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Rat models

Animal models continue to be important tools for understanding disease mechanisms and for preclinical testing of potential therapeutics. Although the mouse is currently the most widely used species to model neurobiological disorders, we recognize that other model systems may also provide important insights.

Relative to the mouse, the rat has a larger brain and exhibits a more complex behavioral repertoire but still retains many tractable characteristics that make it amenable for laboratory research. Rats are sometimes falsely perceived as slightly larger versions of mice; however, the evolutionary distance between rats and mice may be as great as that between humans and Old-World monkeys1. Recent developments in genomic-editing technologies have facilitated the ability to manipulate the rat genome, thus spurring interest in the rat as a model for genetically linked disorders.

As such, SFARI is working with the Medical College of Wisconsin (MCW) to generate and distribute CRISPR/Cas9 rat models of autism. Models will be maintained in the outbred Long-Evans background strain, as this is often the strain of choice for cognitive, behavioral and systems neuroscience studies. The intent is for these models to be available to any qualified researcher, with minimal cost and restrictions. An MCW guide to maintaining outbred colonies can be found here.

Available models

For more information on these models and how to request them, please contact the MCW Gene Editing Rat Resource Center: [email protected].

Characterization

As an initial effort to characterize these lines, these models are being behaviorally phenotyped through a partnership with the Simons Initiative for the Developing Brain (SIDB), at the University of Edinburgh and the Center for Development and Repair in Bangalore. Rat models are phenotyped according to a rigorous pipeline that assesses behaviors relevant to autism spectrum disorder, such as social and motor skills, learning and sensory processing. Different cohorts of rats are run through different subsets of tasks to overcome potential order effects on behaviors and to limit the number of tasks each animal is put through. Resulting data will be available pre-publication via downloadable behavioral datasheets (see links to available datasheets above).

The SIDB behavioral pipeline includes the following tasks:

Learning and memory

  • Auditory and visual fear conditioning (Pavlovian fear conditioning)
  • Water maze (spatial learning and memory and reversal learning)
  • Object recognition task (non-spatial recognition memory)
  • Object location recognition task (spatial recognition memory)
  • Active place avoidance (allocentric spatial learning and memory, cognitive control, cognitive flexibility)
  • Prey-capture task (complex learning, involving various cognitive processes and sensorimotor learning)

Social behavior

  • Paired play paradigm (developmental social behavior)
  • Tube co-occupancy test (adult social behavior)
  • Social habituation paradigm (social learning and memory)

Other behaviors

  • Pup righting (neurodevelopmental reflex)
  • Tail flick (pain response)
  • Rota rod (motor coordination)
  • Wood chew (anxiety marker)
  • Marble interaction task (novel object interaction)

In addition, prior to pipeline phenotyping, some rats are characterized using the following experimental set-ups/methods:

Habitat
Eco-ethological housing system that permits rats to express a wide-range of innate behaviors that can be recorded and analyzed without disturbing animals.

Image of rat in maze
Mimicking rat burrows. Schematic of the Habitat, an experimental set up devised by Peter Kind and colleagues at the University of Edinburgh to study rat social, cognitive and motor behaviors in the lab. These complex behaviors include rat social hierarchies, fear and isolation, communication, play, memory, motor coordination, reaction to novelty and circadian rhythms. Image courtesy of Peter Kind/Edinburgh University.

Motion sequencing (Moseq)
Automated, machine-learning-based method developed by Sandeep Robert Datta and colleagues to characterize behavior in rodents (mice and rats)2. More information about this tool can be found here.

For suggestions and comments on our efforts more generally, please contact SFARI: [email protected].

References

  1. Gibbs R.A. et al. Nature 428, 493-521 (2004) PubMed
  2. Wiltschko A.B. et al. Neuron 88, 1121-1135 (2015) PubMed

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