The pregnant brain and the effects of high fat diet

Secondary Supervisor(s): Dr Hardip Sandhu

University of Registration: Coventry University

BBSRC Research Themes: Integrated Understanding of Health (Diet and Health)

Project Outline

Pregnancy is a period of significant structural and functional changes in the gestational body that are mostly regulated by hormones. Among the changes are the enlargement of maternal organs such as the liver, pancreas, mammary glands, white adipose tissue, uterus, and the formation of the placenta, which must occur to create an appropriate environment to the development of the growing foetus (PMID:32707081Link opens in a new window). The brain has also been considered an organ that adapts to pregnancy by hormonal regulation. For instance, classic studies in rodents have highlighted the role of metabolic hormones such as insulin, leptin and prolactin to the central adaptations in the maternal brain that promotes food intake increase (PMID:17555777Link opens in a new window, PMID:18266946Link opens in a new window, PMID:26101377Link opens in a new window), and steroid hormones, have been associated with preparation of neurocircuitry involved in the expression of maternal behaviour postpartum (PMID:6697968Link opens in a new window, PMID:17186513Link opens in a new window) and with neuroprotective and neurogenesis effects, particularly in the hippocampus (PMID:27442421Link opens in a new window, PMID:24012715Link opens in a new window). In humans, recent studies using magnetic resonance have demonstrated significant widespread reductions in cortical grey matter volume and cortical thickness through the gestational weeks, concomitant with rise in sex steroid hormones (PMID:37612425Link opens in a new window, PMID:39284962Link opens in a new window). These changes during the transition to motherhood are considered a form of neuroplasticity and thought to facilitate maternal behaviours and cognitive adjustments necessary for parenting, which are persistent post-partum (PMID:36414622Link opens in a new window, PMID:39284962Link opens in a new window). Maternal experiences during the postpartum period can further influence brain anatomy, suggesting that these changes are also shaped by behavioural factors (PMID:20939669Link opens in a new window). Moreover, the cognitive implications of these brain changes are significant, as impairments in learning and working memory have been identified in women during pregnancy and post-pregnancy (PMID:29320671Link opens in a new window). It is likely that the neuroanatomical changes do not rely on discrete hormonal effects but on the complex interplay between multiple steroid and peptide hormones, as well as the epigenetic factors. Therefore, we hypothesise that the hormonal action on the maternal brain may be influenced by microRNAs (miRNA), which are small non-coding RNAs that regulate gene function through degradation of mRNAs and/or inhibition of protein translation (PMID:16141061Link opens in a new window). They have been considered an important mechanism by which maternal environment can alter long-term phenotypes in the offspring (PMID:31451874Link opens in a new window, PMID:20631295Link opens in a new window, PMID:33501603Link opens in a new window), including alterations in the fatty acid sensing mechanisms in the offspring’s brain, which impairs the detection of nutrients in the brain and leads to increased consumption of high-fat diet (HFD) and obesity (PMID:38833481Link opens in a new window). However, no studies to date have explored the role of miRNAs in the maternal brain adaptations to pregnancy, neither the effect of a HFD to the microRNA profile in the maternal brain.

Objectives (Figure 1)

1: Investigate the miRNA expression profile over the course of pregnancy in the mice brain and correlate it to the maternal brain adaptations to pregnancy.

2: Understand the effects of HFD to the miRNA profile in the maternal brain during pregnancy and analyse the target genes affected by the miRNA, with focus on genes related to cognition and neuroplasticity.

3: Analyse the overexpression of the miRNA found in the previous analyses to human brain organoids of brain areas (hypothalamus and the hippocampus) at normal and high fat environment.

Figure 1. Illustration of the objectives and main methods of the project.

Methods

Brain samples from pregnant mice at normal chow and exposed to HFD will be studied. Small RNA extraction and miRNA arrays analysis will be performed to investigate potential alterations in the miRNA profile. Screening of target genes for the miRNA with TargetScan/IPA. Target genes expression confirmed by qPCR. Brain organoids will be treated with miRNA mimics, and target genes will be analysed by qPCR.