Maternal Immune Activation Rats Research Articles

Human umbilical cord blood mesenchymal stem cells mediate microglia activation and improve anxiety-like behavior in MIA-induced offspring of schizophrenic rats

Current treatments for schizophrenia (SCZ) remain largely ineffective in one-third of patients. Recent studies using stem cell therapy show a close relationship between stem cell immunomodulatory function and neuroinflammation in SCZ. To better investigate the efficacy of stem cell therapy for SCZ, human umbilical cord blood mesenchymal stem cells (hUC-MSC) with powerful immunomodulatory effects were administered to rats via the tail vein (once a week for 5 consecutive weeks starting from the weaning period) using a maternal immune activation (MIA) rodent model. Open field, PPI, Western blotting, Q-PCR, and immunofluorescence were used to assess the biological effects of repeated tail vein injections of hUC-MSC in offspring rats following the MIA model of SCZ. The results indicated that offspring of MIA rats exhibited schizophrenia-like (SCZ-like) anxiety behavior, with observed microglial activation triggering neuroinflammation. Furthermore, levels of IBA1, HMGB1, and PSD95 were significantly up-regulated, while SYP was significantly down-regulated. It is suggested that hUCB-MSCs may act through HMGB1, Iba1, PSD95, and related pathway molecules to alleviate neuroinflammation and repair synaptic damage by regulating the activity state of microglia. Consequently, this could improve the abnormal behavior observed in MIA offspring rats.

Disrupted hippocampal synchrony following maternal immune activation in a rat model.

Maternal immune activation (MIA) is a risk factor for schizophrenia and other neurodevelopmental disorders. MIA in rats models a number of the brain and behavioral changes that are observed in schizophrenia, including impaired memory. Recent studies in the MIA model have shown that the firing of the hippocampal place cells that are involved in memory processes appear relatively normal, but with abnormalities in the temporal ordering of firing. In this study, we re-analyzed data from prior hippocampal electrophysiological recordings of MIA and control animals to determine whether temporal dysfunction was evident. We find that there is a decreased ratio of slow to fast gamma power, resulting from an increase in fast gamma power and a tendency toward reduced slow gamma power in MIA rats. Moreover, we observe a robust reduction in spectral coherence between hippocampal theta and both fast and slow gamma rhythms, as well as changes in the phase of theta at which fast gamma occurs. We also find the phasic organization of place cell phase precession on the theta wave to be abnormal in MIA rats. Lastly, we observe that the local field potential of MIA rats contains more frequent sharp-wave ripple events, and that place cells were more likely to fire spikes during ripples in these animals than control. These findings provide further evidence of desynchrony in MIA animals and may point to circuit-level changes that underlie failures to integrate and encode information in schizophrenia.

Maternal Immune Activation Induces Adolescent Cognitive Deficits Preceded by Developmental Perturbations in Cortical Reelin Signalling

Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.

Cognitive and arginine metabolic correlates of temporal dysfunction in the MIA rat model of schizophrenia risk.

As a hallmark characteristic of schizophrenia, abnormal perception of time is thought to arise from cognitive impairment; however, the absence of translational models indexing this pathological relationship creates barriers to understanding the functional and biological bases of timing impairments. Here, we investigate the relationship between timing and cognition using the maternal immune activation (MIA) rat model of schizophrenia. We additionally investigate the role of prefrontal cortex L-arginine metabolism in these processes via high-performance liquid chromatography and liquid chromatography/mass spectrometry. Results revealed that MIA rats exhibit greater underestimation of interval durations (2-8 s); greater underestimation corresponded with declines in sustained attention capacity. Working memory impairments were not found to contribute to timing deficits. These findings represent the first direct identification of a timing-attention relationship within rodents and are discussed with respect to the dopamine hypothesis of temporal pace. We also found that MIA exposure altered aspects of arginine metabolism as observed in schizophrenia, and we present preliminary evidence suggesting that these changes have functional consequences for cognition. These findings support the MIA rat model as a valuable tool for future investigations exploring the biological instantiation of interrelated timing and cognitive deficits in schizophrenia. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Epigenetic histone acetylation modulating prenatal Poly I:C induced neuroinflammation in the prefrontal cortex of rats: a study in a maternal immune activation model.

