Widespread Volumetric Brain Changes following Tooth Loss in Female Mice

Abstract

Tooth loss is associated with altered sensory, motor, cognitive and emotional functions. These changes vary highly in the population and are accompanied by structural and functional changes in brain regions mediating these functions. It is unclear to what extent this variability in behavior and function is caused by genetic and/or environmental determinants and which brain regions undergo structural plasticity that mediates these changes. Thus, the overall goal of our research program is to identify genetic variants that control structural and functional plasticity following tooth loss. As a step toward this goal, here our aim was to determine whether structural magnetic resonance imaging (sMRI) is sensitive to detect quantifiable volumetric differences in the brains of mice of different genetic background receiving tooth extraction or sham operation. We used 67 adult female mice of 7 strains, comprising the A/J (A) and C57BL/6J (B) strains and a randomly selected sample of 5 of the 23 AXB-BXA strains (AXB1, AXB4, AXB24, BXA14, BXA24) that were produced from the A and B parental mice by recombinations and inbreeding. This panel of 25 inbred strains of genetically diverse inbred strains of mice is used for mapping chromosomal intervals throughout the genome that harbor candidate genes controlling the phenotypic variance of any trait under study. Under general anesthesia, 39 mice received extraction of 3 right maxillary molar teeth and 28 mice received sham operation. On post-extraction day 21, post-mortem whole-brain high-resolution sMRI was used to quantify the volume of 160 brain regions. Compared to sham operation, tooth extraction was associated with a significantly reduced regional and voxel-wise volumes of cortical brain regions involved in processing somatosensory, motor, cognitive and emotional functions, and increased volumes in subcortical sensorimotor and temporal limbic forebrain regions including the amygdala. Additionally, comparison of the 10 BXA14 and 21 BXA24 mice revealed significant volumetric differences between the two strains in several brain regions. These findings highlight the utility of high-resolution sMRI for studying tooth loss-induced structural brain plasticity in mice, and provide a foundation for further phenotyping structural brain changes following tooth loss in the full AXB-BXA panel to facilitate mapping genes that control brain plasticity following orofacial injury.

Keywords: animal model; brain imaging (MRI); genetic variation; neuroplasticity; plasticity; sMRI; tooth loss; trigeminal nerve.

Figure 1

Representative color-coded t-statistic maps (when all mouse strains were included) superimposed on high-resolution sMRI coronal slices of the mouse brain. Images of coronal slices in the 1st and 4th columns show anatomical annotations. The coronal slices in the 2nd and 3rd columns are presented in a rostrocaudal order from top-left to bottom-right. Maps show normalized voxel-wise volumetric differences between mice receiving tooth extraction and those receiving sham operation. Red indicate regions that have larger voxel volumes in mice receiving tooth extraction than in mice receiving sham operation, whereas those in blue indicate regions that have smaller voxel volumes in mice receiving tooth extraction. All t-statistics shown are significant at a 10% FDR. Peaks associated with t-statistic values < −3.53 or >3.53 are significant at FDR = 5% (t = 3.53 and t = −3.53 are marked as white arrows on the color palettes). No voxel differences were significant at a 1% FDR. BF, barrel field; CC, corpus callosum; CB, cerebellum; CG, cingulate cortex; CLA, claustrum; CP, caudate putamen; cpd, cerebral peduncle; ENT, entorhinal cortex; fi, fimbria; FL, forelimb; GP, globus pallidus; HY, hypothalamus; Ins, insular cortex; IO, inferior olivary complex; ISN, inferior salivary nucleus; M1, primary motor cortex; M2, secondary motor cortex; MED, medulla; MM, mammillary nucleus; OLF, olfactory area; oM1, orofacial primary motor cortex; oS1, orofacial primary somatosensory cortex; PAG, periaqueductal gray; PCG, pontine central gray; PIR, piriform area; PN, pontine nuclei; RN, reticular nuclei; S1, primary somatosensory cortex; SO, superior olivary complex; ST, solitary tract nucleus; STR, striatum; TH, thalamus; VCx, visual cortex; VIIm, facial cranial nerve motor; VP, trigeminal principal nucleus; VSN, trigeminal spinal tract nucleus.

