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Background and significance
Interaction between age and perceptual difficulty in olfactory discrimination learning in F344 rats: relationships with spatial learningWendy M Yoder1 � Leslie Gaynor2 � Sarah N Burke5 � Brandi K Ormerod5 � Barry Setlow1,3,5 � Jennifer L Bizon1,4,5 � David W Smith1,5
1Program in Behavioral and Cognitive Neuroscience, Department of Psychology � 2Program in Interdisciplinary Studies, Neurobiological Sciences � 3Department of Psychiatry � 4Center for Smell and Taste � 5Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida
5 5
Behavioral methodology
Accuracy decreases as ∆carbon atoms decreases A subset of aged rats show spatial memory declines
Acknowledgments
References
Aged rats show greater impairments on harder discriminations
Aging is a complex process and a key risk factor for cognitive and neural dysfunction, but declines are rapid without early intervention. Researchers are scrambling to identify reliable biomarkers.
Fischer 344 rats may be an important piece of the puzzle. As these rats age, some show cognitive declinesthat correlate with olfactory deficits. Olfactory changes could predict memory impairments, but first...
1. Atanasova, B., Graux, J., El Hage, W., Hommet, C., Camus, V., Belzung, C. 2008. Olfaction: a potential cognitive marker of psychiatric disorders. Neuroscience and biobehavioral reviews 32(7), 1315- 25.
2. Johnson, B. A., Woo, C. C., & Leon, M. 1998. Spatial coding of odorant features in the glomerular layer of the rat olfactory bulb. Journal of Comparative Neurology, 393, 457– 471.3. Laska, M., Teubner, P. 1999. Olfactory Discrimination Ability for Homologous Series of Aliphatic Alcohols and Aldehydes. Chemical Senses 24(3), 263-70. 4. LaSarge, C., Montgomery, K.S., Tucker, C., Slaton, S., Griffith, W., Setlow, B., Bizon, J. 2007. Deficits across multiple cognitive domains in a subset of aged Fischer 344 rats.
Neurobiology of aging 28(6), 928-36.5. Linster, C., Hasselmo, M.E. 1999. Behavioral responses to aliphatic aldehydes can be predicted from known electrophysiological responses of mitral cells in the olfactory bulb.
Physiology & behavior 66(3), 497-502.6. Slotnick, B. 2007. Odor-Sampling Time of Mice under Different Conditions. Chemical Senses 32(5), 445-54. 7. Youngentob SL, Johnson BA, Leon M, Sheehe PR, Kent PF. Predicting odorant quality perceptions from multidimensional scaling of olfactory bulb glomerular activity patterns. Behav
Neurosci. 2006;120(6):1337-45.
Olfactory Bulb
Less overlap: Less Confusing
5 carbondifference
More overlap: More Confusing
1 carbondifference
Figure 2: Glomerular Activation Patterns Predict Olfactory Perception. Degree of glomerular overlap affects perceptual similarity (i.e., tendency to confuse odorants). (A) Olfactory bulb activation patterns for the aliphatic alcohols 1-propanol and 1-octanol (a difference of 5 carbon atoms). (B) Activation patterns for 1-heptanol and 1-hexanol (a difference of 1 carbon atom). Glomerular Response Activity Archive: http://gara.bio.uci.edu
Figure 4. Homologous Series Tested. Three functional groups were tested (aliphatic alcohols, aliphatic aldehydes, aliphatic acids) to create 9 novel odorant pairs differing between one and five carbon atoms. Odorant concentration was 1 ppm. Three structurally unrelated controls were also tested.
Stimuli: Aliphatic Functional Groups
We must increase predictive validity by evaluating olfactory acuity across a continuum. This may be achieved by incorporating structure-activity relationships into experimental designs.
Figure 1: Model of olfactory perceptual similarity. Analogous to continuums in other sensory systems, carbon chain length can be used as a gradient of generalization3,5,7. In odor-guided discrimination paradigms, structurally similar odorants are more difficult to distinguish and therefore, more perceptually confusing.
Visual SystemE
N HN F D
Z X T PF T D Z U
H T P N F D
EasyPretty Easy
Fairly EasyModerate
DifficultVery Difficult
Olfactory SystemStructurally Unrelated
5 Carbon Difference4 Carbon Difference
3 Carbon Difference2 Carbon Difference
1 Carbon Difference
(A) (B)
10 blocks total (20 trials each)200 pseudorandomized trials
S+
Target
S-
Control
Discrimination Task
n=23
Aged22 months
n=16
Young6 months
Fischer 344 Rats
Figure 3: General Method. Licking in the presence of the target odorant (S+) results in 5 µl of liquid reinforcement (Ensure). Conversely, incorrectly licking in the presence of the control odorant (S-) results in a 5 second time-out; the rat cannot initiate new trials during this interval.4
Odor Port
Odor Stream
Operant Chamber
Reinforcement
5-s Time-out
Propanol Pentanol
C3 C5
Δ2
Discrimination Pairs12 Total
Figure 5. Accuracy collapsed across ΔC pairs. The accuracy in discrimination performance decreased in both young and aged rats as a function of perceptual similarity between the odorants in each pair. Notably, however, across odor classes, there was a significant Age X Perceptual Similarity interaction, such that aged rats performed disproportionately less accurately on more perceptually-similar problems. Subsequent analyses compared olfactory performance relative to spatial learning performance in the water maze. Notably, aged rats with good water maze performance performed comparably to young rats on the olfactory discrimination problems whereas aged rats with poor water maze performance showed significant impairments on the olfactory discrimination problems relative to young, particularly on the problems that involved perceptually similar odorants.
Funding for this research was provided by NIH R01 AG024671 and the McKnight Brain Research Foundation..
Figure 8. Individual differences in spatial reference memory performance among aged F344 rats, compared with olfactory discrimination learning (Δ1). Together, these findings suggest that a decreased ability to encode perceptual distinctions may contribute to impaired stimulus representations and cognitive impairments in aging. Ongoing studies will test the hypothesis that both olfactory and spatial learning deficits in a subset of aged rats are associated with impaired spatial pattern separation.
Morris Water Maze: a well-characterized task used to evaluate hippocampal-dependent, spatial memory – a sensitive measure of age-related, cognitive decline.
Discussion and translational applications
Is olfactory dysfunction a promising behavioral
biomarker?
This measure could be included in a battery with
other olfactory tests.
Importantly, our laboratory has expertise assessing olfactory acuity in both
humans subjects and animal models.
Carbon chain length is one critical determinant of olfactory perception. Experimental designs incorporating odor-guided tasks should consider the role of chemical structure.
The discrimination measure described here may be particularly useful for evaluating age-associated alterations. Varying the level of difficulty may capture subtle deviations.
Although we know a correlation exists between age-related cognitive decline and olfactory changes, we need to determine which odor-guided tasks will be the most efficacious for predicting onset and progression of memory deficits.
Figure 6. Accuracy across blocks for young and aged rats; ∆1 discriminations. Block data show performance as a function of learning on more difficult discriminations. As a group, young rats perform better overall. As a group, aged rats require additional training to perform on par with young. As noted above, however, this effect is driven primary by a subset of aged rats.
Figure 7. Accuracy across blocks for young and aged rats; ∆5 discriminations. For both aged and young rats, easier discriminations display minimal differences between groups.