Introduction: Neuroinflammation in the central nervous system, particularly the prefrontal cortex (PFC), plays a role in the pathogenesis of schizophrenia, which has been found to be associated with maternal immune activation (MIA). Recent evidence suggests that epigenetic regulation involves in the MIA-induced neurodevelopmental disturbance. However, it is not well-understood how epigenetic modulation is involved in the neuroinflammation and pathogenesis of schizophrenia. Methods: This study explored the modulation of histone acetylation in both neuroinflammation and neurotransmission using an MIA rat model induced by prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure, specifically examining those genes that were previously observed to be impacted by the exposure, including a subunit of nuclear factor kappa-B (Rela), Nod-Like-Receptor family Pyrin domain containing 3 (Nlrp3), NMDA receptor subunit 2A (Grin2a), 5-HT2A (Htr2a), and GABAA subunit β3 (Gabrb3). Results: Our results revealed global changes of histone acetylation on H3 (H3ace) and H4 (H4ace) in the PFC of offspring rats with prenatal Poly I:C exposure. In addition, it revealed enhancement of both H3ace and H4ace binding on the promoter region of Rela, as well as positive correlations between Rela and genes encoding histone acetyltransferases (HATs) including CREB-binding protein (CBP) and E1A-associated protein p300 (EP300). Although there was no change in H3ace or H4ace enrichment on the promoter region of Nlrp3, a significant enhancement of histone deacetylase 6 (HDAC6) binding on the promoter region of Nlrp3 and a positive correlation between Nlrp3 and Hdac6 were also observed. However, prenatal Poly I:C treatment did not lead to any specific changes of H3ace and H4ace on the promoter region of the target genes encoding neurotransmitter receptors in this study. Discussion: These findings demonstrated that epigenetic modulation contributes to NF-κB/NLRP3 mediated neuroinflammation induced by prenatal Poly I:C exposure via enhancement of histone acetylation of H3ace and H4ace on Rela and HDAC6-mediated NLRP3 transcriptional activation. This may further lead to deficits in neurotransmissions and schizophrenia-like behaviors observed in offspring.

Regulatory Effects of Maternal Immune Activation and Environmental Enrichment on Glucocorticoid Receptor and FKBP5 Expression in Stress-sensitive Regions of the Offspring Brain

A mother’s exposure to immune challenge during pregnancy is well known to be a detrimental factor to the development of the offspring’s brain and an impetus for neuropsychiatric disorders. Previous studies have shown that these adverse events can dysregulate the stress response machinery. Two crucial components of the stress axis considered to be affected have been targets in these studies: the glucocorticoid receptor (GR), and FKBP5 which regulates GR activity. The implementation of interventions such as Environmental Enrichment (EE) have shown positive results in protecting the brain against the consequences associated with gestational insults. In light of this, we investigated the transcriptional regulation of GR and FKBP5 from six stress-sensitive brain regions of the offspring using a rat model of maternal immune activation (MIA). Furthermore, we analyzed the effect of an enriched environment on their expression. We found an increase in FKBP5 in MIA rats in five brain regions. RT-qPCR analysis of MIA’s effect on GR yielded insignificant results. However, we found that EE increased GR expression in the medial preoptic area which could be indicative of a positive regulation by EE. This study provides evidence of the impact of both gestational insult and EE on the regulation of stress responsive genes in the developing brain.

Maternal immune activation and adolescent alcohol exposure increase alcohol drinking and disrupt cortical-striatal-hippocampal oscillations in adult offspring

Maternal immune activation (MIA) is strongly associated with an increased risk of developing mental illness in adulthood, which often co-occurs with alcohol misuse. The current study aimed to begin to determine whether MIA, combined with adolescent alcohol exposure (AE), could be used as a model with which we could study the neurobiological mechanisms behind such co-occurring disorders. Pregnant Sprague-Dawley rats were treated with polyI:C or saline on gestational day 15. Half of the offspring were given continuous access to alcohol during adolescence, leading to four experimental groups: controls, MIA, AE, and Dual (MIA + AE). We then evaluated whether MIA and/or AE alter: (1) alcohol consumption; (2) locomotor behavior; and (3) cortical-striatal-hippocampal local field potentials (LFPs) in adult offspring. Dual rats, particularly females, drank significantly more alcohol in adulthood compared to all other groups. MIA led to reduced locomotor behavior in males only. Using machine learning to build predictive models from LFPs, we were able to differentiate Dual rats from control rats and AE rats in both sexes, and Dual rats from MIA rats in females. These data suggest that Dual “hits” (MIA + AE) increases substance use behavior and disrupts activity in reward-related circuits, and that this may be a valuable heuristic model we can use to study the neurobiological underpinnings of co-occurring disorders. Our future work aims to extend these findings to other addictive substances to enhance the translational relevance of this model, as well as determine whether amelioration of these circuit disruptions can reduce substance use behavior.

