Alterations in brain long-chain polyunsaturated fatty acid (LC-PUFA) composition, particularly decreased docosahexaenoic acid (DHA), are implicated as a contributing factor in depression and psychosis. Our preliminary data indicates that pregnancy and lactation can deplete the maternal brain of DHA. Accordingly, these studies are designed to test the HYPOTHESIS that depletion of maternal brain DHA during pregnancy and lactation contributes to postpartum mental illness.
The Specific Aims will use a rat model to: 1. Determine the effects of pregnancy and lactation on levels of maternal brain DHA and other LC-PUFA. Manipulation of dietary fatty acid content will be used to alter maternal brain DHA levels. LC-PUFA will be assessed in four brain regions associated with depression and psychosis, as well as in erythrocytes. These studies will establish a rodent model with which to study the effects of depleted brain DHA levels following pregnancy and lactation on neurochemical parameters associated with depression and psychosis in humans. 2. Determine the effects of reduced brain DHA in the postpartum period on maternal hypothalamic-pituitary-adrenal (HPA) axis activity and regulation. Regulation of the HPA axis will be assessed using a modification of the dexamethasone suppression test. The affinity and density of cerebral cortical corticotrophin releasing factor1 (CRF1) receptors will also be quantified. 3. Determine the effects of reduced brain DHA in the postpartum period on monoamine neurochemistry. The concentrations of serotonin, norepinephrine, and dopamine (and their respective metabolites) will be measured in brain regions relevant to depression or psychosis. The affinity and density of receptors most strongly implicated in depression or psychosis (5-HT1A, 5-TH2A, beta, D2, and D3) will also be quantified. 4. Determine the effects of reduced brain DHA in the postpartum period on expression of brain-derived neurotrophic factor (BDNF) in hippocampus. Hippocampal expression of the BDNF gene, which is decreased in animal models of depression, will be measured by RNAse protectionassay. These experiments will determine whether reproductive activity and the resulting alterations in maternal brain LC-PUFA content are likely to contribute to postpartum mental illness in women. Findings will point to causes of postpartum mental illness and thus the identification of women at risk and the elimination of risk factors. These findings will also suggest novel treatments for such illnesses when they occur.
