Purpose: To characterize longitudinal changes in molecular water diffusion, blood microcirculation, and their contributions to the apparent diffusion changes using intravoxel incoherent motion (IVIM) analysis in an experimental mouse model of liver fibrosis. Materials and Methods:Liver fibrosis was induced in male adult C57BL/6N mice (22-25 g; n ¼ 12) by repetitive dosing of carbon tetrachloride (CCl 4 ). The respiratorygated diffusion-weighted (DW) images were acquired using single-shot spin-echo EPI (SE-EPI) with 8 b-values and single diffusion gradient direction. True diffusion coefficient (D true ), blood pseudodiffusion coefficient (D pseudo ), and perfusion fraction (P fraction ) were measured. Diffusion tensor imaging (DTI) was also performed for comparison. Histology was performed with hematoxylineosin and Masson's trichrome staining.Results: A significant decrease in D true was found at 2 weeks and 4 weeks following CCl 4 insult, as compared with that before insult. Similarly, D pseudo values before injury was significantly higher than those at 2 weeks and 4 weeks after CCl 4 insult. Meanwhile, P fraction values showed no significant differences over different timepoints. For DTI, significant decrease in ADC was observed following CCl 4 administration. Fractional anisotropy at 2 weeks after CCl 4 insult was significantly lower than that before insult, and subsequently normalized at 4 weeks after the insult. Liver histology showed collagen deposition, the presence of intracellular fat vacuoles, and cell necrosis/apoptosis in livers with CCl 4 insult.Conclusion: Both molecular water diffusion and blood microcirculation contribute to the alteration in apparent diffusion changes in liver fibrosis. Reduction in D true and D pseudo values resulted from diffusion and perfusion changes, respectively, during the progression of liver fibrosis. IVIM analysis may serve as valuable and robust tool in detecting and characterizing liver fibrosis at early stages, monitoring its progression in a noninvasive manner.

Mice lacking a functional Biogenesis of Lysosome-related Organelles Complex 1 (BLOC-1), such as those of the pallid line, display cognitive and behavioural impairments reminiscent of those presented by individuals with intellectual and developmental disabilities. Although disturbances in the sleep/wake cycle are commonly lamented by these individuals, the underlying mechanisms, including the possible role of the circadian timing system, are still unknown. In this paper, we have explored sleep/circadian malfunctions and underlying mechanisms in BLOC-1-deficient pallid mice. These mutants exhibited less sleep behaviour in the beginning of the resting phase than wild-type mice with a more broken sleeping pattern in normal light-dark conditions. Furthermore, the strength of the activity rhythms in the mutants were reduced with significantly more fragmentation and lower precision than in age-matched controls. These symptoms were accompanied by an abnormal preference for the open arm in the elevated plus maze in the day and poor performance in the novel object recognition at night. At the level of the central circadian clock (the suprachiasmatic nucleus, SCN), loss of BLOC-1 caused subtle morphological changes including a larger SCN and increased expression of the relative levels of the clock gene Per2 product during the day but did not affect the neuronal activity rhythms. In the hippocampus, the pallid mice presented with anomalies in the cytoarchitecture of the Dentate Gyrus granule cells, but not in CA1 pyramidal neurones, along with altered PER2 protein levels as well as reduced pCREB/tCREB ratio during the day. Our findings suggest that lack of BLOC-1 in mice disrupts the sleep/wake cycle and performance in behavioural tests associated with specific alterations in cytoarchitecture and protein expression.

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The function(s) of the Biogenesis of Lysosome‐related Organelles Complex‐1 (BLOC‐1) during brain development is to date largely unknown. Here, we investigated how its absence alters the trajectory of postnatal brain development using as model the pallid mouse. Most of the defects observed early postnatally in the mutant mice were more prominent in males than in females and in the hippocampus. Male mutant mice, but not females, had smaller brains as compared to sex‐matching wild types at postnatal day 1 (P1), this deficit was largely recovered by P14 and P45. An abnormal cytoarchitecture of the pyramidal cell layer of the hippocampus was observed in P1 pallid male, but not female, or juvenile mice (P45), along with severely decreased expression levels of the radial glial marker Glutamate‐Aspartate Transporter. Transcriptomic analyses showed that the overall response to the lack of functional BLOC‐1 was more pronounced in hippocampi at P1 than at P45 or in the cerebral cortex. These observations suggest that absence of BLOC‐1 renders males more susceptible to perinatal brain maldevelopment and although most abnormalities appear to have been resolved in juvenile animals, still permanent defects may be present, resulting in faulty neuronal circuits, and contribute to previously reported cognitive and behavioral phenotypes in adult BLOC‐1‐deficient mice.