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. 2014 Mar;88(3):789-98.
doi: 10.1007/s00204-013-1161-y. Epub 2013 Nov 29.

Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins

Masaki Kakeyama  1 , Toshihiro Endo, Yan Zhang, Wataru Miyazaki, Chiharu Tohyama
Affiliations

Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins

Masaki Kakeyama et al. Arch Toxicol. 2014 Mar.

Abstract

The prevalence of cognitive abnormalities in children has partly been ascribed to environmental chemical exposure. Appropriate animal models and tools for evaluating higher brain function are required to examine this problem. A recently developed behavioral test in which rats learn six unique flavor-location pairs in a test arena was used to evaluate paired-associate learning, a hallmark of the higher cognitive function that is essential to language learning in humans. Pregnant Long-Evans rats were dosed by gavage with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) at a dose of 0, 200, or 800 ng/kg (referred as Control, TCDD-200, TCDD-800, TBDD-200, or TBDD-800, hereafter) on gestational day 15, and the offspring was tested during adulthood. Paired-associate learning was found to be impaired in the TCDD-200 and TBDD-200 groups, but not in either group exposed to 800 ng/kg, the observations of which were ensured by non-cued trials. As for the emotional aspect, during habituation, the TCDD-200 and TBDD-200 groups showed significantly longer latencies to enter the test arena from a start box than the Control, TCDD-800, and TBDD-800 groups, suggesting that the TCDD-200 and TBDD-200 groups manifested anxiety-like behavior. Thus, both the chlorinated dioxin and its brominated congener affected higher brain function to a similar extent in a nearly identical manner. Use of the behavioral test that can evaluate paired-associate learning in rats demonstrated that in utero and lactational exposure to not only TCDD but also TBDD perturbed higher brain function in rat offspring in a nonmonotonic manner.

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Figures

Fig. 1
Fig. 1
a The event arena is composed of a test arena [1,600 (w) × 1,600 (d) × 300 (h) mm] with a start box [250 (w) × 250 (d) × 300 (h) mm] at the center of each sidewall. b Arrangement of six flavor-location paired associations (F-L pairs) in the event arena. At each location (1–6), there was a well in which a specific-flavored rat chow (as described in the following parentheses) was concealed under sand. 1 F1-L1 (chocolate); 2 F2-L2 (cherry); 3 F3-L3 (anise); 4 F4-L4 (bacon); 5 F5-L5 (coconut); and 6 F6-L6 (strawberry). Rats were presented with flavored lab chow in the start box as a cue, and they were allowed to recall the spatial location with which it was associated and to go into the arena to search for the rat chow with the identical flavor (Tse et al. 2007)
Fig. 2
Fig. 2
Acquisition of paired-associate memory in the behavioral test. For readability, the performance index in the 3-session block, which comprised data from each animal per session for three consecutive sessions, is shown. Control, offspring born to dams that were administered corn oil; TCDD 200 and TCDD 800, offspring born to dams that were administered TCDD at an oral dose of 200 and 800 ng/kg, respectively; TBDD 200 and TBDD 800, offspring born to dams that were administered TBDD at an oral dose of 200 and 800 ng/kg, respectively. The Control group was commonly compared with the TCDD- and TBDD-exposed groups. a The performance indices of the Control and TCDD-800 groups increased with the sessions and were significantly higher than the chance value [Control, p < 0.001, F(1,14) = 14.6; TCDD-800, p < 0.001, F(1,14) = 15.1], whereas the performance index of the TCDD-200 group did not differ from the chance value [TCDD-200, p = 0.87, F(1,14) = 0.58]. The performance index of the TCDD-200 group was significantly lower than that of the Control group [p < 0.05, analysis of variance with Dunnett’s post hoc test]. b The performance index of the TBDD-exposed rat offspring showed a similar trend as that observed in TCDD-exposed rats. The performance index of the TBDD-800 group was significantly higher than the chance value [p < 0.001, F(1,14) = 4.58], whereas no significant difference was observed for the TBDD-200 group [p = 0.35, F(1,14) = 1.14]
Fig. 3
Fig. 3
Verification of paired-associate learning by non-cued trials. The non-cued session (session 46; six non-cued trials), followed by the cued session (session 47; regular session), was assessed in the last part of the experiment. In the non-cued condition, a flavored diet pellet as a cue was not set in the start box, and a reward-flavored diet pellet was set in a sand well. * p < 0.05 versus  chance value
Fig. 4
Fig. 4
Simple memory formation. Between-group difference in simple memory performance was assessed with the following three indices of simple memory: a “memory in seconds”, b “memory in hours”, and c “memory in days”. Black bars correspond to the indices that represent the probability to choose the previously rewarded sand well as the first choice (but see “Materials and methods” for each detailed definition). Gray bars indicate the probability to choose the correct sand well in the session which was different from the previously rewarded one. White bars indicate the probability to choose other sand wells as the first choice. Dotted line indicates a chance level (16.7 %)
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