Loss of molars early in life develops behavioral lateralization and impairs hippocampus-dependent recognition memory

Abstract

Background: Using senescence-accelerated mouse prone 8 (SAMP8), we examined whether reduced mastication from a young age affects hippocampal-dependent cognitive function. We anesthetized male SAMP8 mice at 8 weeks of age and extracted all maxillary molar teeth of half the animals. The other animals were treated similarly, except that molar teeth were not extracted. At 12 and 24 weeks of age, their general behavior and their ability to recognize novel objects were tested using the open-field test (OFT) and the object-recognition test (ORT), respectively.

Results: The body weight of molarless mice was reduced significantly compared to that of molar-intact mice after the extraction and did not recover to the weight of age-matched molar-intact mice throughout the experimental period. At 12 weeks of age, molarless mice showed significantly greater locomotor activity in the OFT than molar-intact mice. However, the ability of molarless mice to discriminate a novel object in the ORT was impaired compared to that of molar-intact mice. The ability of both molarless and molar-intact SAMP8 mice to recognize objects was impaired at 24 weeks of age. These results suggest that molarless SAMP8 mice develop a deficit of cognitive function earlier than molar-intact SAMP8 mice. Interestingly, both at 12 and 24 weeks of age, molarless mice showed a lateralized preference of object location in the encoding session of the ORT, in which two identical objects were presented. Their lateralized preference of object location was positively correlated with the rightward turning-direction preference, which reached statistical significance at 24 weeks of age.

Conclusions: Loss of masticatory function in early life causes malnutrition and chronic stress and impairs the ability to recognize novel objects. Hyperactivation and lateralized rotational behavior are commonly observed with dysfunction of the dopaminergic system, therefore, reduced masticatory function may deplete the mesolimbic and mesocorticolimbic dopaminergic systems to impair the cognitive functions of selective attention and recognition memory in the prefrontal cortex and the hippocampus.

Figure 1

Change in mean body weight of molar-intact and molarless mice. Open and filled circles indicate mean body weight of molar-intact (control group) and molarless (molarless group) mice, respectively. We subjected 28 of 58 mice to the behavioral test and sacrificed them at 12 weeks old (15 molar-intact and 13 molarless). Therefore, the number of subjects was 15 each in control and molarless groups at 16, 20, and 24 weeks old. Data are presented as means ± SEM. Asterisks indicate statistically significant differences between groups (9, 10, 12 weeks old Mann–Whitney test, P < 0.05 , 16, 20, 24 weeks old Student t-test, P < 0.05).

Figure 2

Scatter plots showing correlation between the side preferences of rotation and object location. Scatter plots with regression lines for molar-intact mice (control group) are shown in (A) and those for molarless mice (molarless group) are shown in (B). Filled triangles: 12 weeks of age (n = 15), open triangles: 24 weeks of age (n = 15), filled circles: 12 weeks of age (n = 13), open circles: 24 weeks of age (n = 6). Rotation preference = 100 × the number of turns to the right / the number of turns in both directions. Object preference = 100 × search time for object placed on the right / search time for both objects.

Figure 3

An overhead view of the open field used in the OFT and ORT. In the OFT, we divided the oblong field (55 cm × 40 cm) into three subdivisions of center (gray; 15 cm × 10 cm), intermediate (white; 25 cm × 20 cm), and peripheral (black) and counted the number of entrances for each subdivision in addition to measuring the total path length. In the ORT, two objects were placed at the positions indicated as “R (object on the right)” and “L (object on the left)”, and time spent to explore each object was measured. In all experiments, the mouse was always placed at the position “M” at the beginning of the test, with its face oriented to the wall.

Figure 4

Definition of turns during object exploration. A turn, either to the left (counterclockwise traveling) or to the right (clockwise traveling), was defined if the mouse turned more than 180° from the original position indicated as “M” (A). If the mouse consecutively turned more than 360° in one direction at once, we counted the first 360° as one turn and then started counting the new one. For example, a consecutive turn from 180° to 540° was counted as single turn (B) and that from 540° to 720° was counted as two turns (C).