Executive functions are important cognitive processes critical for survival. Damage to the prefrontal cortex impairs executive functions, such as working memory, decision making and set-shifting. Interestingly, patients diagnosed with different psychiatric disorders are also impaired in executive functions, especially in the set-shift domain, often measured by the Wisconsin Card Sorting Task (WCST). Set-shifting is an essential cognitive process, in that it allows the individual to suppress non-reinforcing strategies and engage in new rewarding strategies. To date, little is known about the etiology of executive dysfunction in psychiatric disorders. However, some epidemiological and serological experiments have shown strong correlations between prenatal infection and the increased risk to develop psychiatric disorders in the adult offspring. One study found that schizophrenic patients pre-exposed to a prenatal infection perseverated more during the WCST, than non-pre-exposed patients. Despite these findings, there are still numerous limitations (e.g., ethical concerns) when conducting these studies. Thus, animal models are important and can further elucidate the etiology of executive dysfunctions in psychiatric disorders. Prenatal infection animal models have consistently shown that inflammation during gestation in rodents induces behavioural, anatomical and cognitive changes in the adult offspring similar to psychiatric patients. However, no studies have investigated the effects of prenatal infection on set-shifting in the adult offspring. Therefore, the present thesis examined whether prenatal treatment with PolyI:C (a viral mimetic) during middle/late gestation of the rat would induce cognitive inflexibilities (i.e., set-shifting and reversal learning in an operant based task analogous to the WCST) in the adult male and female offspring. The results showed PolyI:C male offspring perseverated during the set-shift but had fewer regressive errors during the reversal learning day. PolyI:C treated female offspring were not impaired during any of the test days; however, females were slower to respond to the lever and required more training when compared the male rats. Taken together, these results give support for prenatal infection in inducing cognitive inflexibility, by potentially altering the PFC in the adult offspring. MS-based thesis: Zhang, Y., Cazakoff, B. N., Thai, C. A., & Howland, J. G. (2011). Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats. Neuropharmacology, [epub ahead of print]. doi:10.1016/j.neuropharm.2011.02.022

Executive functions are important cognitive processes critical for survival. Damage to the prefrontal cortex impairs executive functions, such as working memory, decision making and set-shifting. Interestingly, patients diagnosed with different psychiatric disorders are also impaired in executive functions, especially in the set-shift domain, often measured by the Wisconsin Card Sorting Task (WCST). Set-shifting is an essential cognitive process, in that it allows the individual to suppress non-reinforcing strategies and engage in new rewarding strategies. To date, little is known about the etiology of executive dysfunction in psychiatric disorders. However, some epidemiological and serological experiments have shown strong correlations between prenatal infection and the increased risk to develop psychiatric disorders in the adult offspring. One study found that schizophrenic patients pre-exposed to a prenatal infection perseverated more during the WCST, than non-pre-exposed patients. Despite these findings, there are still numerous limitations (e.g., ethical concerns) when conducting these studies. Thus, animal models are important and can further elucidate the etiology of executive dysfunctions in psychiatric disorders. Prenatal infection animal models have consistently shown that inflammation during gestation in rodents induces behavioural, anatomical and cognitive changes in the adult offspring similar to psychiatric patients. However, no studies have investigated the effects of prenatal infection on set-shifting in the adult offspring. Therefore, the present thesis examined whether prenatal treatment with PolyI:C (a viral mimetic) during middle/late gestation of the rat would induce cognitive inflexibilities (i.e., set-shifting and reversal learning in an operant based task analogous to the WCST) in the adult male and female offspring. The results showed PolyI:C male offspring perseverated during the set-shift but had fewer regressive errors during the reversal learning day. PolyI:C treated female offspring were not impaired during any of the test days; however, females were slower to respond to the lever and required more training when compared the male rats. Taken together, these results give support for prenatal infection in inducing cognitive inflexibility, by potentially altering the PFC in the adult offspring. MS-based thesis: Zhang, Y., Cazakoff, B. N., Thai, C. A., & Howland, J. G. (2011). Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats. Neuropharmacology, [epub ahead of print]. doi:10.1016/j.neuropharm.2011.02.022

