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.

Youth-Physical Activity Towards Health: evidence and background to the development of the Y-PATH physical activity intervention for adolescents

Background: Despite known benefits of regular physical activity for health and well-being, many studies suggest that levels of physical activity in young people are low, and decline dramatically during adolescence. The purpose of the current research was to gather data on adolescent youth in order to inform the development of a targeted physical activity intervention. Methods: Cross-sectional data on physical activity levels (using self report and accelerometry), psychological correlates of physical activity, anthropometic characteristics, and the fundamental movement skill proficiency of 256 youth (53% male, 12.40 ± 0.51 years) were collected. A subsample (n = 59) participated in focus group interviews to explore their perceptions of health and identify barriers and motivators to participation in physical activity. Results: Findings indicate that the majority of youth (67%) were not accumulating the minimum 60 minutes of physical activity recommended daily for health, and that 99.5% did not achieve the fundamental movement skill proficiency expected for their age. Body mass index data showed that 25% of youth were classified as overweight or obese. Self-efficacy and physical activity attitude scores were significantly different (p < 0.05) between low, moderate and high active participants. Active and inactive youth reported differences in their perceived understanding of health and their barriers to physical activity participation, with active youth relating nutrition, exercise, energy and sports with the definition of ‘being healthy’, and inactive youth attributing primarily nutritional concepts to ‘being healthy’. Conclusions: Data show a need for targeting low levels of physical activity in youth through addressing poor health related activity knowledge and low fundamental movement skill proficiency. The Y-PATH intervention was developed in accordance with the present study findings; details of the intervention format are presented.