The Poly I:C maternal immune stimulation model shows unique patterns of brain metabolism, morphometry, and plasticity in female rats

Abstract

Introduction: Prenatal infections are associated with an increased risk of the onset of schizophrenia. Rodent models of maternal immune stimulation (MIS) have been extensively used in preclinical studies. However, many of these studies only include males, omitting pathophysiological features unique to females. The aim of this study is to characterize the MIS model in female rats using positron emission tomography (PET), structural magnetic resonance imaging (MR), and neuroplasticiy studies.Methods: In gestational day 15, Poly I:C (or Saline) was injected into pregnant Wistar rats to induce the MIS model. Imaging studies: [18F]-fluoro-2-deoxy-D-glucose-PET scans of female-offspring were acquired at post-natal day (PND) 35 and PND100. Furthermore, T2-MR brain images were acquired in adulthood. Differences in FDG uptake and morphometry between groups were assessed with SPM12 and Regions of Interest (ROI) analyses. Ex vivo study: The density of parvalbumin expressing interneurons (PV), perineuronal nets (PNN), and parvalbumin expressing interneurons surrounded by perineuronal nets (PV-PNN) were evaluated in the prelimbic cortex and basolateral amygdala using confocal microscopy. ROIs and neuroplasticity data were analyzed by 2-sample T-test and 2-way-ANOVA analyses, respectively.Results: A significant increase in brain metabolism was found in all animals at adulthood compared to adolescence. MIS hardly modified brain glucose metabolism in females, highlighting a significant hypometabolism in the thalamus at adulthood. In addition, MIS induced gray matter (GM) enlargements in the pituitary, hippocampus, substantia nigra, and cingulate cortex, and GM shrinkages in some thalamic nuclei, cerebelar areas, and brainstem. Moreover, MIS induced white matter shrinkages in the cerebellum, brainstem and corpus callosum, along with cerebrospinal fluid enlargements in the lateral and 4th ventricles. Finally, MIS reduced the density of PV, PNN, and PV-PNN in the basolateral amygdala.Conclusion: Our work showed in vivo the differential pattern of functional and morphometric affectation in the MIS model in females, as well as the deficits caused at the synaptic level according to sex. The differences obtained highlight the relevance of including both sexes in psychiatric research in order to consider their pathophysiological particularities and successfully extend the benefits obtained to the entire patient population.

N-acetylcysteine during critical neurodevelopmental periods prevents behavioral and neurochemical deficits in the Poly I:C rat model of schizophrenia

“…Firstly, the study was conducted exclusively in male-offspring. It is known that the effects of MIS differ between males and females in terms of functional and morphological changes [ 58 ]. Additionally, the onset of schizophrenia symptoms occurs later in women than in men.…”

Maternal Supplementation with N-Acetylcysteine Modulates the Microbiota-Gut-Brain Axis in Offspring of the Poly I:C Rat Model of Schizophrenia

“…On post-natal day (PND) 21, male-offspring were weaned and housed 2–4 per cage. Females were not studied because they do not reproduce the well-characterized SCZ-like deficits in males of the MIS model at PND100 [ 32 ].…”

Maternal immune activation affects female offspring whisker movements during object exploration in a rat model of neurodevelopmental disorders

“…Measuring whisker movements during object exploration can identify sensory and attentional deficits (5xFAD mice in Grant et al, 2018; 3xTg-AD mice in Simanaviciute et al, 2022 ), and reveal sex differences in mouse models of Alzheimer's (Grant et al, 2018) and Huntington's disease ( Simanaviciute et al, 2020 ), which makes it especially aligned for the study of NDDs. Indeed, Lins et al (2019) specifically recommend investigating sex differences in MIA research, since rat models of NDDs exhibit sex-dependent phenotypes ( Snigda et al, 2011 ; Leger and Neill, 2016 ; Nikolić et al, 2017 ; Casquero-Veiga et al, 2023 ; Potter et al, 2023 ).…”