…The approaches to mouse frailty assessment described above vary in terms of their invasiveness, but they invariantly require handling and/or exposure to a non-standard environment in order to be performed. Handling and exposure to novel environments both cause stress in laboratory mice (Balcombe et al, 2004; Baran et al, 2022). The frailty indexes described above invariantly include parameters known to be modified by handling-related stress: posture, response to stimuli, exploratory behavior, and blood chemistry among them (Hurst & West, 2010; Ghosal et al, 2015; Gouveia & Hurst, 2017).…”

Section: Introductionmentioning

confidence: 99%

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A home-cage, video monitoring-based mouse frailty index detects age-associated morbidity in the absence of handler-induced stress

Ruby

Ylagan

Francesco

et al. 2022

Preprint

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Frailty indexes provide quantitative measurements of non-specific health decline and are particularly useful as longitudinal monitors of pre-mortal morbidity in aging studies. For mouse studies, frailty assessments can be taken non-invasively, but they require handling and direct observation that is labor-intensive to the scientist and stress-inducing to the animal. Here, we implement, evaluate, and provide a digital frailty index composed entirely of computational analyses of home-cage video and compare it to manually obtained frailty scores in genetically diverse mice. We show that the frailty scores assigned by our digital index correlate with both manually obtained frailty scores and chronological age. Thus, we provide a tool for frailty assessment that reduces stress to the animal and can be collected consistently, at scale, without substantial labor cost.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A home-cage, video monitoring-based mouse frailty index detects age-associated morbidity in the absence of handler-induced stress

Ruby

Ylagan

Francesco

et al. 2022

Preprint

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“…Analysis was carried out using the software EthoVision XT 15 (EthoVision XT, RRID:SCR_000441), based on the counts (one rotation of the wheel) registered per minute. Bench-top assessment (Baran et al, 2022) focusing on activity patterns was conducted in the PhenoTyper cages using the tracking software Ethovision XT 15. On the third day after the mice were introduced to the PhenoTyper cages (adaptation time approximately: 60-64 h), we analyzed parameters of activity (distance, velocity) during a time slot of exactly 60 min shortly after the beginning of the dark phase.…”

Section: Voluntary Wheel Running and Bench-top Assessmentmentioning

confidence: 99%

Phenotyping Young GluA1 Deficient Mice – A Behavioral Characterization in a Genetic Loss-of-Function Model

Reiber

Stirling

Sprengel

et al. 2022

Front. Behav. Neurosci.

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Alterations of glutamatergic neurotransmission have been implicated in neurodevelopmental and neuropsychiatric disorders. Mice lacking the GluA1 AMPA receptor subunit, encoded by the Gria1 gene, display multiple phenotypical features associated with glutamatergic dysfunction. While the phenotype of adult GluA1 deficient (Gria1–/–) mice has been studied comprehensively, there are relevant gaps in knowledge about the course and the onset of behavioral alterations in the Gria1 knockout mouse model during post-weaning development. Based on former investigations in young wild-type mice, we exposed female and male adolescent Gria1–/– mice to a behavioral home-cage based testing battery designed for the purpose of severity assessment. Data obtained from mice with a constitutive loss of GluA1 were compared with those from wild-type littermates. We identified several genotype-dependent behavioral alterations in young Gria1–/– mice. While the preference for sweetness was not affected by genotype during adolescence, Gria1–/– mice displayed limited burrowing performance, and reached lower nest complexity scores. Analysis of home-cage based voluntary wheel running performance failed to confirm genotype-dependent differences. In contrast, when exposed to the open field test, Gria1–/– mice showed pronounced hyperlocomotion in early and late adolescence, and female Gria1–/– mice exhibited thigmotaxis when prepubescent. We found increased corticosterone metabolite levels in fecal samples of adolescent Gria1–/– mice with females exhibiting increased adrenocortical activity already in prepubescence. Considering the course of behavioral modifications in early and late adolescence, the results do not support a persistent level of distress associated with GluA1 deficiency in the line. In contrast, the laboratory-specific readouts indicate transient, mild impairments of behavioral patterns relevant to animal welfare, and suggest a mild overall burden of the line.

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“…[11, 12] suitable for a vivarium of small rodents. As recently reviewed [13-15], such HCM systems provide an excellent opportunity to collect cumulative unsupervised records of in-cage rest and PA on a large scale. The purpose of this study was to characterize spontaneous in-cage activity and rest across the circadian cycle and cycles of recurrent husbandry routines over multiple weeks to provide base line data on duration and frequency of bouts of rest and [physical] activity (PA), and how the animals use the cage floor as well as rhythmicity of rest and PA. For this purpose, we recorded cumulative data with a home-cage monitoring system (DVC® Tecniplast SpA) of C57BL/6J mice in standard IVC cages (GM500), kept either in isolation (x1) or in groups at different densities (x2, x3, x4).…”

Section: Introductionmentioning

confidence: 99%

Bouts of rest and physical activity in C57BL/6J mice

Pernold¹,

Rullman²,

Ulfhake³

2023

Preprint

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The objective was to exploit the raw data output from a scalable home cage (type IIL IVC) monitoring (HCM) system (DVC®), to characterize pattern of undisrupted rest and physical activity (PA) of C57BL/6J mice. The system's tracking algorithm show that mice in isolation spend 67% of the time in bouts of long rest (>=40s) and 59 % of the time was interpreted as sleep. Twenty percent is physical activity (PA), split equally between local movements and locomotion. Decomposition revealed that a day contains ~6500 discrete bouts of short and long rest, local and locomotor movements. Mice travel ~330m per day, mainly during the dark hours, while travelling speed is similar through the light-dark cycle. Locomotor bouts are usually <0.2m and <1% are >1m. Tracking revealed also fits of abnormal behaviour. The starting positions of the bouts showed no preference for the rear over the front of the cage floor, while there was a strong bias for the peripheral (75%) over the central floor area. The composition of bouts has a characteristic circadian pattern, however, intrusive husbandry routines increased bout fragmentation by ~40%. Extracting electrode activations density (EAD) from the raw data yielded results close to those obtained with the tracking algorithm, with 59% of time in long rest (<1 EAD s-1) and 20% in PA. We confirm that EAD correlates closely with movement distance (rs>0.95) and the data agreed in ~96% of the file time. Thus, albeit EAD being less informative it may serve as a proxy for PA and rest, enabling monitoring group housed mice. The data show that a change in housing density from one to two, and up to three mice had the same effect size on EAD (~2) with no difference between sexes. The EAD deviated significantly from this stepwise increase with 4 mice per cage, suggesting a crowdedness stress inducing sex specific adaptations. We conclude that informative metrics on rest and PA can be automatically extracted from the raw data flow in near-real time (< 1 hrs). These metrics relay useful longitudinal information to those that use or care for the animals.

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Emerging Role of Translational Digital Biomarkers Within Home Cage Monitoring Technologies in Preclinical Drug Discovery and Development

Cited by 29 publications

References 74 publications

A home-cage, video monitoring-based mouse frailty index detects age-associated morbidity in the absence of handler-induced stress

A home-cage, video monitoring-based mouse frailty index detects age-associated morbidity in the absence of handler-induced stress

Phenotyping Young GluA1 Deficient Mice – A Behavioral Characterization in a Genetic Loss-of-Function Model

Bouts of rest and physical activity in C57BL/6J mice

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