Investigating the developmental and behavioral consequences of maternal immune activation on affected offspring

Maternal infection during pregnancy increases the risk of several neuropsychiatric disorders later in life, many of which have a component of dopaminergic (DA) dysfunction, including schizophrenia, autism spectrum disorders (ASD), and attention deficit hyperactivity disorder (ADHD). The majority of DA neurons are found in the adult midbrain; as such the midbrain is a key region of interest regarding these disorders. The literature is conflicting regarding the behavioral alterations following maternal immune activation (MIA) exposure, and the cellular and molecular consequences of MIA on the developing midbrain remain to be fully elucidated. Thus, this thesis aimed to establish the consequences of acute and mild MIA on offspring dopamine-related behaviors, as well as the associated cellular and molecular disturbances of MIA on offspring midbrains. We utilized a rat model of MIA using low dose (50μg/kg, I.P.) of LPS administered at different gestational ages. Our first study indicated that MIA at later gestational ages significantly increased pro-inflammatory IL-1β expression, and reduced HSD11B2 expression in the placenta, which is an important regulator of fetal development. In utero LPS exposure at later gestational ages also impaired the growth of neurons from affected offspring. This study identified key gestational stages during which MIA resulted in differential effects. We utilized these time points in subsequent studies, the next of which investigated neurobehavioral outcomes following MIA. Our results from that study showed that motor differences occurred in juvenile offspring following MIA at E16 only, and these differences were compensated for in adolescence. Then, there was a decline in motor behavior capabilities in adulthood, again only for animals exposed to MIA on E16 (and not E12). Furthermore, our results also demonstrated adolescent and adult offspring that were exposed to MIA at E12 had diminished responses to amphetamine in reward seeking behaviors. In our final study, we aimed to investigate the molecular and cellular changes following MIA which might explain these behavioral alterations. This final study showed a differential inflammatory response in fetal midbrains depending on gestational age of exposure as well as differential developmental alterations. For example, LPS exposure at E16 resulted in decreased VM neurosphere size after 7DIV and this was associated with an increased susceptibility to neurotoxic effects of pro-inflammatory cytokines for VM neurospheres and VM DA neurons treated in culture. In utero LPS exposure at E16 also reduced DA neuron count of fetal VM, measured by TH staining. However, there were no differences in DA neuron number in juvenile, adolescent, or adult offspring. Similarly, LPS exposure did not alter cell number or morphology of glial cells in the midbrains of affected offspring. In conclusion, this thesis indicated later rat pregnancy (E16) as vulnerable time for MIA to affect the development of the nigrostriatal pathway and subsequent behavioral outcomes, possibly implicating a role for MIA in increased risk for disorders associated with motor behavior, like PD. These effects may be mediated through alterations in the placenta and altered inflammatory mediators in the offspring brain. This thesis has also shown that MIA in earlier rat pregnancy (E12) results in altered mesocorticolimbic function, and in particular MIA on E12 resulted in a differential response to amphetamine in affected offspring, which may implicate a role for MIA in increasing the risk for disorders associated with this pathway, including drug tolerance and addiction.

Hazardous alcohol consumption among university students in Ireland: a cross-sectional study

Objective: There is considerable evidence of a cultural shift towards heavier alcohol consumption among university students, especially women. The aim of this study is to investigate the prevalence and correlates of hazardous alcohol consumption (HAC) among university students with particular reference to gender and to compare different modes of data collection in this population. Setting: A large Irish university. Design: A cross-sectional study using a classroom distributed paper questionnaire. Participants: A total of 2275 undergraduates completed the classroom survey, 84% of those in class and 51% of those registered for the relevant module. Main outcome measures: Prevalence of HAC measured using the Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) and the proportion of university students reporting 1 or more of 13 adverse consequences linked to HAC. HAC was defined as an AUDIT-C score of 6 or more among males and 5 or more among females. Results: In the classroom sample, 66.4% (95% CI 64.4 to 68.3) reported HAC (65.2% men and 67.3% women). In women, 57.4% met HAC thresholds for men. Similar patterns of adverse consequences were observed among men and women. Students with a hazardous consumption pattern were more likely to report smoking, illicit drug use and being sexually active. Conclusions: The findings highlight the high prevalence of HAC among university students relative to the general population. Public policy measures require review to tackle the short-term and long-term risks to physical, mental and social health and well-being.

Practice Links [Issue 47, April 2012]

Practice Links is a free e-publication for practitioners working in Irish social services, voluntary and nongovernmental sectors. Practice Links was created to enable practitioners to keep up-to-date with new publications, electronic resources and conference opportunities. issue 47 includes research into the follow-up treatment of women in the aftermath of miscarriage and effects upon employment outcomes for those suffering Autism Spectrum Disorders.