Imaging extra-striatal dopamine D2 receptors in a maternal immune activation rat model

Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents can be induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreased striatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic system in the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2R abnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) in vivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anterior cingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, a high affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation of dopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC of offspring, similar to the neuronal pathology reported in patients with schizophrenia.

A schizophrenia risk factor induces marked anatomical deficits at GABAergic-dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies.

To develop new therapies for schizophrenia, evidence accumulated over decades highlights the essential need to investigate the GABAergic synapses that presynaptically influence midbrain dopaminergic neurons. Since current technology restricts these studies to animals, and evidence accumulated in recent decades indicates a developmental origin of schizophrenia, we investigated synaptic changes in male rat offspring exposed to maternal immune activation (MIA), a schizophrenia risk factor. Using a novel combination of lentiviruses, peroxidase-immunogold double labeling, three-dimensional serial section transmission electron microscopy and stereology, we observed clear anatomical alterations in synaptic inputs on dopaminergic neurons in the midbrain posterior ventral tegmental area (pVTA). These changes relate directly to a characteristic feature of schizophrenia: increased dopamine release. In 3-month-old and 14-month-old MIA rats, we found a marked decrease in the volume of presynaptic GABAergic terminals from the rostromedial tegmental nucleus (RMTg) and in the length of the synapses they made, when innervating pVTA dopaminergic neurons. In MIA rats in the long-term, we also discovered a decrease in the volume of the postsynaptic density (PSD) and in the maximum thickness of the PSD at the same synapses. These marked deficits were evident in conventional GABA-dopamine synapses and in synaptic triads that we discovered involving asymmetric synapses that innervated RMTg GABAergic presynaptic terminals, which in turn innervated pVTA dopaminergic neurons. In triads, the PSD thickness of asymmetric synapses was significantly decreased in MIA rats in the long-term cohort. The extensive anatomical deficits provide a potential basis for new therapies targeted at synaptic inputs on midbrain pVTA dopaminergic neurons, in contrast to current striatum-targeted antipsychotic drugs.

Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile.

Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain–gut–microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain–gut–microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.

Maternal immune activation alters the sequential structure of ultrasonic communications in male rats

Maternal immune activation (MIA) is a risk factor for schizophrenia and many of the symptoms and neurodevelopmental changes associated with this disorder have been modelled in the rodent. While several previous studies have reported that rodent ultrasonic vocalizations (USVs) are affected by MIA, no previous study has examined whether MIA affects the way that individual USVs occur over time to produce vocalisation sequences. The sequential aspect of this behaviour may be particularly important because changes in sequencing mechanisms have been proposed as a core deficit in schizophrenia. The present research generates MIA with POLY I:C administered to pregnant Sprague-Dawley rat dams at GD15. Male pairs of MIA adult offspring or pairs of their saline controls were placed into a two-chamber apparatus where they were separated from each other by a perforated plexiglass barrier. USVs were recorded for a period of 10 ​min and automated detection and call review were used to classify short call types in the nominal 50 ​kHz band of social affiliative calls. Our data show that the duration of these 50-kHz USVs is longer in MIA rat pairs and the time between calls is shorter. Furthermore, the transition probability between call pairs was different in the MIA animals compared to the control group, indicating alterations in sequential behaviour. These results provide the first evidence that USV call sequencing is altered by the MIA intervention and suggest that further investigations of these temporally extended aspects of USV production are likely to reveal useful information about the mechanisms that underlie sequence generation. This is particularly important given previous research suggesting that sequencing deficits may have a significant impact on both behaviour and cognition.

