Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model

Abstract

Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a signi cant role in the neurodevelopment and behavioral outcomes of offspring. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroin ammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modi ed form of the viral mimic polyinosinic:polycytidylic acid at the end of the rst trimester. Control dams received saline injections at the end of the rst trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months of age. Offspring born to MIA-exposed dams showed signi cantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. Additionally, offspring gray matter free water in this region was signi cantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. These ndings provide strong evidence for the construct validity of the NHP MIA model as a system of relevance for investigations of the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

Altered Extracellular Matrix Structure and Elevated Stiffness in a Brain Organoid Model for Disease

“…1b-e) 51 . Notably, this range aligns with the lower spectrum of brain tissue stiffness, which typically spans from 0.1 to 2 kilopascals 52 . With time, the CorticOs stiffen, likely due to continuous ECM deposition and/or fibrillation.…”

“…To test this directly, we employed Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) to compare differences in the structural organization of day18 control, LIS1 +/− , and MMP-treated LIS1 +/− CorticOs. Notably, DW-MRI was previously shown to provide noninvasive means for identifying changes in ECM organization 51 , extracellular free water component 52 , stiffness, and other structural parameters 53 . To examine the sensitivity of DW-MRI, groups of control, LIS1 +/− , and MMP-treated LIS1 +/− containing multiple CorticOs were placed in separate wells and scanned (Fig.…”

“…ADC values decrease in pathologies that involve cell swelling (edema) and can increase in chronic phases of stroke or other diseases involving necrotic cell death 70, 71 . A monkey model employed to simulate a developmental brain disorder known as maternal immune activation (MIA), considered a model for autism spectrum disorders, displayed a significant elevation in the presence of extracellular free water within the gray matter of the cingulate cortex 52 .…”

IL-6 Enhances the Activation of PI3K-AKT/mTOR-GSK-3β by Upregulating GRPR in Hippocampal Neurons of Autistic Mice

“…Large epidemiologic studies have shown that maternal immune activation (MIA) caused by prenatal exposure to bacterial or viral infections increases the risk of ASD (Careaga et al 2017 ; Lombardo et al 2018 ). Animal researches have revealed that MIA exacerbates ASD-like behavioral abnormalities by causing brain inflammation in offspring (Cieślik et al 2023 ), and they have also identified some potential mechanisms, such as the inflammatory injury of cytokines like interleukin (IL)-6 (Brown et al 2014 ; Lesh et al 2023 ) and IL-17 (Bagcioglu et al 2023 ; Sarieva et al 2023 ) in the brain. It is important to note that blocking IL-6 (Smith et al 2007 ) or IL-17 A (Reed et al 2020 ) signaling effectively alleviated behavioral abnormalities in ASD mice, although the specific neural mechanisms are still unclear.…”