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.

Can you be too old for oral implants? An update on ageing and plasticity in the oro‐facial sensorimotor system

“…These studies suggest that impaired mastication because of either reduced masticatory activity or reduced sensory input (achieved experimentally by trimming or extracting molars) results in reduced cell growth and synaptic connections in the CNS, and impaired function of neurotransmitters involved in learning, 133,134 and then, there are the studies noted above (Section 4.3) that have shown structural and functional changes occurring in several CNS areas, including the oro-facial sensorimotor cortex, as a result of trimming or extraction of teeth, replacing the extracted teeth with implants and orthodontically induced tooth movement. [84][85][86][87][88] These findings collectively do support the view that dental manipulations, including tooth loss, do cause alterations in the brain. That being said, it needs to be kept in mind that the changes may not be the direct result of the dental manipulations per se producing changes in sensory inputs to these CNS area but reflect instead or as well changes in chewing and other sensorimotor functions or indeed alterations in stress levels as a result of the manipulations and their consequences.…”

“…Nonetheless, recent findings in animal models do point to a causal relationship. These studies suggest that impaired mastication because of either reduced masticatory activity or reduced sensory input (achieved experimentally by trimming or extracting molars) results in reduced cell growth and synaptic connections in the CNS, and impaired function of neurotransmitters involved in learning, and then, there are the studies noted above (Section 4.3) that have shown structural and functional changes occurring in several CNS areas, including the oro‐facial sensorimotor cortex, as a result of trimming or extraction of teeth, replacing the extracted teeth with implants and orthodontically induced tooth movement . These findings collectively do support the view that dental manipulations, including tooth loss, do cause alterations in the brain.…”

“…These include alterations to the dental occlusion such as trimming of teeth to take them out of occlusal contacts, orthodontic tooth movement and incisor or molar tooth extraction. [84][85][86][87] It has also been recently shown in rodents that as well as the tooth extraction-induced functional changes in the oro-facial sensorimotor cortex, there are also structural changes in this cortical region that are manifested as alterations in the number and morphology of glia and a decreased volume of this cortical region 88,89 ; this latter finding is consistent with the findings of functional neuroplastic changes in the oro-facial sensorimotor cortex reflected as decreased jaw and tongue motor representations in this region following tooth extraction in rodents 84,86 and with reports from studies in humans and laboratory animals that tooth loss is associated with reduced activation in the sensorimotor cortex (and other CNS areas) 90-92 although a brief loss of sensory input (produced by local anaesthesia) from a single tooth may be insufficient to produce evidence of neuroplasticity of the oro-facial sensorimotor cortex. 93 Of particular relevance to the topic of this article is that the extraction-induced neuroplasticity in the rodent oro-facial sensorimotor cortex can be reversed within 1-2 months when the extracted teeth are replaced with dental implants which themselves can induce neuroplastic changes.…”

“…Furthermore, additional findings that neuroplasticity occurred in other CNS areas (prefrontal cortex, Broca's area, supplementary motor area, hippocampus, basal ganglia) as well as the oro-facial sensorimotor cortex emphasises the point that dental manipulations can have widespread effects in the CNS. Molar tooth extraction in rodents may have effects in CNS areas well beyond the oro-facial sensorimotor cortex (see above), and tooth loss in humans as well as laboratory animals has been reported to be associated with widespread structural and functional changes in CNS regions involved not only in sensorimotor behaviours but also in CNS regions contributing to such diverse functions as memory, cognition, attention and emotion 88,[90][91][92] ; indeed, some of these studies have reported deficits in one or more of these functions following extensive tooth loss. This is further considered in relation to effects of tooth loss in the elderly and brings us to consider ageing-related changes in sensorimotor and related functions and the peripheral and CNS substrates underlying them.…”

Donor specific transcriptomic analysis of Alzheimer’s disease associated hypometabolism highlights a unique donor, microglia, and ribosomal proteins

“…This subcortical degeneration is thought to occur early in the disease process (Mesulam et al, 2004) . In the context of the gingipain hypothesis, we note that reduced basal forebrain volume and cholinergic function follow after the removal of teeth in rodents (Avivi-Arber et al, 2016;Kato et al, 1997;Onozuka et al, 2002) . The ER translocation genes, which are strongly aligned with the hypometabolism pattern in brain 10021/H0351.2002 are highly expressed in the substantia innominata.…”