Effects of iTBS-rTMS on the Behavioral Phenotype of a Rat Model of Maternal Immune Activation.

Repetitive transcranial magnetic stimulation (rTMS) is considered a promising therapeutic tool for treating neuropsychiatric diseases. Previously, we found intermittent theta-burst stimulation (iTBS) rTMS to be most effective in modulating cortical excitation-inhibition balance in rats, accompanied by improved cortical sensory processing and sensory learning performance. Using an animal schizophrenia model based on maternal immune activation (MIA) we tested if iTBS applied to either adult or juvenile rats can affect the behavioral phenotype in a therapeutic or preventive manner, respectively. In a sham-controlled fashion, iTBS effects in MIA rats were compared with rats receiving vehicle NaCl injection instead of the synthetic viral strand. Prior to iTBS, adult MIA rats showed deficits in sensory gating, as tested with prepulse inhibition (PPI) of the acoustic startle reflex, and deficits in novel object recognition (NOR). No differences between MIA and control rats were evident with regard to signs of anxiety, anhedonia and depression but MIA rats were somewhat superior to controls during the training phase of Morris Water Maze (MWM) test. MIA but not control rats significantly improved in PPI following iTBS at adulthood but without significant differences between verum and sham application. If applied during adolescence, verum but not sham-iTBS improved NOR at adulthood but no difference in PPI was evident in rats treated either with sham or verum-iTBS. MIA and control rat responses to sham-iTBS applied at adulthood differed remarkably, indicating a different physiological reaction to the experimental experiences. Although verum-iTBS was not superior to sham-iTBS, MIA rats seemed to benefit from the treatment procedure in general, since differences—in relation to control rats declined or disappeared. Even if classical placebo effects can be excluded, motor or cognitive challenges or the entire handling procedure during the experiments appear to alleviate the behavioral impairments of MIA rats.

Maternal immune activation alters adult behavior, intestinal integrity, gut microbiota and the gut inflammation.

BackgroundSchizophrenia is characterized by several core behavioral features, in which the gastrointestinal symptoms are frequently reported. Maternal immune activation (MIA) has been developed in a rodent model to study neurodevelopmental disorders such as schizophrenia. However, the changes in the gut environment of MIA rats remain largely unknown.Methods10 mg/kg of polyinosinic:polycytidylic acid (Poly I:C) on gestational day 9 was intravenously administered to rats to induce MIA in order to assess changes in behavior, the intestinal barrier and microbiota in offspring.ResultsMaternal immune activation offspring shown increased anxiety as indicated by reduced exploration of central area in open field test and decreased exploration of open arms in elevated plus test. Cognitive impairment of MIA offspring was confirmed by reduced exploration of novel arm in Y maze test and deficiency of PPI. Intestinal muscle thickness became thinner and some specific microbial anomalies previously identified clinically were observed in MIA offspring. In addition, an increase of inflammatory responses was found in the gut of MIA offspring.ConclusionsMaternal immune activation alters behavior, intestinal integrity, gut microbiota and the gut inflammation in adult offspring.

Maternal immune activation and repeated maternal separation alter offspring conditioned avoidance response learning and antipsychotic response in male rats

Previous work shows that repeated administration of several commonly used antipsychotic drugs, such as olanzapine (OLZ) over several days, induces an enhanced disruption of conditioned avoidance response (CAR) (termed antipsychotic sensitization) in normal adolescent and adult rats. However, it is unclear whether the same phenomenon can also be demonstrated in rat models of schizophrenia. The present study investigated OLZ sensitization in a combined maternal immune activation (MIA) and repeated maternal separation (RMS) model of schizophrenia. Sprague-Dawley male rats were first subjected to an early prenatal exposure to polyinosinic:polycytidylic acid (PolyI:C) on gestation days 13 (4 mg/kg, iv) and 15 (6 mg/kg, iv). They were then repeatedly separated from their mothers for 3 h daily during the first two weeks of postpartum. After they became adolescent (on postnatal day, PND 43), acute and OLZ sensitization effects in the CAR model was assessed. Adolescent MIA rats showed an impaired acquisition of conditioned avoidance response, but displayed a normal acute OLZ-induced avoidance suppression and OLZ sensitization effect. In adulthood (PND 81), MIA rats again showed an impairment in the acquisition of CAR. However, they showed a reduced response to OLZ (1.0 mg/kg; sc) treatment during the repeated drug test days, indicating a disruption of the induction of OLZ sensitization. In the OLZ sensitization challenge test, both MIA and control rats exhibited a robust and similar sensitization effect. In both adolescence and adulthood, RMS alone had no effect on any of the behavioral outcomes, and combined MIA-RMS even abolished the MIA alone-induced disruption of avoidance acquisition and the induction of OLZ sensitization. These results indicate that MIA disrupts associative learning and may reduce antipsychotic efficacy in the early stage of OLZ treatment. RMS does not appear to affect associative learning and behavioral responses to OLZ, and may possibly attenuate MIA-induced deficits. Our findings demonstrate that OLZ sensitization is a robust phenomenon but its magnitude can be altered by early MIA.

