Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring (original) (raw)
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Brain, Behaviour and Immunity, 2017
Maternal exposure to infectious agents during gestation has been identified as a significant risk factor for schizophrenia. Using a mouse model, past work has demonstrated that the gestational timing of the immune-activating event can impact the behavioural phenotype and expression of dopaminergic and glutamatergic neurotransmission markers in the offspring. In order to determine the inter-species generality of this effect to rats, another commonly used model species, the current study investigated the impact of a viral mimetic Poly (I:C) at either an early (gestational day 10) or late (gestational day 19) time-point on schizophrenia-related behaviour and neurotransmitter receptor expression in rat offspring. Exposure to Poly (I:C) in late, but not early, gestation resulted in transient impairments in working memory. In addition, male rats exposed to maternal immune activation (MIA) in either early or late gestation exhibited sensorimotor gating deficits. Conversely, neither early nor late MIA exposure altered locomotor responses to MK-801 or amphetamine. In addition, increased dopamine 1 receptor mRNA levels were found in the nucleus accumbens of male rats exposed to early gestational MIA. The findings from this study diverge somewhat from previous findings in mice with MIA exposure, which were often found to exhibit a more comprehensive spectrum of schizophrenia-like phenotypes in both males and females, indicating potential differences in the neurodevelopmental vulnerability to MIA exposure in the rat with regards to schizophrenia related changes.
Priming of Metabolic Dysfunctions by Prenatal Immune Activation in Mice: Relevance to Schizophrenia
Schizophrenia Bulletin, 2013
Schizophrenia is associated with increased risk for multiple metabolic abnormalities, including altered glucose homeostasis, type-2 diabetes, obesity, and cardiovascular disease. Some of the metabolic alterations can already exist in psychosis-prone subjects prior to the onset of chronic schizophrenic disease and pharmacotherapy, indicating that they may have a developmental origin. In the present study, we tested the hypothesis that metabolic alterations pertinent to schizophrenic disease can be primed by an environmental risk factor associated with the disorder, namely prenatal exposure to immune challenge. We used a well-established mouse model of prenatal immune challenge induced by maternal gestational treatment with poly(I:C) (5''polyriboinosinic-polyribocytidilic acid''), an analog of double-stranded RNA that stimulates a cytokine-associated viral-like acute phase response. Metabolic effects were studied using highresolution computed tomography and fully automated indirect calorimetry system, along with an oral glucose tolerance test and plasma cytokine and corticosterone measurements. We found that prenatal immune activation caused altered glycemic regulation and abnormal ingestive behavior in periadolescence and led to an adult onset of excess visceral and subcutaneous fat deposition. These effects were accompanied by age-dependent changes in peripheral secretion of proinflammatory (interleukin [IL]-6 and tumor necrosis factor [TNF]-a) and T cell-related (IL-2 and interferon [IFN]g) cytokines and by increased release of the stress hormone corticosterone in periadolescence. Our findings show that schizophrenia-relevant metabolic and physiological abnormalities can be primed by prenatal viral-like immune activation, but at the same time, our study emphasizes that this environmental insult is unlikely to precipitate the full spectrum of metabolic and immunological changes pertinent to chronic schizophrenic disease.
