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NC3Rs: National Centre for the Replacement Refinement & Reduction of Animals in Research
Project grant

Assessing cumulative severity in macaques used in neuroscience research

Two macaques looking towards the camera

At a glance

Award date
July 2013 - December 2016
Grant amount
Principal investigator
Professor Melissa Bateson
Newcastle University


  • Refinement
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Application abstract

It is assumed that there are cumulative effects of repeated invasive procedures and contingent stressors on the welfare of non-human primates used in neuroscience research. The new EU Directive (2010/63/EU) on the use of animals in research emphasises the "lifetime experience" of animals and requires assessment of the "cumulative severity" of experiments. However, there are currently few data on the long-term impacts of repeated procedures to inform severity banding.

We aim to develop novel psychobiomarkers of cumulative stress based on our knowledge of major depressive disorder in humans and apply these measures to macaques involved in neuroscience research. We will take two main approaches: (1) measurement via qPCR of changes in leukocyte telomere length, and (2) measurement via MRI of structural and functional changes in the brain. These dependent variables will be taken at 6-monthly intervals from a group of 40+ animals involved in various types of neuroscience research; telomere measurements will also be made in 30+ control animals not subject to invasive procedures. Information on sources of possible stress (our independent variables, e.g. number and type of procedures, days on antibiotics or fluid control) will be collated for all animals in the study. Statistical modelling will be used to explore the relationships between potential stressors and our candidate psychobiomarkers.

These analyses will allow us to answer the question of whether the number and/or type of stressors a monkey has experienced predict changes in psychobiomarkers of cumulative stress. If cumulative effects of stressors are found, we will attempt to identify the shape of the relationship between stressors and our psychobiomarkers. Our results will: (1) provide a scientific basis for determining the cumulative severity rating of procedures, (2) reveal procedures that are most in need of refinement, and (3) permit adjudication on the relative costs of continued use of animals.


  1. Milham M et al. (2020). Accelerating the Evolution of Nonhuman Primate Neuroimaging. Neuron 105(4):600-603. doi: 10.1016/j.neuron.2019.12.023
  2. Bateson M et al. (2019). Smoking does not accelerate leucocyte telomere attrition: a meta-analysis of 18 longitudinal cohorts. Royal Society Open Science 6(6):190420. doi: 10.1098/rsos.190420
  3. Bateson M et al. (2019). Controlling for baseline telomere length biases estimates of the rate of telomere attrition. Royal Society Open Science 6(10):190937. doi: 10.1098/rsos.190937
  4. Nettle D et al. (2019). Consequences of measurement error in qPCR telomere data: A simulation study. PLoS One 14(5): e0216118. doi: 10.1371/journal.pone.0216118
  5. Poirier C et al. (2019). Validation of hippocampal biomarkers of cumulative affective experience. Neuroscience and Biobehavioural Reviews 101:113-121. doi: 10.1016/j.neubiorev.2019.03.024
  6. Poirier C et al. (2019). Pacing behaviour in laboratory macaques is an unreliable indicator of acute stress. Scientific Reports 9:7476. doi :10.1038/s41598-019-43695-5
  7. Pepper GV et al. (2018). Telomeres as integrative markers of exposure to stress and adversity: a systematic review and meta-analysis. Royal Society open science 5(8):180744. doi: 10.1098/rsos.180744
  8. Milham MP et al. (2018). An open resource for non-human primate imaging. Neuron 100(1):61-74. doi: 10.1016/j.neuron.2018.08.039
  9. Bateson M, Poirier C (2018). Can biomarkers of biological age be used to assess cumulative lifetime experience? Animal Welfare 28:41-56. doi: 10.7120/09627286.28.1.041
  10. Bateson M, Nettle D (2017). The telomere lengthening conundrum - it could be biology. Aging cell 16(2):312-319. doi: 10.1111/acel.12555
  11. Nettle D, Bateson M (2017). Detecting telomere elongation in longitudinal datasets: analysis of a proposal by Simons, Stulp and Nakagawa. PeerJ 5:e3265. doi: 10.7717/peerj.3265
  12. Poirier C, Bateson M (2017). Pacing stereotypies in laboratory rhesus macaques: Implications for animal welfare and the validity of neuroscientific findings. Neuroscience and biobehavioral reviews 83:508-515. doi: 10.1016/j.neubiorev.2017.09.010
  13. Bateson M (2016). Optimistic and pessimistic biases: a primer for behavioural ecologists. Current Opinion in Behavioral Sciences 12:115-121. doi: 10.1016/j.cobeha.2016.09.013
  14. Bateson M (2015). Cumulative stress in research animals: Telomere attrition as a biomarker in a welfare context? BioEssays 38(2):201-12. doi: 10.1002/bies.201500127
  15. Bateson M, Nettle D (2015). Development of a cognitive bias methodology for measuring low mood in chimpanzees. PeerJ 3:e998. doi: 10.7717/peerj.998