Anterior cingulate cortex and ventral tegmental area activity during cost-benefit decision-making following maternal immune activation

Abstract Schizophrenia is associated with deficits in memory, behavioural flexibility, and motivation, which can result in difficulties in decision-making. The anterior cingulate cortex (ACC) and ventral tegmental area (VTA) are two brain regions that are involved in decision-making, and display dysfunction in schizophrenia. We investigated ACC and VTA activity in the maternal immune activation (MIA) model of a schizophrenia risk factor. Control and MIA rats completed a cost-benefit decision-making task in a continuous T-maze, choosing between a high cost and high reward (HCHR), and a low cost and low reward (LCLR), option. A choice reversal occurred halfway through each session. Single unit activity in the ACC and local field potentials (LFPs) in the VTA were monitored. Overall, MIA and control rats made a similar proportion of HCHR and LCLR choices across the whole recording session, suggesting similar levels of motivation. However, MIA rats made different decisions than controls during periods of increased uncertainty. This appeared to reflect memory deficits and behavioural inflexibility. MIA animals displayed an increase in ACC activity associated with cost, an increase in synchrony of ACC neurons to the VTA theta oscillation, and a decrease in coherence in the delta frequency between the ACC and VTA. These changes suggest that MIA animals may be biased towards focussing on the cost rather than the benefits of the task, a change also seen in schizophrenia. Here, however, the MIA animals may be able to increase motivation to maintain behaviour despite this change.

Mitogen-activated protein kinase (MAPK) signalling corresponds with distinct behavioural profiles in a rat model of maternal immune activation

Dysfunction within the mitogen-activated protein kinase (MAPK) cascade has been recognised as a pathological feature of schizophrenia, however the possible mechanistic connection to the disease phenotype remains unexplored. Using the maternal immune activation (MIA) rat model of schizophrenia, the present study investigated the involvement of prefrontal cortex (PFC) MAPK in sensorimotor gating and adaptive learning deficits via western blot, pre-pulse inhibition (PPI) testing, and a contingency degradation operant task, respectively. Principle findings identified a negative relationship between basal MAPK expression and PPI exclusively in MIA rats, suggesting a modulatory role for MAPK in sensorimotor gating pathology. In addition, the correlation between MAPK and adaptive learning capacity observed in control rats was absent for rats exposed to MIA. Findings are considered with respect to the glutamatergic NMDA hypofunction theory of schizophrenia, as well as the critical role of PFC in contingency learning.

Discrimination difficulty, cognitive burden, and reversal impairments in a maternal immune activation model of schizophrenia risk

Reversal-learning impairments in the maternal immune activation (MIA) model of schizophrenia risk have been interpreted as being indicative of deficits in reinforcement learning. Here we sought to assess the specific role of cognitive burden in discrimination learning and reversal performance in this model. Control and MIA rats were trained on a visual discrimination task in which responses on either a left or right lever were rewarded depending on the location of a cue light at the beginning of the trial. Groups of MIA and control rats differed in the difficulty of the discrimination rule they initially learned (pressing the lever on the same side vs the opposite side of the cue light). Once the discrimination was learned, performance was tested across four reversals. Across all phases of the experiment, rats in Group Same performed better than rats in Group Opposite. There was no difference in performance of control and MIA rats during acquisition or baseline, but MIA rats displayed impaired performance across reversals, with performance decrements manifesting later in reversals after the new discrimination rule had been learnt. Across reversals, MIA rats also made more perseverative errors than control rats. These results are consistent with others that have shown reversal learning impairments in MIA rats. The results further suggest that impaired behavioural flexibility in the MIA model is not due to a deficit in reinforcement learning, but due to an impaired ability to organize information gained from experience into an accurate and stable representation of the current task requirements.

