Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring

Abstract

Abnormally elevated expression of the imprinted PHLDA2 gene has been reported in the placenta of human babies that are growth restricted in utero in several studies. We previously modelled this gene alteration in mice and found that just two-fold increased expression of Phlda2 resulted in placental endocrine insufficiency. In addition, elevated Phlda2 was found to drive fetal growth restriction (FGR) of transgenic offspring and impaired maternal care by their wild type mothers. Being born small and being exposed to suboptimal maternal care have both been associated with the increased risk of mental health disorders in human populations. In the current study we probed behavioural consequences of elevated Phlda2 for the offspring. We discovered increased anxiety-like behaviours, deficits in cognition and atypical social behaviours, with the greatest impact on male offspring. Subsequent analysis revealed alterations in the transcriptome of the adult offspring hippocampus, hypothalamus, and amygdala, regions consistent with these behavioural observations. The inclusion of a group of fully wild type controls raised in a normal maternal environment allowed us to attribute behavioural and molecular alterations to the adverse maternal environment induced by placental endocrine insufficiency rather than the specific gene change of elevated Phlda2. Our work demonstrates that a highly common alteration reported in human fetal growth restriction is associated with negative behavioural outcomes later in life. Importantly, we also establish the experimental paradigm that placental endocrine insufficiency can program atypical behaviour in offspring highlighting the under-appreciated role of placental endocrine insufficiency in driving disorders of later life behaviour.

Prenatal health behaviours as predictors of human placental lactogen levels

“…Our work on mice with placental endocrine insufficiency driven by genetically modified changes in the expression of imprinted genes further demonstrates a role for placental hormones in regulating birthweight with a reduction in the number of placental endocrine cells linked to low birthweight in several models (39-41). We also reported both maternal neglect and maternal anxiety in response to the loss of placental endocrine lineages (42, 43) with the mouse offspring exhibiting anxiety-like behaviours later in life (44). Together, these data highlight the importance of placental hormones, and more specifically placental lactogens, for pregnancy health.…”

The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders

“…A 2-fold increase of expression of one of these imprinted genes, Phlda2 , in the mouse foetus leads to a 50% decrease in the size of the placental endocrine compartment; conversely, loss of Phlda2 expression results in a doubling in size of the endocrine compartment [ 87 ]. Both these manipulations of Phlda2 expression in the foetal placenta have consequences for gene expression in the maternal brain and parental care behaviour in the early postnatal phase [ 88 ]; this in turn can have knock-on consequences for offspring brain and behaviour later in life [ 89 ].…”

In support of the placental programming hypothesis: Placental endocrine insufficiency programs atypical behaviour in mothers and their offspring

“…We have demonstrated that placental endocrine insufficiency can cause low birth weight (Salas et al., 2004; Tunster et al., 2010, 2014; Tunster, McNamara, et al., 2016) and alterations in the behaviour of the mother (Creeth et al., 2018; McNamara et al., 2018) and her offspring (Harrison et al., 2021) in mice (Figure 1a). These studies in experimental animal models identify an alternative mechanism whereby adversity‐driven placental endocrine insufficiency causes both the mood disorder in the mother and the poor health outcome for the child.…”

“…In order to distinguish between the direct effect of genetically elevated Phlda2 and the indirect effect of an adverse environment, we generated litters in which half the pups carried the Phlda2 transgene (low birth weight plus adverse environment; transgenic) and half were genetically wild‐type but raised in the same adverse environment (which we refer to as non‐transgenic). These offspring were studied concurrently alongside fully wild‐type litters raised by wild‐type dams as environmental controls (Harrison et al., 2021 ). Both male and female offspring were put through a battery of behavioural tests to probe anxiety‐associated behaviours, depression‐like behaviours, aspects of learning and attention, and social behaviours.…”