Early or Late Gestational Exposure to Maternal Immune Activation Alters Neurodevelopmental Trajectories in Mice: An Integrated Neuroimaging, Behavioral, and Transcriptional Study

Guma, Elisa; Bordignon, Pedro do Couto; Devenyi, Gabriel A.; Gallino, Daniel; Anastassiadis, Chloe; Cvetkovska, Vedrana; Barry, Amadou; Snook, Emily; Germann, Jürgen; Greenwood, Celia; Mišić, Bratislav; Bagot, Rosemary C.; Chakravarty, M. Mallar

doi:10.1016/j.biopsych.2021.03.017

Cited by 53 publications

(116 citation statements)

References 160 publications

(167 reference statements)

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“…Statistical analyses were performed using the R software package (R version 3.5.1, RMINC version 1.5.2.2 www.r-project.org). First, we confirmed that there were no statistically significant differences between our two control groups (SAL E and SAL L), which allowed us to combine them into a single group, leaving us with three groups: saline (SAL), GD 9-poly I:C (POL E), and GD 17-poly I:C (POL L), consistent with our previous work (11). To assess the effects of poly I:C exposure either early or late in gestation on neonatal neuroanatomy, we ran a whole-brain voxel-wise linear mixed-effects model (lme4_1.1-21 package; (29)) on the relative Jacobian determinant files using group and sex as fixed effects, and number of pups per litter (ranging from 2-10; Table 1) as random intercepts.…”

Section: Neuroimaging Data Analysissupporting

confidence: 87%

“…In contrast, late exposed embryos (GD17) had striking brain-wide volume increases, particularly in the basal ganglia, hippocampus, cortex, corpus callosum, thalamus, and cerebellum (10). Furthermore, we previously identified significant deviation in neurodevelopmental trajectories of early MIA-exposed offspring in the adolescent and early adult period, again with a similar sample size, wherein accelerated volume increase, followed by a normalization were observed in the hippocampus, anterior cingulate cortex, striatum, and lateral septum, amongst other regions; in contrast, late-exposed offspring displayed only subtle deviations in trajectory (11). Thus, it is possible that the changes detected in the embryo brain are a result of acute remodeling in response to the increased inflammation in utero, but that these changes resolve in the neonatal period.…”

Section: Discussionsupporting

confidence: 58%

“…This approach requires a significant amount of development, which our scanner was not equipped for at the time that this experiment was designed. This approach has been successful at uncovering sex differences throughout mouse brain development (36), and in previous work by our group examining offspring development from weaning to adulthood (11). Furthermore, we only assayed communicative abilities, as this is one of the few complex behaviours testable in neonate mice.…”

Section: Discussionmentioning

confidence: 99%

“…In the embryo brain, we observed striking brain volume increases following MIA-exposure late in gestation (gestational day [GD]-17), while exposure in early gestation (GD9) resulted in more focal volumetric decreases (10). In our investigations of brain development trajectories from adolescence to adulthood, we observed early MIA-exposure to induce greater neuroanatomical and behavioural alterations than either late exposure or saline exposure, particularly in adolescence and early adulthood (11). This raises the question of what processes are occurring throughout the period between the embryo and childhood; namely: the neonatal period.…”

Section: Introductionmentioning

confidence: 93%

“…A partial least squares (PLS) analysis, previously applied by our group (11), was used to investigate putative brain-behaviour relationships between neonate neuroanatomy and USV behaviour. This is a multivariate technique for relating two sets of variables to each other by finding the optimal weighted linear combinations of variables that maximally covary with each other (33)(34)(35).…”

Section: Partial Least Squares Analysismentioning

confidence: 99%

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Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation

Guma

Snook

Spring

et al. 2021

Preprint

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Prenatal exposure to maternal immune activation (MIA) is a risk factor for a variety of neurodevelopmental and psychiatric disorders. The timing of MIA-exposure has been shown to affect adolescent and adult offspring neurodevelopment, however, less is known about these effects in the neonatal period. To better understand the impact of MIA-exposure on neonatal brain development, we first assess neonate communicative abilities with the ultrasonic vocalization task, followed by high-resolution ex vivo magnetic resonance imaging (MRI) on the neonatal (postnatal day 8) brain. Early exposed offspring displayed decreased communicative ability, while brain anatomy appeared largely unaffected, apart from some subtle alterations. By integrating MRI and behavioural assays to investigate the effects of MIA-exposure on neonatal neurodevelopment we show that offspring neuroanatomy and behaviour are only subtly affected by both early and late exposure. This suggests that the deficits often observed in later stages of life may be dormant, not yet developed in the neonatal period, or not as easily detectable using a cross-sectional approach.

