A translational approach to investigate mechanisms underlying intergenerational inheritance of depression

Alyamani, Reema Abdulrahman Saad (2019) A translational approach to investigate mechanisms underlying intergenerational inheritance of depression. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Stress during early life such as exposure to prenatal and postnatal depression or receiving reduced levels of parental care can produce long-lasting behavioural effects. Such long-term disruptions in stress-related behaviours have been seen in both human and rodent studies in offspring exposed to a variety early-life stressors such as maternal depression. Importantly, offspring exposed to early life stress have increased susceptibility to maternal depression themselves suggesting a mechanism by which stress could be intergenerationally inherited through maternal stress. The overall aim of this study was to explore the major possible mechanisms underlying how maternal stress and reduced care is able to increase the risk of developing stress-related behavioral disorders in the offspring. This included: 1) programming neuroendocrine and immune changes; 2) epigenetic alterations driving changes in regulation of stress-related genes; 3) alterations in endocrine and immune factors in milk. This study investigated a rat model of intergenerational inheritance of maternal depressed maternal care stress and two human studies of maternal depression. Endocrine and immune factors were measured using ELISA and epigenetic changes in a rat model and 2 human cohorts using bisulphite pyrosequecning. RNASeq was used to investigate genomewide RNA, transcriptome, changes across generations. A literature review found supporting evidence for the hypotheses and revealed key targets for endocrine, immune and epigenetic regulation that became a focus of the following studies. Analyses in Study 1 showed alterations between the generations in endocrine factors important for stress and maternal care with further changes in specific immune factors and epigenetic alterations at key genes involved in stress regulation. Tanscriptome analyses in Study 2 revealed changes in genes important for calcium binding signaling and levels of shared gene expression between generations. Epigenetic investigations in Study 3 found associations with maternal depression and stress with at at homologous gene regions tested in Study 1 suggesting a level of conservation in mechanisms important for stress regulation in maternal depression. Within Study 4 milk from stressed dams there were reduced levels of endocrine stress factors important in regulation of stress and maternal behavior. This thesis found important evidence to support the involvement of immune and endocrine factors in the transmission of maternal stress together with epigenetic changes at key genes and transcriptome alterations.