Figure 2

Representative color-coded t-statistic maps (when only the BXA14 and BXA24 strains were included) superimposed on high-resolution sMRI coronal slices of the mouse brain. Images of coronal slices in the 1st and 4th rows show anatomical annotations. The coronal slices in the 2nd and 3rd rows are presented in a rostrocaudal order from top-left to bottom-right. Maps show normalized voxel-wise volumetric differences between mice receiving tooth extraction and those receiving sham operation. Red indicate regions that have larger voxel volumes in mice receiving tooth extraction than in mice receiving sham operation, whereas blue indicate regions that have smaller voxel volumes in mice receiving tooth extraction. All t-statistics shown are significant at a 10% FDR. White contour lines delineate regions where the statistical maps are significant at 5% FDR. No voxel differences were significant at a 1% FDR. AG, amygdalar cortex; BF, barrel field; BFB, basal forebrain; CC, corpus callosum; CB, cerebellum; cpd, cerebral peduncle; DG, dentate gyrus; ENT, entorhinal cortex; FCx, frontal cortex; GP, globus pallidus; HIP, hippocampus; HP, hypothalamic nucleus; HY, hypothalamus; ic, internal capsule; IC, inferior colliculus; Ins, insular cortex; LOCx, lateral orbital cortex; M1, primary motor cortex; M2, secondary motor cortex; MED, medulla; oM1, orofacial primary motor cortex; oS1, orofacial primary somatosensory cortex; PAG, periaqueductal gray; PCx, Parietal cortex; PC, Piriform cortex; PHY, perihypoglossal nuclei; RF, reticular formation; RN, reticular nucleus; RS, retrosplenial; SC, superior colliculus motor related; SN, substantia nigra; SO, superior olivary complex; ST, solitary tract nucleus; STR, striatum; TH, thalamus; VSN, trigeminal spinal nucleus; VTA, ventral tegmental area.

Figure 3

Representative color-coded t-statistic maps superimposed on high-resolution sMRI coronal slices of the mouse brain. Images of coronal slices in the 1st and 4th columns show anatomical annotations. The coronal slices in the 2nd and 3rd columns are presented in a rostrocaudal order from bottom-right to top-left. Maps show normalized voxel-wise volumetric differences between BXA14 and BXA24 mice. Red indicate regions that have larger voxel volumes in BXA24 mice than in BXA14 mice, whereas those in blue indicate regions that have larger voxel volumes in BXA14 mice. All t-statistic values shown are significant at 1% FDR. Abbreviations: aco, anterior commissure; AG, amygdalar cortex; arb, arbor vitae; BF, barrel field; BST, bed nucleus of stria terminalis; CB, cerebellum; CC, corpus callosum; CG, cingulate cortex; CP, caudate putamen; cpd, cerebral peduncle; DG, dentate gyrus; ec, external capsule; ENT, entorhinal cortex; fi, fimbria; FL, forelimb; HIP, hippocampus; HL, hindlimb; HY, hypothalamus; ic, internal capsule; icp, inferior cerebellar peduncle; Ins, insular cortex; LSX, lateral septal complex; M1, primary motor cortex; M2, secondary motor cortex; MBmot, midbrain, motor related; MED, medulla; MM, mammillary nucleus; MRN, midbrain reticular nucleus; NA, nucleus accumbens; oS1, orofacial primary somatosensory cortex; PAG, periaqueductal gray; PAL, pallidum; PCx, posterior parietal association area; PIR, piriform area; PRT, pretectal region; PSV, principal sensory nucleus of the trigeminal; PVR, periventricular area; RS, retrosplenial; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; SC, superior colliculus; SN, substantia nigra; Sp, septal nuclei; sptV, spinal tract of the trigeminal nerve; STR, striatum; TH, thalamus; VL, lateral ventricle; VTA, ventral tegmental area.