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Section: Neuroimaging Data Analysissupporting

confidence: 87%

Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Partial Least Squares Analysismentioning

confidence: 99%

See 3 more Smart Citations

Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation

Guma

Snook

Spring

et al. 2021

Preprint

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Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

et al. 2022

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Purpose Prenatal infection during pregnancy is a risk factor for schizophrenia, as well as for other developmental psychiatric disorders, such as autism and bipolar disorder. Schizophrenia patients were reported to have altered brain metabolism and neuroinflammation. However, the link between prenatal infection, altered brain inflammation and metabolism, and schizophrenia remains unclear. In this project, we aimed to evaluate whether there are changes in brain glucose consumption and microglia activation in the offspring of pregnant rats exposed to maternal immune activation (MIA), and if so, whether these changes occur before or after the initiation of schizophrenia-like behaviour. Procedures Pregnant rats were treated with the viral mimic polyinosinic-polycytidylic acid (MIA group) or saline (control group) on gestational day 15. Static PET scans of the male offspring were acquired on postnatal day (PND) 21, 60, and 90, using [11C]-PK11195 and deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) as tracers to measure TSPO expression in activated microglia and brain glucose consumption, respectively. On PND60 and PND90, anxiety-like behaviour, recognition memory, and sensorimotor gating were measured using the open field test (OFT), novel object recognition test (NOR), and prepulse inhibition test (PPI). Results [18F]-FDG PET demonstrated that MIA offspring displayed higher brain glucose consumption in the whole brain after weaning (p = 0.017), and in the frontal cortex during late adolescence (p = 0.001) and adulthood (p = 0.037) than control rats. [11C]-PK11195 PET did not reveal any changes in TSPO expression in MIA offspring. Prenatal infection induced age-related behavioural alterations. Adolescent MIA offspring displayed a more anxious state in the OFT than controls (p = 0.042). Adult MIA offspring showed recognition memory deficits in the NOR (p = 0.003). Our study did not show any PPI deficits. Conclusions Our results suggest that prenatal immune activation changed neurodevelopment, resulting in increased brain glucose consumption, but not in microglia activation. The increased brain glucose consumption in the frontal cortex of MIA offspring remained until adulthood and was associated with increased anxiety-like behaviour during adolescence and recognition memory deficits in adulthood.

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Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring

Perez-Palomar

Erdozain

Erkizia-Santamaría

et al. 2023

J Neuroimmune Pharmacol

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Background Impairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal exposure to infections represents an environmental risk factor for schizophrenia development in adulthood. However, it remains largely unknown whether the prenatal infection-induced changes in the brain may be associated with concrete switches in a particular neurochemical circuit, and therefore, if they could alter behavioral functions. Methods In vitro and in vivo neurochemical evaluation of the PFC catecholaminergic systems was performed in offspring from mice undergoing maternal immune activation (MIA). The cognitive status was also evaluated. Prenatal viral infection was mimicked by polyriboinosinic-polyribocytidylic acid (poly(I:C)) administration to pregnant dams (7.5 mg/kg i.p., gestational day 9.5) and consequences were evaluated in adult offspring. Results MIA-treated offspring showed disrupted recognition memory in the novel object recognition task (t = 2.30, p = 0.031). This poly(I:C)-based group displayed decreased extracellular dopamine (DA) concentrations compared to controls (t = 3.17, p = 0.0068). Potassium-evoked release of DA and noradrenaline (NA) were impaired in the poly(I:C) group (DA: Ft[10,90] = 43.33, p < 0.0001; Ftr[1,90] = 1.224, p = 0.2972; Fi[10,90] = 5.916, p < 0.0001; n = 11); (NA: Ft[10,90] = 36.27, p < 0.0001; Ftr[1,90] = 1.841, p = 0.208; Fi[10,90] = 8.686, p < 0.0001; n = 11). In the same way, amphetamine‐evoked release of DA and NA were also impaired in the poly(I:C) group (DA: Ft[8,328] = 22.01, p < 0.0001; Ftr[1,328] = 4.507, p = 0.040; Fi[8,328] = 2.319, p = 0.020; n = 43); (NA: Ft[8,328] = 52.07; p < 0.0001; Ftr[1,328] = 4.322; p = 0.044; Fi[8,398] = 5.727; p < 0.0001; n = 43). This catecholamine imbalance was accompanied by increased dopamine D1 and D2 receptor expression (t = 2.64, p = 0.011 and t = 3.55, p = 0.0009; respectively), whereas tyrosine hydroxylase, DA and NA tissue content, DA and NA transporter (DAT/NET) expression and function were unaltered. Conclusions MIA induces in offspring a presynaptic catecholaminergic hypofunction in PFC with cognitive impairment. This poly(I:C)-based model reproduces catecholamine phenotypes reported in schizophrenia and represents an opportunity for the study of cognitive impairment associated to this disorder.

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Early or Late Gestational Exposure to Maternal Immune Activation Alters Neurodevelopmental Trajectories in Mice: An Integrated Neuroimaging, Behavioral, and Transcriptional Study

Cited by 53 publications

References 160 publications

Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation

Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation

Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring

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