Molecular Neurobiology, 2020
Schizophrenia is a complex neuropsychiatric disorder, influenced by a combined action of genes and environmental factors. The neurodevelopmental origin is one of the most widely recognized etiological models of this heterogeneous disorder. Environmental factors, especially infections during gestation, appear to be a major risk determinant of neurodevelopmental basis of schizophrenia. Prenatal infection may cause maternal immune activation (MIA) and enhance risk of schizophrenia in the offspring. However, the precise mechanistic basis through which MIA causes long-lasting schizophrenia-like behavioral deficits in offspring remains inadequately understood. Herein, we aimed to delineate whether prenatal infection-induced MIA causes schizophrenia-like behaviors through its long-lasting effects on immune-inflammatory and apoptotic pathways, oxidative stress toxicity, and antioxidant defenses in the brain of offspring. Sprague-Dawley rats were divided into three groups (n = 15/group) and were injected with poly (I:C), LPS, and saline at gestational day (GD)-12. Except IL-1β, plasma levels of IL-6, TNF-α, and IL-17A assessed after 24 h were significantly elevated in both the poly (I:C)-and LPS-treated pregnant rats, indicating MIA. The rats born to dams treated with poly (I:C) and LPS displayed increased anxiety-like behaviors and significant deficits in social behaviors. Furthermore, the hippocampus of the offspring rats of both the poly (I:C)-and LPS-treated groups showed increased signs of lipid peroxidation, diminished total antioxidant content, and differentially upregulated expression of inflammatory (TNFα, IL6, and IL1β), and apoptotic (Bax, Cas3, and Cas9) genes but decreased expression of neuroprotective (BDNF and Bcl2) genes. The results suggest long-standing effects of prenatal infections on schizophrenia-like behavioral deficits, which are mediated by immune-inflammatory and apoptotic pathways, increased oxidative stress toxicity, and lowered antioxidant and neuroprotective defenses. The findings suggest that prenatal infections may underpin neurodevelopmental aberrations and neuroprogression and subsequently schizophrenia-like symptoms.
Molecular Psychiatry, 2010
It has been hypothesized that the maternal immune response to infection may influence fetal brain development and lead to schizophrenia. Animal experimentation has supported this notion by demonstrating altered sensorimotor gating (prepulse inhibition, PPI) in adult rats prenatally exposed to an immune challenge. In the present study, pregnant rats were exposed to the bacterial endotoxin lipopolysaccharide (LPS) throughout gestation and the offspring were examined by evaluating the PPI, dopaminergic function, brain protein expression and cytokine serum levels from weaning to late adulthood. Prenatal LPS exposure induced a deficit in PPI that emerged at 'puberty' and that persisted throughout adult life. This prenatal insult caused age-specific changes in accumbal dopamine levels and in synaptophysin expression in the frontal cortex. Moreover, serum cytokine levels were altered in an age-and cytokinedependent manner. Here we show that prenatal LPS administration throughout pregnancy causes maturation-dependent PPI deficits and age-dependent alterations in dopamine activity, as well as in synaptophysin expression and cytokine levels.
eneuro
Influenza during pregnancy is associated with the development of psychopathology in the offspring. We sought to determine whether maternal cytokines produced following administration of viral mimetic polyinosinicpolycytidylic acid (polyI:C) to pregnant rats were predictive of behavioral abnormalities in the adult offspring. Timed-pregnant Sprague Dawley rats received a single intravenous injection of 4-mg/kg polyI:C or saline on gestational day (GD)15. Blood was collected 3 h later for serum analysis of cytokine levels with ELISA. Male offspring were tested in a battery of behavioral tests during adulthood and behavior was correlated with maternal cytokine levels. Maternal serum levels of CXCL1 and interleukin (IL)-6, but not tumor necrosis factor (TNF)-␣ or CXCL2, were elevated in polyI:C-treated dams. PolyI:C-treated dams experienced post-treatment weight loss and polyI:C pups were smaller than controls at postnatal day (PND)1. Various behavior alterations were seen in the polyI:C-treated offspring. Male polyI:C offspring had enhanced MK-801-induced locomotion, and reduced sociability. PolyI:C offspring failed to display crossmodal and visual memory, and oddity preference was also impaired. Set-shifting, assessed with a lever-based operant conditioning task, was facilitated while touchscreenbased reversal learning was impaired. Correlations were found between maternal serum concentrations of CXCL1, acute maternal temperature and body weight changes, neonatal pup mass, and odd object discrimination and social behavior. Overall, while the offspring of polyI:C-treated rats displayed behavior abnormalities, maternal serum cytokines were not related to the long-term behavior changes in the offspring. Maternal sickness effects and neonatal pup size may be better indicators of later effects of maternal inflammation in the offspring.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2009
Maternal infection during pregnancy enhances the offspring's risk for severe neuropsychiatric disorders in later life, including schizophrenia. Recent attempts to model this association in animals provided further experimental evidence for a causal relationship between in-utero immune challenge and the postnatal emergence of a wide spectrum of behavioural, pharmacological and neuroanatomical dysfunctions implicated in schizophrenia. However, it still remains unknown whether the prenatal infection-induced changes in brain and behavioural functions may be associated with multiple changes at the neurochemical level. Here, we tested this hypothesis in a recently established mouse model of viral-like infection. Pregnant dams on gestation day 9 were exposed to viral mimetic polyriboinosinic-polyribocytidilic acid (PolyI:C, 5 mg/kg i.v.) or vehicle treatment, and basal neurotransmitter levels were then compared in the adult brains of animals born to PolyI:C- or vehicle-treated mothers ...
