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Regulation of genomic function by prenatal choline availability to confer protection against behavioral and neural outcomes in rat models of depression

A major objective of our research is to uncover the ways in which perinatal choline availability may confer neuroprotective effects in rat models for psychological disorders. Choline is a vital nutrient that serves numerous biological roles, including membrane integrity, cell signaling, and production of the neurotransmitter, acetylcholine. As the major source of methyl groups in the body it also acts epigenetically to alter gene transcription. Thus, levels of it early in development exert widespread effects on behavior and brain function. The Glenn Lab is particularly interested in the capacity for early life choline supplementation to reduce the risk for depression and schizophrenia and study this using genetic rat models.

Project Summary

The increasing prevalence of stress disorders, like depression, and their negative outcomes for physical and mental health warrant investigations into new strategies to limit risk and improve treatment. Little is known about the ways in which levels of specific nutrients available during developmental sensitive periods, when the brain is very plastic, may modulate neural, physiological, and behavioral responses to stress in adults to alter the onset or course of depression. Several recent findings suggest that the nutrient choline may play such a role. In the present proposal there are two major aims to address this: one aim focuses on whether prenatal choline supplementation may inoculate individuals against depression by protecting them from precipitating factors, like stress and the second aim focuses on whether prenatal choline deficiency may make individuals more vulnerable to depression. To address these aims, pregnant rats will be treated with a choline-supplemented, choline-sufficient, or choline-deficient diet. The offspring of these mothers will be reared into adulthood and assessed in one of two models of depression: stress-induced depressive symptoms or a genetic rat model. Stressful experiences will include forced swim stress or chronic mild and unpredictable stress; the genetic model is a mono-allelic deletion of the brain-derived neurotrophic factor (BDNF) gene. Stress and BDNF knockdown are expected to induce anhedonia, anxiety, despair, and memory deficits. We expect that prenatal choline supplementation will attenuate these effects, while prenatal choline deficiency will worsen them. Candidate mechanims for these effects will be explored: physiological and neural responses of rats in each model will be gauged by measuring levels of stress hormones and examining patterns of neurotrophic gene expression and function in the hippocampus, amygdala, and prefrontal cortex, three brain regions well known for their importance in mediating stress responses and affected in depression. Epigenetic regulation of gene transcription in these brain areas will also be examined by investigating the extent to which choline availability in development exerts persistent effects on histone acetylation and DNA methylation at specific sites in adulthood.

Relevance of Research

Genetic factors in humans may increase requirements for choline; in these cases inadequate intake has profound implications for physical health. The present research aims to determine whether choline intake also regulates an individual’s risk for depression, associated outcomes, and the efficacy of treatments for it. It will also enhance our understanding of the epigenetic mechanisms by which choline may exert its effects on human health.