Brain microstructural changes in mice persist in adulthood and are modulated by the palmitoyl acyltransferase ZDHHC7

Abstract

For a long time, mice have been classified as adults with completely mature brains at 8 weeks of age, but recent research suggests that developmental brain changes occur for up to 6 months. In particular, adolescence coincides with dramatic changes of neuronal structure and function in the brain that influence the connectivity between areas like hippocampus and medial prefrontal cortex (mPFC). Neuronal development and plasticity are regulated in part by the palmitoyl acyltransferase ZDHHC7, which modulates structural connectivity between hippocampus and mPFC. The aim of the current study was to investigate whether developmental changes take place in hippocampus and mPFC microstructure even after 8 weeks of age and whether deficiency of ZDHHC7 impacts such age‐dependent alterations. Altogether, 46 mice at 11, 14 or 17 weeks of age with a genetic Zdhhc7 knockout (KO) or wild type (WT) were analysed with neuroimaging and diffusion tensor‐based fibre tractography. The hippocampus and mPFC regions were compared regarding fibre metrics, supplemented by volumetric and immunohistological analyses of the hippocampus. In WT animals, we identified age‐dependent changes in hippocampal fibre lengths that followed a U‐shaped pattern, whereas in mPFC, changes were linear. In Zdhhc7‐deficient animals, the fibre statistics were reduced in both regions, whereas the hippocampus volume and the intensities of myelin and neurofilament were higher in 11‐week‐old KO mice compared to WTs. Our results confirmed ongoing changes of microstructure in mice up to 17 weeks old and demonstrate that deleting the Zdhhc7 gene impairs fibre development, suggesting that palmitoylation is important in this process.

Leveraging genetic diversity in mice to inform individual differences in brain microstructure and memory

“…Performing CFC in mice at 5 months of age allowed mice to recover from anesthesia and the stress of MRI imaging and enabled us to prepare for and arrange CFC assays. We are confident that our experimental design did not confound the correlations between dMRI values and CFM observed in Ntg mice ( Figure 9 ) because Ntg mice do not exhibit behavioral differences between 3 and 6 months of age (data not shown), and because mice are not expected to show differences in microstructure between 3 and 5 months of age ( Flurkey et al, 2007 ; Hammelrath et al, 2016 ; Kerkenberg et al, 2021 ). It is important to mention that no correlations between dMRI values and CFM performance were significant after FDR-adjustment.…”

“…At 5 months of age, after preliminary analysis had demonstrated effects of strain on brain microstructure and after mice had recovered from anesthesia, these mice underwent CFC. As mice between three and 6 months of age exhibit similar health and macro- and microstructural neural features ( Flurkey et al, 2007 ; Hammelrath et al, 2016 ; Kerkenberg et al, 2021 ), this experimental timeline enabled us to investigate (a) if brain microstructure varied with strain, sex, or 5XFAD genotype, (b) if short- and long-term fear memory varied with strain, sex, or 5XFAD genotype, and (c) if strain-related dMRI measurements could predict cognitive health in Ntg mice, thus determining the likelihood that brain microstructure confers brain reserve to AD.…”

“…Between 3 and 6 months of age, mice are considered mature adults, comparable to humans at 20-30 years of age. During this age range, CFC performance (data unpublished), DTI values, volumes, and myelination in regions throughout the mouse brain, as well as general health and mouse survivability, have been demonstrated not to vary notably in Ntg mice (Flurkey et al, 2007;Hammelrath et al, 2016;Kerkenberg et al, 2021). Therefore, our study design enabled us to capture cognition and microstructure in mature adult mice and had the added benefit of allowing mice to recover from anesthesia during imaging, which may affect cognitive performance (Liu et al, 2014).…”

“…To capture neurological features that may contribute to brain reserve, we performed imaging at 3 months of age, at which mice are expected to be mature young adults ( Flurkey et al, 2007 ), but prior to expected onset of cognitive senescence. At 5 months of age, during which non-transgenic (Ntg) mice are still considered to be in early adulthood and are not expected to exhibit differences in health and microstructure from 3 months of age ( Flurkey et al, 2007 ; Hammelrath et al, 2016 ; Kerkenberg et al, 2021 ), mice underwent contextual fear conditioning (CFC) to assess the impacts and interactions of strain, sex, and the 5XFAD transgene on cognitive health and to investigate relationships between brain microstructure and memory.…”

Dynamic Expression of Palmitoylation Regulators across Human Organ Development and Cancers Based on Bioinformatics

“…Most studies in search results have explored their function in cancer, compared to few studies in organ development. Nicole et al demonstrated that ZDHHC7 deficiency changes the brain microstructure and connectivity in young people between 11 and 17 weeks of age, suggesting that palmitoylation plays an important role during the early stages of brain development [ 39 ]. Similarly, studies have shown that due to the PPT1 expression pattern differing from the two other lysosomal enzymes implicated in NCL disease, PPT1 has a distinctive role in brain development [ 8 ].…”