Reversal learning impairments in the maternal immune activation rat model of schizophrenia.

One of the cognitive symptoms observed in schizophrenia is decreased flexibility in several tasks, including reversal learning. Reversal learning has previously been tested in rats following maternal immune activation (MIA), a risk factor for schizophrenia, with varying results. Whereas some previous studies have shown that MIA rats are slower to learn a reversal, others have reported more rapid learning compared with controls. Several of these latter studies have, however, used a T-maze task with aversive, negative reinforcement as a motivating factor. Because most human studies use positive reinforcement in reversal tasks, here we tested whether reinforcement valence might be a critical factor. We ran male MIA and control rats in a T-maze reversal procedure that was very similar to previous studies except that positive, appetitive reinforcement was used for motivation. The results showed that MIA animals performed similarly to controls during training, but in contrast to the previous, aversively motivated T-maze studies, slower reversal learning was observed. These results show that MIA animals are impaired in reversal learning under conditions of positive reinforcement, consistent with the effects observed in individuals with schizophrenia. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Spared motivational modulation of cognitive effort in a maternal immune activation model of schizophrenia risk.

Maternal immune activation (MIA) during gestation is a significant risk factor for development of schizophrenia and other neurodevelopmental diseases. In animal models of this risk factor, MIA during pregnancy can produce offspring that recapitulate certain aspects of the behavioral and neurophysiological impairments seen in schizophrenia. Here, the authors tested the effect of polyinosinic-polycytidylic acid (poly I:C)-induced MIA in a task that explicitly assays the interaction between motivation and cognition. In our paradigm, discrimination accuracy during a sustained-attention task is differentially impacted by environmental cues that signal the probability of reward for accurate performance. Cognition-motivation interactions are implicated in producing functional impairments in patients. Therefore, to the extent that this MIA model recapitulates such impairments, the authors predicted impaired ability of reward-associated signals to modulate cognitive performance in MIA rat offpsring. Adult offspring of dams in which MIA was induced displayed impaired prepulse inhibition relative to controls, verifying a functional effect of poly I:C induction. Despite this deficit, there were no differences between MIA and control rats in any aspects of task learning or performance, including under extinction and reacquisition conditions. These results indicate that MIA spares functioning of some of the cognitive, motivational, and decision-making processes that are impacted in schizophrenia and suggest that MIA as an isolated manipulation does not model the full range and nuance of the cognitive and motivational impairments in the disease. The authors suggest that some aspects of the functional impairment in schizophrenia and other neurodevelopmental diseases may be better modeled using multiple "hit" models of disease risk. (PsycINFO Database Record

Maternal immune activation in rats produces temporal perception impairments in adult offspring analogous to those observed in schizophrenia.

The neurophysiology underlying temporal perception significantly overlaps with areas of dysfunction identified in schizophrenia. Patients commonly exhibit distorted temporal perception, which likely contributes to functional impairments. Thus, study of temporal perception in animal models of the disease may help to understand both cognitive and neurobiological factors involved in functional impairments in patients. As maternal immune activation (MIA) has been shown to be a significant etiological risk factor in development of schizophrenia and other developmental psychiatric diseases, we tested interval timing in a rat model of MIA that has previously been shown to recapitulate several behavioural and neurophysiological impairments observed in the disease. Rats were tested on a temporal-bisection task, in which temporal duration stimuli were categorized as either “short” or “long” by responding to a corresponding lever. Data from this task were modeled to provide estimates of accuracy and sensitivity of temporal perception. Parameter estimates derived from the model fitting showed that MIA rats significantly overestimated the passage of time compared to controls. These results indicate that the MIA rat paradigm recapitulates timing distortions that are phenotypical of schizophrenia. These findings lend further support to the epidemiological validity of this MIA rat model, supporting its relevance for future research into the role of maternal immune activation in producing neurobiological and behavioural impairments in schizophrenia.