Longitudinal studies on brain pathology and assessment of therapeutic strategies rely on a fully mature adult brain to exclude confounds of cerebral developmental changes. Thus, knowledge about onset of adulthood is indispensable for discrimination of developmental phase and adulthood. We have performed a high-resolution longitudinal MRI study at 11.7T of male Wistar rats between 21days and six months of age, characterizing cerebral volume changes and tissue-specific myelination as a function of age. Cortical thickness reaches final value at 1month, while volume increases of cortex, striatum and whole brain end only after two months. Myelin accretion is pronounced until the end of the third postnatal month. After this time, continuing myelination increases in cortex are still seen on histological analysis but are no longer reliably detectable with diffusion-weighted MRI due to parallel tissue restructuring processes. In conclusion, cerebral development continues over the first three months of age. This is of relevance for future studies on brain disease models which should not start before the end of month 3 to exclude serious confounds of continuing tissue development.

The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy. Significance We present an identification of the relevance of WD40-repeat (WDR) genes in brain connectivity, highlighting the power of unbiased mouse studies in the field of neuroscience. We focus on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. WDR47 plays a role in progenitor proliferation, neuronal migration, and fiber tract projections in a similar fashion to LIS1 but with the distinctive particularity that WDR47 inhibits autophagic flux. This provides a functional link between autophagy biology and the C-terminal to LisH domain in mammals. Importantly, WDR47 uncovers an aspect of corpus callosum biology pointing toward a link between the regulation of microtubule dynamics and autophagic flux for axonal outgrowth and guidance.

It took decades to arrive at the general consensus dismissing the notion that the immune system is independent of the central nervous system. In the case of uncontrolled systemic inflammation, the relationship between the two systems is thrown off balance and results in cognitive and emotional impairment. It is specifically true for autoimmune pathologies where the central nervous system is affected as a result of systemic inflammation. Along with boosting circulating cytokine levels, systemic inflammation can lead to aberrant brain-resident immune cell activation, leakage of the blood–brain barrier, and the production of circulating antibodies that cross-react with brain antigens. One of the most disabling autoimmune pathologies known to have an effect on the central nervous system secondary to the systemic disease is systemic lupus erythematosus. Its neuropsychiatric expression has been extensively studied in lupus-like disease murine models that develop an autoimmunity-associated behavioral syndrome. These models are very useful for studying how the peripheral immune system and systemic inflammation can influence brain functions. In this review, we summarize the experimental data reported on murine models developing autoimmune diseases and systemic inflammation, and we explore the underlying mechanisms explaining how systemic inflammation can result in behavioral deficits, with a special focus on in vivo neuroimaging techniques.