Modeling normal mouse uterine contraction and placental perfusion with non-invasive longitudinal dynamic contrast enhancement MRI.

BACKGROUND: The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individual's entire life. Although being recognized by the NIH Human Placenta Project as an important organ, the placenta remains understudied, partly because of a lack of non-invasive tools for longitudinally evaluation for key aspects of placental functionalities. OBJECTIVE: Our goal is to create a non-invasive preclinical imaging pipeline that can longitudinally probe murine placental health in vivo. We use advanced imaging processing schemes to establish functional biomarkers for non-invasive longitudinal evaluation of placental development. METHODOLOGY: We implement dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) and analysis pipeline to quantify uterine contraction and placental perfusion dynamics. We use optic flow and time-frequency analysis to quantify and characterize contraction-related placental motion. Our novel imaging and analysis pipeline uses subcutaneous administration of gadolinium for steepest slope-based perfusion evaluation, enabling non-invasive longitudinal monitoring. RESULTS: We demonstrate that the placenta exhibits spatially asymmetric contractile motion that develops from E14.5 to E17.5. Additionally, we see that placental perfusion, perfusion delivery rate, and substrate delivery all increase from E14.5 to E17.5, with the High Perfusion Chamber (HPC) leading the placental changes that occur from E14.5 to E17.5. DISCUSSION: We advance the placental perfusion chamber paradigm with a novel, physiologically based threshold model for chamber localization and demonstrate spatially varying placental chambers using multiple functional metrics that assess mouse placental development and remodeling throughout gestation. CONCLUSION: Our pipeline enables the non-invasive, longitudinal assessment of multiple placenta functions from a single imaging session. Our pipeline serves as a key toolbox for advancing research in mouse models of placental disease and disorder.

STAT1 regulates neutrophil gelatinase B-associated lipocalin induction in influenza-induced myocarditis.

Influenza is a significant public health and economic threat around the world. Epidemiological studies have demonstrated a close association between influenza pandemics and cardiovascular mortality. Moreover, it has been shown that there is a decrease in cardiovascular mortality in high-risk patients following vaccination with the influenza vaccine. Here, we have investigated the role of anti-viral STAT1 signaling in influenza-induced myocarditis. Wild-type mice (C57BL/6) were infected with either influenza A/PR/8/34 or control, and cellular response and gene expression analysis from the heart samples were assessed 7 days later. The expression of interferon response genes STAT1, STAT2, Mx1, OASL2, ISG15, chemokines CCL2, CCL3, CXCL9 and CXCL10, and the frequency of neutrophils (CD45+CD11b+Ly6G+) and CD4+ T cells (CD45+CD4+) were all significantly increased in influenza-infected mice when compared to vehicle controls. These data suggest that influenza infection induces interferons, inflammatory chemokines, and cellular recruitment during influenza infection. We further investigated the role of STAT1 in influenza-induced myocarditis. The frequency of neutrophils and the levels of lipocalin 2 were significantly increased in STAT1-/- mice when compared to WT controls. Finally, we investigated the role of Lcn2 in viral-induced myocarditis. We found that in the absence of Lcn2, there was preserved cardiac function in Lcn2-/- mice when compared to WT controls. These data suggest that the absence of Lcn2 is cardioprotective during viral-induced myocarditis.

Modeling Normal Mouse Uterine Contraction and Placental Perfusion with Non-invasive Longitudinal Dynamic Contrast Enhancement MRI.

The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individual's entire life. Although being recognized by the NIH Human Placenta Project as an important organ, the placenta remains understudied, partly because of a lack of non-invasive tools for longitudinally evaluation for key aspects of placental functionalities. Non-invasive imaging that can longitudinally probe murine placental health in vivo are critical to understanding placental development throughout pregnancy. We developed advanced imaging processing schemes to establish functional biomarkers for non-invasive longitudinal evaluation of placental development. We developed a dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) pipeline combined with advanced image process methods to model uterine contraction and placental perfusion dynamics. Our novel imaging pipeline uses subcutaneous administration of gadolinium for steepest-slope based perfusion evaluation. This enables non-invasive longitudinal monitoring. Additionally, we advance the placental perfusion chamber paradigm with a novel physiologically-based threshold model for chamber localization and demonstrate spatially varying placental chambers using multiple functional metrics that assess mouse placental development and continuing remodeling throughout gestation. Lastly, using optic flow to quantify placental motions arisen from uterine contractions in conjunction with time-frequency analysis, we demonstrated that the placenta exhibited asymmetric contractile motion.

Apolipoprotein-E deficiency leads to brain network alteration characterized by diffusion MRI and graph theory.

Late-onset Alzheimer's disease (LOAD) is a major health concern for senior citizens, characterized by memory loss, confusion, and impaired cognitive abilities. Apolipoprotein-E (ApoE) is a well-known risk factor for LOAD, though exactly how ApoE affects LOAD risks is unknown. We hypothesize that ApoE attenuation of LOAD resiliency or vulnerability has a neurodevelopmental origin via changing brain network architecture. We investigated the brain network structure in adult ApoE knock out (ApoE KO) and wild-type (WT) mice with diffusion tensor imaging (DTI) followed by graph theory to delineate brain network topology. Left and right hemisphere connectivity revealed significant differences in number of connections between the hippocampus, amygdala, caudate putamen and other brain regions. Network topology based on the graph theory of ApoE KO demonstrated decreased functional integration, network efficiency, and network segregation between the hippocampus and amygdala and the rest of the brain, compared to those in WT counterparts. Our data show that brain network developed differently in ApoE KO and WT mice at 5 months of age, especially in the network reflected in the hippocampus, amygdala, and caudate putamen. This indicates that ApoE is involved in brain network development which might modulate LOAD risks via changing brain network structures.