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Title: Foetal programming of brain function and behaviour : a behavioural and molecular characterisation of a murine placental imprinted gene deletion model
Author: Mikaelsson, Mikael Allan
ISNI:       0000 0004 2750 2211
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2010
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Foetal programming describes the process whereby exposure to environmental stimuli or insults during early development can lead to enduring change in structure and function in later life. This concept has found much support in terms of altered metabolic and cardiovascular function from a range of epidemiological and animal studies, but more recent work is highlighting the role that poor foetal nutrition may have on the development of behavioural and psychiatric problems. The biological mechanisms underlying nutritional programming remain uncertain, however compromised placental deficiency and/or foetal endocrine systems (particularly the IGF axis), have been considered to be of paramount importance at the nexus of this foetal-environmental interplay. In the present study, two knockout mouse models of the imprinted Igf2 gene were used to investigate the effects of placental deficiency and foetal growth restriction on brain development and behaviour in later life. Total deletion of the Igf2 gene (7g/2-Null KO) leads to complete ablation of Igf2 expression from all foetal and placental tissue, severe growth deficiency of both the foetus and placenta, and a mouse that is born small (50% of normal size) and remains small for life. However, the Igf2-0 knockout (Igf2-P0 KO) model, where Igf2 expression is only suppressed in the placenta (deletion of the P0 promoter) results in moderate foetal and placental growth retardation and an adult of equivalent size of normal. Intrauterine growth restricted mice from both Igf2 knockout models were tested on a wide range of behavioural batteries, and performance compared with that of wild-type littermates. Since epidemiological studies of humans have commonly demonstrated linkage between nutritional compromise in early life, and ADHD symptoms and anxiety disorders in later life, behavioural tasks sensitive to these behavioural phenotypes were selected for the purpose of present experiments. 7g/2-P0 KO mice displayed heightened levels of stress and anxiety, as indicated by greater startle responses and a marked increase in avoidance behaviour on several conflict-based tests of anxiety. Mice from both Igf2 knockout models exhibited heightened discriminative accuracy in the 5-choice serial reaction time task, but Tg/2-PO KO mice also showed enhanced impulse control. Real-time qPCR revealed differential expression of both GABA- and 5-HT-ergic receptor subtypes in the hippocampus of Igf2-Q KO mice, which may correlate with the observed stress and anxiety related phenotypes. Moreover, alternate splicing of the 5-HT2C receptor in the striatum could underlie the increased impulse control shown by ig/2-P0 KO mice. While the findings of elevated anxiety levels among the Igf2-P0 KO mice are in line with previous work on humans and animals, the heightened attentional performance and impulse control is entirely novel and highlight the importance of further research on the relationship between early life adversities and later ADHD risk.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available