Maternal immune activation in mid-late gestation alters amphetamine sensitivity and object recognition, but not other schizophrenia-related behaviours in adult rats

Gray, Alex M.; Tattoli, R.; Dunn, Ariel; Hodgson, Deborah M.; Michie, Patricia T.; Harms, Lauren

doi:10.1016/j.bbr.2018.08.016

Cited by 23 publications

(18 citation statements)

References 48 publications

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“…However, on the whole males were more sensitive to both neurodevelopmental interventions. This parallels the incidence of conditions like schizophrenia and ASD (Aleman et al, 2003;Werling and Geschwind, 2013), as well as the apparent greater magnitude or earlier onset of behavioral, structural and functional responses in males exposed to PIC (Piontkewitz et al, 2011;Zhang et al, 2012;Patrich et al, 2016;De Felice et al, 2018;Drazanova et al, 2018;Lins et al, 2018;Gray et al, 2019;Haida et al, 2019;Lins et al, 2019) or reared in isolation (Weiss et al, 2001;Weiss et al, 2004;Fabricius et al, 2010;Pisu et al, 2016;Chmelova et al, 2019).…”

Section: Discussionmentioning

confidence: 84%

“…Although these calls have traditionally been assumed to reflect a positive emotional state they are also emitted during aggression and submission (Wöhr et al, 2008) and can be dissociated from changes in prosocial behavior. For example, oxytocin-induced increases in anogenital and body sniffing can occur without alteration USV alterations (Kohli et al, 2019), whereas PIC-exposed offspring lacking marked social behavior changes (Gray et al, 2019) emitted more step-type 50 kHz USVs here. Cognitive deficits appear more variable, and indeed our desire for a more robust phenotype stimulated combination of these models.…”

Section: Discussionmentioning

confidence: 87%

“…Subtle opposing changes in 5-HT and SERT expression in the orbitofrontal cortex suggest the potential for a localized serotonergic deficit (Bickerdike et al, 1993) in a region where 5-HT depletion impairs reversal learning by increasing perseveration (Clarke et al, 2007), and isolation-induced mTOR activation is also linked to cognitive impairment (Meffre et al, 2012). Although gestational PIC may impair NOD (Vernon et al, 2015;Osborne et al, 2017;Gray et al, 2019) and reversal learning (Wallace et al, 2014;Lins et al, 2018) after i.v. administration, it does not always influence PPI (Vorhees et al, 2012;Lins et al, 2018;Gray et al, 2019), CFR (Vorhees et al, 2015) or frontal cortical 5-HT (Hadar et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…To address requirements for laboratory-specific optimization (Roderick and Kentner, 2019;Murray et al, 2019;Gray et al, 2019) we confirmed expected responses to our batch of PIC in vitro, by assessing induction of the early-response immune and inflammatory regulator microRNA-155 (upregulated by TLR3 ligands like PIC: O'Connell et al, 2007;Swaminathan et al, 2012) in primary bone marrow-derived macrophages (Supplementary material 1). We also performed pilot studies to verify PIC-induced 'sickness behavior' in vivo (Supplementary material 1).…”

Section: Introductionmentioning

confidence: 96%

“…However, it is becoming increasingly clear that such models are variable, subject to PIC batch effects (Careaga et al, 2018;Kowash et al, 2019;Mueller et al, 2019), and at least in some laboratories do not adequately model the full range of cognitive or motivational impairments seen in patients (Bates et al, 2018;Gray et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Gestational poly(I:C) attenuates, not exacerbates, the behavioral, cytokine and mTOR changes caused by isolation rearing in a rat ‘dual-hit’ model for neurodevelopmental disorders

Goh

O’Sullivan

Shortall

et al. 2020

Brain, Behavior, and Immunity

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Many psychiatric illnesses have a multifactorial etiology involving genetic and environmental risk factors that trigger persistent neurodevelopmental impairments. Several risk factors have been individually replicated in rodents, to understand disease mechanisms and evaluate novel treatments, particularly for poorly-managed negative and cognitive symptoms. However, the complex interplay between various factors remains unclear.Rodent dual-hit neurodevelopmental models offer vital opportunities to examine this and explore new strategies for early therapeutic intervention. This study combined gestational administration of polyinosinic:polycytidylic acid (poly(I:C); PIC, to mimic viral infection during pregnancy) with post-weaning isolation of resulting offspring (to mirror adolescent social adversity).After in vitro and in vivo studies required for laboratory-specific PIC characterization and optimization, we administered 10 mg/kg i.p. PIC potassium salt to time-mated Lister hooded dams on gestational day 15. This induced transient hypothermia, sickness behavior and weight loss in the dams, and led to locomotor hyperactivity, elevated striatal cytokine levels, and increased frontal cortical JNK phosphorylation in the offspring at adulthood.Remarkably, instead of exacerbating the well-characterized isolation syndrome, gestational PIC exposure actually protected against a spectrum of isolation-induced behavioral and brain regional changes. Thus isolation reared rats exhibited locomotor hyperactivity, impaired associative memory and reversal learning, elevated hippocampal and frontal cortical cytokine levels, and increased mammalian target of rapamycin (mTOR) activation in the frontal cortex -which were not evident in isolates previously exposed to gestational PIC. Brains from adolescent littermates suggest little contribution of cytokines, mTOR or JNK to early development of the isolation syndrome, or resilience conferred by PIC. But notably hippocampal oxytocin, which can protect against stress, was higher in adolescent PICexposed isolates so might contribute to a more favorable outcome. These findings have implications for identifying individuals at risk for disorders like schizophrenia who may benefit from early therapeutic intervention, and justify preclinical assessment of whether adolescent oxytocin manipulations can modulate disease onset or progression.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Gestational poly(I:C) attenuates, not exacerbates, the behavioral, cytokine and mTOR changes caused by isolation rearing in a rat ‘dual-hit’ model for neurodevelopmental disorders

Goh

O’Sullivan

Shortall

et al. 2020

Brain, Behavior, and Immunity

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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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Maternal immune activation in mid-late gestation alters amphetamine sensitivity and object recognition, but not other schizophrenia-related behaviours in adult rats

Cited by 23 publications

References 48 publications

Gestational poly(I:C) attenuates, not exacerbates, the behavioral, cytokine and mTOR changes caused by isolation rearing in a rat ‘dual-hit’ model for neurodevelopmental disorders

Gestational poly(I:C) attenuates, not exacerbates, the behavioral, cytokine and mTOR changes caused by isolation rearing in a rat ‘dual-hit’ model for neurodevelopmental disorders

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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