Estrogens can signal through either estrogen receptor ␣ (ER␣) or  (ER) to ameliorate experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of multiple sclerosis (MS). Cellular targets of estrogen-mediated neuroprotection are still being elucidated. Previously, we demonstrated that ER␣ on astrocytes, but not neurons, was critical for ER␣ ligand-mediated neuroprotection in EAE, including decreased T-cell and macrophage inflammation and decreased axonal loss. Here, we determined whether ER on astrocytes or neurons could mediate neuroprotection in EAE, by selectively removing ER from either of these cell types using Cre-loxP gene deletion. Our results demonstrated that, even though ER ligand treatment was neuroprotective in EAE, this neuroprotection was not mediated through ER on either astrocytes or neurons and did not involve a reduction in levels of CNS inflammation. Given the differential neuroprotective and anti-inflammatory effects mediated via ER␣ versus ER on astrocytes, we looked for molecules within astrocytes that were affected by signaling through ER␣, but not ER. We found that ER␣ ligand treatment, but not ER ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together, our data show that neuroprotection in EAE mediated via ER signaling does not require ER on either astrocytes or neurons, whereas neuroprotection in EAE mediated via ER␣ signaling requires ER␣ on astrocytes and reduces astrocyte expression of proinflammatory chemokines. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ER␣ and ER in EAE.
Objective: To determine brain magnetic resonance imaging (MRI) measures of cerebrospinal fluid (CSF) and whole brain volume of full-term and premature infants following surgical treatment for thoracic non-cardiac congenital anomalies requiring critical care. Methods: Full-term ( n = 13) and pre-term ( n = 13) patients with long-gap esophageal atresia, and full-term naïve controls ( n = 19) < 1 year corrected age, underwent non-sedated brain MRI following completion of thoracic non-cardiac surgery and critical care treatment. Qualitative MRI findings were reviewed and reported by a pediatric neuroradiologist and neurologist. Several linear brain metrics were measured using structural T1-weighted images, while T2-weighted images were required for segmentation of total CSF and whole brain tissue using the M orphologically A daptive N eonatal T issue S egmentation ( MANTiS ) tool. Group differences in absolute (mm, cm 3 ) and normalized (%) data were analyzed using a univariate general linear model with age at scan as a covariate. Mean normalized values were assessed using one-way ANOVA. Results: Qualitative brain findings suggest brain atrophy in both full-term and pre-term patients. Both linear and volumetric MRI analyses confirmed significantly greater total CSF and extra-axial space, and decreased whole brain size in both full-term and pre-term patients compared to naïve controls. Although linear analysis suggests greater ventricular volumes in all patients, volumetric analysis showed that normalized ventricular volumes were higher only in premature patients compared to controls. Discussion: Linear brain metrics paralleled volumetric MRI analysis of total CSF and extra-axial space, but not ventricular size. Full-term infants appear to demonstrate similar brain vulnerability in the context of life-saving thoracic non-cardiac surgery requiring critical care as premature infants.
Gray matter atrophy has been shown to be a strong correlate to clinical disability in multiple sclerosis (MS) and its most commonly used animal model, experimental autoimmune encephalomyelitis (EAE). However, the relationship between gray mater atrophy and the spinal cord pathology often observed in EAE has never been established. Here EAE was induced in Thy1.1-YFP mice and their brains imaged using in vivo magnetic resonance imaging (MRI). The brains and spinal cords were subsequently optically cleared using Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY). Axons were followed 5 mm longitudinally in three dimensions in intact spinal cords revealing that 61% of the axons exhibited a mean of 22 axonal ovoids and 8% of the axons terminating in axonal end bulbs. In the cerebral cortex, we observed a decrease in the mean number of layer V pyramidal neurons and a decrease in the mean length of the apical dendrites of the remaining neurons, compared to healthy controls. MRI analysis demonstrated decreased cortical volumes in EAE. Cross-modality correlations revealed a direct relationship between cortical volume loss and axonal end bulb number in the spinal cord, but not ovoid number. This is the first report of the use of CLARITY in an animal model of disease and the first report of the use of both CLARITY and MRI.
Introduction Little is known regarding the impact of concurrent critical illness and thoracic noncardiac perioperative critical care on postnatal brain development. Previously, we reported smaller total brain volumes in both critically ill full‐term and premature patients following complex perioperative critical care for long‐gap esophageal atresia (LGEA). Our current report assessed trends in regional brain sizes during infancy, and probed for any group differences. Methods Full‐term (n = 13) and preterm (n = 13) patients without any previously known neurological concerns, and control infants (n = 16), underwent non‐sedated 3 T MRI in infancy (<1 year old). T2‐weighted images underwent semi‐automated brain segmentation using Morphologically Adaptive Neonatal Tissue Segmentation (MANTiS). Regional tissue volumes of the forebrain, deep gray matter (DGM), cerebellum, and brainstem are presented as absolute (cm3) and normalized (% total brain volume (%TBV)) values. Group differences were assessed using a general linear model univariate analysis with corrected age at scan as a covariate. Results Absolute volumes of regions analyzed increased with advancing age, paralleling total brain size, but were significantly smaller in both full‐term and premature patients compared to controls. Normalized volumes (%TBV) of forebrain, DGM, and cerebellum were not different between subject groups analyzed. Normalized brainstem volumes showed group differences that warrant future studies to confirm the same finding. Discussion Both full‐term and premature critically ill infants undergoing life‐saving surgery for LGEA are at risk of smaller total and regional brain sizes. Normalized volumes support globally delayed or diminished brain growth in patients. Future research should look into neurodevelopmental outcomes of infants born with LGEA.
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