Brain LC-PUFAs and Maternal Mental Health

描述(由申请人提供)：大脑长链多不饱和脂肪酸(LC-PUFA)组成的变化，特别是二十二碳六烯酸(DHA)的减少，被认为是抑郁症和精神病的一个促成因素。我们的初步数据表明，怀孕和哺乳会耗尽DHA的母体大脑。因此，这些研究旨在检验这一假设，即怀孕和哺乳期间母亲大脑DHA的枯竭会导致产后精神疾病。特定的目标将使用大鼠模型来： 1.确定妊娠和哺乳期对母体脑组织DHA和其他LC-PUFA水平的影响。控制饮食中的脂肪酸含量将被用来改变母亲大脑中的DHA水平。LC-PUFA将在与抑郁症和精神病相关的四个大脑区域以及红细胞中进行评估。这些研究将建立一个啮齿动物模型，用来研究怀孕和哺乳后大脑DHA水平枯竭对与人类抑郁和精神病相关的神经化学参数的影响。 2.探讨产后脑DHA减少对母体下丘脑-垂体-肾上腺(HPA)轴活动和调节的影响。对HPA轴的调节将通过修改地塞米松抑制试验进行评估。大脑皮质促肾上腺皮质激素释放因子1(CRF1)受体的亲和力和密度也将被量化。 3.测定产后脑DHA减少对单胺类神经化学的影响。5-羟色胺、去甲肾上腺素和多巴胺(以及它们各自的代谢物)的浓度将在与抑郁症或精神病相关的大脑区域进行测量。与抑郁症或精神病关系最密切的受体(5-HT1A、5-TH2 A、β、D2和D3)的亲和力和密度也将被量化。 4.观察产后减少脑DHA对大鼠海马区脑源性神经营养因子(BDNF)表达的影响。在抑郁症动物模型中，脑源性神经营养因子基因在海马区的表达减少，将通过核糖核酸酶保护试验进行检测。 这些实验将确定生殖活动和由此导致的母体大脑LC-PUFA含量的变化是否可能导致女性产后精神疾病。调查结果将指出产后精神疾病的原因，从而确定处于危险中的妇女并消除危险因素。这些发现还将为此类疾病的发生提供新的治疗方法。

DESCRIPTION (provided by applicant): 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.