Foetal programming of brain function and behaviour : A behavioural and molecular characterisation of a murine placental imprinted gene deletion model

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

The role of imprinted genes in mediating susceptibility to neuropsychiatric disorders

Imprinted genes, which are thought to comprise < 1% of the mammalian genome, are defined by their parent-of-origin specific monoallelic expression arising as a consequence of differential epigenetic marking of alleles in the paternal and maternal germlines. Such genes are highly represented in the brain and placental transcriptomes, and have been shown to exert significant influence on fundamental developmental processes in these organs. Converging evidence from work in man and animal models has shown that imprinted genes can influence a variety of brain and behavioral endophenotypes. In this article, we review the current evidence that imprinted gene dysfunction is associated with vulnerability to several common psychiatric disorders. We also discuss how studying imprinted gene (dys)function may provide mechanistic insights into two important areas in modern psychiatry: first, how environmental factors (especially in utero) interact with genetic liability via epigenetic mechanisms to predispose to later mental illness, and second, the molecular underpinnings of sex-specific vulnerability to psychiatric disorders

Placental programming of anxiety in adulthood revealed by lgf2-null models

Imprinted, maternally silenced insulin-like growth factor-2 is expressed in both the foetus and placenta and has been shown to have roles in foetal and placental development in animal models. Here we compared mice engineered to be null for the placenta-specific P0 transcript (insulin-like growth factor-2-P0 KO) to mice with disruptions of all four insulin-like growth factor-2 transcripts, and therefore null for insulin-like growth factor-2 in both placenta and foetus (insulin-like growth factor-2-total KO). Both models lead to intrauterine growth restriction but dissociate between a situation where there is an imbalance between foetal demand and placental supply of nutrients (the insulin-like growth factor-2-P0 KO) and one where demand and supply is more balanced (the insulin-like growth factor-2-total KO). Increased reactivity to anxiety-provoking stimuli is manifested later in life only in those animals where there is a mismatch between placental supply and foetal demand for nutrients during gestation. Our findings further distinguish placental dysfunction from intrauterine growth restriction and reveal a role for the placenta in long-term programming of emotional behaviour

Comparison and analysis of national climate change adaptation policies in the Nordic region

This report presents the findings from a comparative study of climate change adaptation policy in Denmark, Finland, Iceland, Norway, and Sweden. Based on a comparative analysis of the policy landscape, including legislative frameworks, policy instruments, and financing mechanisms, the report identifies best practices and main challenges as well as key factors influencing the progress of national adaptation. Despite considerable progress in several of the Nordic countries, the report identifies multiple challenges, including lack of systems for monitoring, reporting and evaluation, lack of sufficient funding and economic incentives and lack of appropriate tools and knowledge for aligning adaptation with other societal goals, such as mitigation and sustainable development. The report ends by suggesting ways to enhance adaptation in the Nordic countries

Towards enhanced climate change adaptation in the Nordic Region : Policy recommendations based on an assessment of best practices and key challenges for adaptation policy in the Nordic countries

This policy brief presents the findings from the report "Comparison and analysis of national adaptation policies in the Nordic region", along with a set of policy recommendations directed at public authorities in the Nordic countries. After summarizing key progress factors and best practices and main challenges, the policy brief presents five main recommendations: 1) reframe adaptation as transformation; 2) establish mechanisms for systematic knowledge generation and develop appropriate indicators; 3) break down silo-structure between sectors and develop a clearly articulated policy cycle; 4) enhance adaptation financing and economic incentive mechanisms and translate knowledge on risks and vulnerabilities to local adaptation measures; 5) enhance the political mandate for adaptation and strengthen international commitments, including through Nordic collaboration