Cognition Models in Rats and Mice

Cognition Models in Rats and Mice

Cognitive function is generally described as the life-long process of learning, the creation of long- and short-term memories, and the use of quantitative reasoning[1]. There are many disorders that can result in the decline of cognitive function, most notably Alzheimer’s disorder and dementia, making cognitive decline a matter of great concern. Furthermore, life/environmental factors, such as obesity, aging, cancer treatments [1, 2], cardiovascular disease [3], brain injury [4,5], toxins [6], infections and genetic or metabolic disorders [7], can also affect cognitive function.

Cognitive impairments are caused by the gradual losses of neurons and synapses in the brain. As these connections are lost, the brain becomes less capable of processing and storing new experiences, and deficits in learning and memory become evident.  Learning and memory can be evaluated in rodents with several established techniques in highly controlled environments [8].  Such techniques include the Morris water maze, Barnes maze, radial arm maze, novel object recognition, and contextual fear conditioning.  Behaviors similar to those tested by these “maze” approaches can also be incorporated into technologies like the cognition wall that require less interaction between the animals and their human observers.

Induction:

Depending on what aspect of cognition is targeted, the potential effects of compounds, proteins, biologics and/or genetic modification on cognition can be assessed by one, or by a combination, of the above models.  Timing is also important when modeling a particular disease, since one disease model does not affect cognition at the same rate as another.  For example, the Tg2576 mouse model of Alzheimer’s disease does not develop cognitive symptoms until approximately 11 months of age [9], but daily scopolamine injections can induce cognitive dysfunction in rats over the course of a week [10].  In contrast, some dietary inductions in normal animals require 2 generations and up to 11-12 weeks of treatment to detect changes in cognition [11].

Studies will be designed with an N=12 animals per test arm plus an N=12 for the control arm.    All animals will habituate in the facility for at least one week, and, depending on the model and on the nature of the intervention, test article administration can occur at any given time.

Disease Parameters & clinical assessment:

If more than one test of rodent cognitive behavior is desired, each successive test should be more stressful than the last.  For example, an approach in rats may look like the following:

  • Novel Object Recognition- time spent with familiar object, time spent with novel object, ratio of novel:familiar (i.e. recognition index)
  • Barnes Maze- time to find the escape hole over 4 training days, memory probe of time spent in the vicinity of target escape hole 1 week after training, reversal learning
  • Morris Water Maze- time to find the hidden platform over 4 training days, memory probe of time spent in the correct quadrant 1 week after training, reversal learning

Optional Endpoints:

  • Open field assay (OFA): to test for locomotor performance and rough measures of anxiety prior to cognitive testing
  • Gait analysis: analysis for movement abnormalities after cognitive testing
  • Blood and tissue collections
  • Brain area dissections
  • Cytokine/chemokine analyses of blood and brain via Luminex or ELISA
  • CBC/clinical chemistry analysis
  • Histopathology
  • Other immunohistochemistry analyses

Sample Data (Click on Image to Enlarge): TBA when available

References

  1. Gareau, M.G., Cognitive Function and the Microbiome. Int Rev Neurobiol, 2016. 131: p. 227-246.
  2. Correa, D.D. and L.M. Hess, Cognitive function and quality of life in ovarian cancer. Gynecol Oncol, 2012. 124(3): p. 404-9.
  3. Logan, S., et al., Simultaneous assessment of cognitive function, circadian rhythm, and spontaneous activity in aging mice. Geroscience, 2018. 40(2): p. 123-137.
  4. Rice, V.J., et al., The Effect of Traumatic Brain Injury (TBI) on Cognitive Performance in a Sample of Active Duty U.S. Military Service Members. Mil Med, 2020. 185(Supplement_1): p. 184-189.
  5. Kunker, K., D.M. Peters, and S. Mohapatra, Long-term impact of mild traumatic brain injury on postural stability and executive function. Neurol Sci, 2020.
  6. Jacob, A. and P. Wang, Alcohol Intoxication and Cognition: Implications on Mechanisms and Therapeutic Strategies. Front Neurosci, 2020. 14: p. 102.
  7. Moulignier, A. and D. Costagliola, Metabolic Syndrome and Cardiovascular Disease Impacts on the Pathophysiology and Phenotype of HIV-Associated Neurocognitive Disorders. Curr Top Behav Neurosci, 2020.
  8. Arakawa, H. and Y. Iguchi, Ethological and multi-behavioral analysis of learning and memory performance in laboratory rodent models. Neurosci Res, 2018. 135: p. 1-12.
  9. https://www.alzforum.org/research-models/tg2576
  10. Tottori, K., et al., Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quino linone monomethanesulfonate). J Pharmacol Exp Ther, 2002. 301(1): p. 249-57.
  11. Fedorova, I., et al., An n-3 fatty acid deficiency impairs rat spatial learning in the Barnes maze. Behav Neurosci, 2009. 123(1): p. 196-205.

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