Neuropsychopharmacology, 2002
Increasing evidence associates schizophrenia with prenatal exposure to infection. Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) of the acoustic startle reflex. We analyzed the effect of a prenatal immune challenge-peripheral administration of bacterial endotoxin lipopolysaccharide (LPS) to pregnant female rats-upon PPI and immune function in adult offspring. Prenatal LPS treatment disrupted PPI which was reversed by antipsychotics. Serum levels of interleukin-2 and interleukin-6 were increased. In addition, histopathological features in brain areas related with PPI circuitry were observed. These results illustrate the critical influence of prenatal immune events upon adult CNS functioning in association with the putative role of the immune system in the etiopathogenesis of schizophrenia.
Frontiers in cellular neuroscience, 2015
Data from epidemiological studies suggest that prenatal exposure to bacterial and viral infection is an important environmental risk factor for schizophrenia. The maternal immune activation (MIA) animal model is used to study how an insult directed at the maternal host can have adverse effects on the fetus, leading to behavioral and neurochemical changes later in life. We evaluated whether the administration of LPS to rat dams during late pregnancy affects astroglial markers (S100B and GFAP) of the offspring in later life. The frontal cortex and hippocampus were compared in male and female offspring on postnatal days (PND) 30 and 60. The S100B protein exhibited an age-dependent pattern of expression, being increased in the frontal cortex and hippocampus of the MIA group at PND 60, while at PND 30, male rats presented increased S100B levels only in the frontal cortex. Considering that S100B secretion is reduced by elevation of glutamate levels, we may hypothesize that this early incr...
Journal of Neuroimmune Pharmacology
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 recog...
Neuropsychopharmacology, 2007
Increasing evidence suggests that pre-or perinatal events that influence the immune system contribute to the development of behavioral or neuropsychiatric disorders. For instance, exposure of pregnant rats to the bacterial endotoxin lipopolysaccharide (LPS) disrupts sensorimotor information processing, as assessed by the prepulse inhibition test (PPI), and also the immune function in adult offspring, which might be of particular relevance as regards schizophrenia. However, the consequences of maternal LPS exposure during pregnancy on synaptic functioning in adult offspring and, more importantly, the therapeutic opportunity to re-establish PPI and immune function have still to be demonstrated. In this work, we analyzed the consequences of prenatal LPS exposure on dopaminergic neurotransmission and presynaptic markers in adult brain areas related to PPI circuitry. In addition, we tested whether oral treatment with the typical antipsychotic drug haloperidol (HAL) could reinstate PPI performances and cytokine serum levels in six-month-old male rats with prenatal LPS exposure. Both sensory information processing deficits and immune anomalies induced by prenatal exposure to LPS were accompanied by changes in dopaminergic neurotransmission and synaptophysin expression. It is important to note that PPI disruption and serum increases in cytokines induced by prenatal LPS exposure were both reversed by HAL. Taken together, these results demonstrate the critical influence of prenatal immune events on the functioning of adult nervous and immune systems, in association with the putative role of the immune system in the development of behavior relevant to schizophrenia.