Résumé : Le streptocoque de groupe B (SGB) est une bactérie commensale présente dans le tractus génito-urinaire de 10 à 30 % des femmes enceintes en santé. Ce pathogène est responsable de chorioamnionite, associée aux naissances prématurées et aux dommages cérébraux du nouveau-né. Les infections durant la grossesse, la chorioamnionite et la prématurité sont associées au développement de troubles du spectre de l’autisme. Notre hypothèse est qu’une exposition subclinique au SGB induit une réponse inflammatoire maternofoetale, menant à des troubles neurodéveloppementaux et comportementaux de type autistique dans la progéniture. L’objectif principal est d’étudier, à l’aide d’un nouveau modèle animal (rat) préclinique, les impacts d’une exposition au SGB en période prénatale sur le développement cérébral de la progéniture. Les rates Lewis gestantes sont injectées au jour de gestation 19 avec une dose de SGB de sérotype Ia (108 UFC/100µl) ou de saline. La réponse inflammatoire placentaire est caractérisée par immunohistochimie. Des tests comportementaux sont effectués entre les jours postnataux 7 et 40 afin d’évaluer la communication, le comportement exploratoire, l’intégration sensorielle et les interactions sociales. Une chorioamnionite dichotomique selon le genre est observée dans les placentas exposés au SGB, via une infiltration de cellules polymorphonucléaires. Cette infiltration est significativement plus proéminente dans les placentas associés aux fœtus mâles que ceux des fœtus femelles. Les mâles exposés au SGB ont un amincissement de la substance blanche cérébrale adjacente aux ventricules latéraux élargis. La progéniture mâle exposée au SGB présente des anomalies comportementales associées aux traits cardinaux des troubles du spectre de l’autisme, soit des déficits au niveau de la communication, des interactions sociales, du traitement de l’information sensorielle ainsi qu’au niveau d’autres comorbidités classiques de l’autisme, comme l’hyperactivité. Ces données démontrent pour la première fois que l’activation immune maternelle induite par l’infection au SGB joue un rôle dans l’induction d’anomalies neurodéveloppementales récapitulant celles observées chez les patients autistes, incluant la dichotomie de genre et le phénotype neurocomportemental. Ces résultats fournissent de nouvelles évidences en faveur du rôle dans la physiopathologie de l’autisme d’un facteur environnemental commun, et modifiable, d’inflammation gestationnelle. / Abstract : Group B Streptococcus (GBS) is a commensal bacterium present in the vagina of 10 to 30% of healthy pregnant women. GBS is responsible for chorioamnionitis, which can cause preterm birth and cerebral injuries in the newborn most often in the absence of maternofetal pathogen translocation. Maternal infection, chorioamnionitis and preterm birth are associated to autism spectrum disorders (ASD) in the progeny. Our hypothesis is that GBS-induced gestational infection induces a maternofetal inflammatory response leading to neurodevelopmental impairments and ASD-like behaviour in the offspring. Our goal was to study, with a new preclinical animal model, the impacts of GBS-induced gestational inflammation on the neurodevelopmental features in the offspring. We characterized GBS-induced placental and neurobehavioural outcomes. Dams were exposed at gestational day 19 to live GBS or saline. The placental inflammatory response was studied by immunohistochemistry. Behavioural tests were performed between postnatal days 7 and 40 to assess communication, exploratory abilities, sensory integration and social interactions. GBS-exposed placentas displayed chorioamnionitis featured by infiltration of polymorphonuclear cells, which was significantly more prominent in males than in females. GBS-exposed males showed a reduced thickness of periventricular white matter. Male offspring exposed to GBS had early onset of cardinal ASD-like traits affecting social interaction, communication (ultrasonic vocalizations), treatment of sensory information (prepulse inhibition), preference toward mother cue (nest-seeking), and some other classic ASD comorbidities such as hyperactivity (open field). Overall, these data show for the first time that maternal immune activation due to live GBS plays a key role in the induction of neurodevelopmental abnormalities recapitulating those of human ASD, including gender dichotomy and neurobehavioural phenotype. These results provide new evidence in favor of the role of a common and modifiable infectious/inflammatory environmental factor in human ASD pathophysiology.

