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Basic Mouse Neurobehavioral Exam (or how to give a mouse a physical)

Basic Mouse Neurobehavioral Exam (or how to give a mouse a physical). Julie Watson Vet MB DACLAM. Resources. Jacqueline Crawley Crawley,J and Paylor,R. Hormones & Behavior 197-211 (1997) “What’s Wrong with my Mouse?” Wiley-Liss 2000. Samuel Irwin - First Phenotyping Screen

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Basic Mouse Neurobehavioral Exam (or how to give a mouse a physical)

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  1. Basic Mouse Neurobehavioral Exam(or how to give a mouse a physical) Julie Watson Vet MB DACLAM

  2. Resources • Jacqueline Crawley • Crawley,J and Paylor,R. Hormones & Behavior 197-211 (1997) • “What’s Wrong with my Mouse?” Wiley-Liss 2000. • Samuel Irwin - First Phenotyping Screen • Psychopharmacologia (Berl.) 13 222-257 (1968) • SHIRPA stage I • Mamm Genome. 1997 Oct;8(10):711-Rogers DC, Fisher EM, Brown SD, Peters J, Hunter AJ, Martin JE • Websites: • Eumorphia http://www.eumorphia.org/EMPReSS/servlet/EMPReSS.Frameset • MRC Mutagenesis Program • http://www.mgu.har.mrc.ac.uk/facilities/mutagenesis/mutabase/ • Clinical approach

  3. Goals • Detect abnormalities likely to affect future behavioral tests • Blindness • Physical defects • Deafness

  4. Age-related hearing loss & vestibular defects (<3m) Many 129 strains A/J C57BR, C57L DBA I, LP, NOD, ALR, ALS C57BL/6J @12-18m Blindness (rd1 gene) FVB C3H BUB CBA SJL SWR NON P, PL Background Strain

  5. Goals (2) 2. Suggest further testing • Presence of abnormal behaviors • Absence of normal behaviors • Motor or neurological deficits

  6. Pitfalls • Variations due to: • Husbandry methods (see John Crabbe, Science 1999) • Age/sex/background strain • Noise/temperature/humidity/location etc. • Time of day • Detect only sizeable deficits • Background strain not inbred. F1’s, N2’s • Are controls comparable ? • Insufficient group size • Limited statistical analysis available - ordinal data • Check genotyping reliability

  7. BIOSAFETY CABINET

  8. SIMPLEEQUIPMENT

  9. WEIGHT PERTINENT INFORMATION TESTER BLINDED TO GENOTYPE

  10. Tests • Behavior in Empty Cage: • Gait, posture, general appearance • Are normal behaviors present? • Exploring, thigmotaxis, digging, grooming, rearing • Are abnormal behaviors present? • freezing, wild running, stereotypies, seizures, pruritus

  11. REARING/ESCAPE

  12. DIGGING

  13. Knockout Mouse LIMITED REARING

  14. Tests Pick up, record abnormal physical features Whisker loss Bald patches or unkempt haircoat, piloerection Eyes Legs and tail

  15. NORMAL WHISKERS

  16. WHISKER LOSS

  17. General Reactivity • Response to approach • Body tone • Petting escape • Passivity

  18. Normal Response to Approach

  19. NORMAL BODY TONE

  20. HIGH BODY TONE

  21. PETTING ESCAPE

  22. Unusual Escape Attempts

  23. PASSIVITY

  24. Postural Reactions and Reflexes • Trunk curl • Righting reflex • Forelimb proprioceptive positioning • Rearlimb withdrawal

  25. TRUNK CURL

  26. RIGHTING REFLEX

  27. PROPRIOCEPTIVE POSITIONING

  28. WITHDRAWAL - FAST

  29. WITHDRAWAL - SLOW

  30. Tests –V & VII NerveFacial sensory and motor • Whisker response • Ear twitch • Palpebral reflex (V, VII)

  31. EAR TWITCH

  32. EAR TWITCH – WHOLE HEAD RESPONSE

  33. WHISKER RESPONSE (?)

  34. PALPEBRAL RESPONSE

  35. Sight • Placing – visual II • Placing – tactile

  36. VISUAL PLACING

  37. Tactile Placing

  38. Tests • Clicker / hearing • Pupil / response to light • Biting / aggression

  39. CLICKER

  40. Provoked Aggression

  41. Grip Strength Normal

  42. Grip Strength Abnormal

  43. Impact of Physical Deficits on Behavioral Tests Impact of Blindness • Learning and memory tests • Water maze, contextual fear conditioning • animal cannot learn? • has limited spatial abilities? • Consider alternatives • 2 lever or hole-poke test in operant chamber • Anxiety tests • Visual cliff, elevated T maze, light- dark box • Low anxiety?

  44. Whisker Deficits, Itchy Skin • Lack of Whiskers • Anxiety tests e.g.visual cliff, elevated T maze – • Skew response compared with mice with whiskers • ? Remove whiskers • Itchy skin (B6 dermatitis) • open field, aggression • hyperirritability, • increased activity • increased aggression

  45. Hearing Deficits • Cued fear conditioning • Use contextual fear conditioning • Prepulse inhibition • Nb DBA still works

  46. Examples of Further Testing • Open Field • Light Dark Box • Elevated Plus Maze • Accelerating Rotarod • Cued and Contextual Fear Conditioning • Morris Water Maze

  47. Open Field total activity, discrete movements, distance traveled rearing

  48. Light Dark Box • Conflict between novelty exploration and avoidance of light open spaces • Strain variations • Responsive to anxiolytics

  49. Elevated Plus Maze • Exploration vs. aversion to open space - prefers dark enclosed arms • Score entries into arms over 5 min trial • Anxiolytics increase entries into open arms - widely used in drug discovery PICTURE CREDITS: EUROPEAN MOLECULAR BIOLOGY LABORATORY

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