Activation of the maternal immune system and resultant maternal cytokine expression due to prenatal infection has been implicated as a significant contributor to the pathology of neuropsychiatric and neurodevelopmental disorders such as schizophrenia and Autism Spectrum Disorder (ASD). Increased maternal interleukin-6 (IL-6) expression, observed clinically and in animal models of prenatal infection, and resultant activation of key signaling pathways, has been shown to be a biological indicator of pathology, and a central component of the pathological mechanism. In animal models of prenatal infection and clinically in pregnancy disorders hallmarked by immunological irregularities and increased IL-6 expression, inhibition of IL-6 has been shown to reduce pathological symptoms both maternally and in the exposed offspring. This study aims to demonstrate the ability of IL-6 expression, resulting from prenatal infection, to induce neuropathological and behavioral outcomes that mirror clinical observations seen in disorders such as ASD. More importantly, it shows how flavones luteolin and diosmin, a subclass of the flavonoid family, through inhibition of IL-6 mediated activation of Signal Transducer and Activator of Transcription-3 (Stat3) can reduce these pathologies both in vitro and in vivo. Evidence suggests that flavonoids, a polyphenolic class of naturally occurring plant secondary metabolites, are potent anti-inflammatory agents that can attenuate the expression of cytokines such as IL-6, possibly through the modulation of tyrosine kinase activity. They have been shown to have significant therapeutic potential in disorders hallmarked by increased inflammation or disruptions in immune regulation, such as neurodegenerative disorders and certain cancers. Members such as diosmin have also been shown to be safe during pregnancy, and are currently utilized in the treatment of certain vascular disorders associated with pregnancy. In vitro work undertaken in this study showed that co-administration of luteolin with IL-6 in neural stem cells (NSC) was able to attenuate pathological outcomes induced by IL-6 including aberrant proliferation, over expression of astroglial marker, glial fibrillary acidic protein (GFAP) and changes in cellular morphology. In vivo studies involving luteolin and diosmin further confirmed the therapeutic efficacy of these compounds as similar attenuation of IL-6 mediated maternal and fetal pro-inflammatory cytokine expression and abnormal behaviors in prenatally exposed offspring was observed. Mechanistically, these effects were mediated through inhibition of Stat3 activation although other pathways activated by IL-6 were modulated by flavone co-treatment. Flavonoid treatment during periods of prenatal infection may prove to be a therapeutic intervention for the resultant pathological outcomes seen in offspring through attenuation of the maternal and fetal immune response to infection as well as modulation of signaling pathways in the fetal brain. These compounds may prove therapeutically efficacious for the application in perinatal conditions hallmarked by increased inflammation during pregnancy.

The memory and spatial navigation are extremely important brain functions for humans, but they are often the question of life and death for animals. In humans, memory can be disrupted by various neuropsychiatric disorders. The patients suffering from Alzheimer's dementia (AD) have impaired working and long-term memory, spatial navigation, higher cognitive functions and social memory. The deficit of cognitive coordination (the skill to recognize the relevancy of incoming information) and disorientation belong to the symptomatology of schizophrenia. Intelectual disability appears in some patients with autism spectrum disorder. Unfortunately, it is not possible to cure these disorders efficiently because the etiology is not known in the majority of patients. The causes leading to development of these disorders could be revealed using animal models. This thesis contributes to the characterization of the cognitive skills disruptions - as well as other behavioral alterations - in selected rat models of AD (transgenic McGill rat, non-transgenic Samaritan rat) and schizophrenia (lipopolysaccharide model of early postnatal, or prenatal, bacterial infection). The thesis also discusses the validity and limitations of these models. Our results showed a severe deficit of spatial navigation, learning and...