Maternal N-3 Fatty Acid-Deficient Diet on Hypothalamic-Pituitary-Adrenal Axis Responses and Feedback Regulation to Stress in Postpartum Rats and in the Offspring( I )

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Project title/計畫英文名

Project Number/計畫編號

NSC101-2321-B002-083

Translated Name/計畫中文名

親代n-3脂肪酸缺乏飲食對產後及子代HPA壓力反應及回饋調控之影響( I )

Project Principal Investigator/計畫主持人

HUI-MIN SU

Funding Organization

National Science and Technology Council

Website

link

Start date/計畫起

01-08-2012

Expected Completion/計畫迄

12-07-2013

摘要：本計畫研究目的是要探討親代飲食n-3 脂肪酸缺乏對親代產後及子代成長後下視丘-腦下垂體-腎上腺體(hypothalamic-pituitary-adrenal, HPA axis)對壓力反應及負回饋調控之影響。二十二碳六烯酸(Docosahexaenoic acid, DHA, 22:6n-3)富含於腦部，對維持正常神經功能表現非常重要。大部分DHA 在腦部堆積是在大腦發育期，即胚胎泌乳期時由親代提供。我們之前研究發現在親代攝取n-3脂肪酸缺乏飼料，其親代或子代腦區尤其是下視丘和海馬迴最易被剝奪或缺乏。下視丘和海馬迴負責掌控對HPA 壓力反應及負回饋調節。若其調節不規則時，會增加對壓力敏感性而過度反應，產生焦慮及憂鬱行為。目前研究指出產後憂鬱者有較低DHA 含量，胚胎發育期的營養攝取不均衡，易導致成長後慢性疾病如精神疾病發生。所以本計畫假設親代在懷孕泌乳期攝取n-3 脂肪酸缺乏飼料，造成親代及子代大腦發育期下視丘及海馬迴DHA 缺乏，將影響其親代對子代的照顧，及產後及子代成長後，易因壓力，誘發較多腎皮質素等相關HPA 內分泌分泌，提高壓力相關過度生理反應如體溫、血壓、心跳等上升較快或恢復較慢，導致焦慮及憂鬱情緒。並將探討其原因是否因主要調控HPA 負回饋的海馬迴血清素訊息或下視丘GABA 抑制神經傳替受損引起。並進一步瞭解壓力過度反應是否因性別而不同，適時魚油補充是否可改善。大鼠在懷孕泌乳期攝取 n-3 脂肪酸適量、缺乏飼料補充魚油有否，母鼠產後或子代成長後進行焦慮或憂鬱行為實驗。利用束縛(restrain)或藥物產生壓力，測量其血漿HPA 相關賀爾蒙、神經傳導物質之變化，及生理反應高低。檢驗由血清素啟動海馬迴腎皮質素接受器基因之相關訊息傳替及GABA抑制神經傳替相關蛋白的改變。本計畫將有助於瞭解親代在懷孕泌乳期因缺乏 n-3 脂肪酸攝取，對親代產後及子代發育後對壓力反應及焦慮憂鬱行為影響及其可能作用機制。
Abstract: The aim of this proposal is to evaluate whether maternal n-3 fatty acid-deficient dietduring pregnancy and lactation alters the hypothalamic-pituitary-adrenal (HPA) axisresponse and negative feedback regulation leading to anxiety and depression behaviorsin postpartum rats and in the offspring later in life. Docosahexaenoic acid (DHA,22:6n-3), is specifically enriched in the brain and is essential for normal neurologicalfunction. Most DHA accumulation in the brain occurs during brain development and issupplied via the placenta to the fetus and in the breast-fed milk to the pup. We haveobserved that, in the rat, the hypothalamus and hippocampus are two of the brain regionsmost susceptible to DHA deprivation in postpartum rats and to DHA deficiency in theoffspring induced by feeding a maternal n-3 fatty acid-deficient diet. Hypothalamus andhippocampus are responsible for controlling the HPA axis responses and negativefeedback regulation to stress. Dysregulation of the HPA axis has been suggested to leadto depression or anxiety. It has been reported that postpartum depression is associatedwith lower DHA status. Exposure to maternal stress, including nutritional insult, has aprofound impact on stress-induced HPA axis activity and is associated with an increasedrisk of neuropsychiatric disorders in the offspring later in life.We then propose to study the potential mechanism of maternal n-3 fattyacid-deficient dietary stress on HPA axis activity and feedback regulation in postpartumrats and in the offspring later in life. We hypothesize that maternal n-3 fatty acidsdeficient diet decrease hypothalamic and hippocampal DHA levels in postpartum ratsand in the offspring leading to hyperactivity and dysregulation of the HPA axis resultingin depression and anxiety. We propose that DHA may alter GABA inhibitory circuits andserotonin signaling of HPA axis activity and regulation. We also hypothesize that theHPA hyperactivity resulted from maternal n-3 fatty acid-deficient diet may via lowermaternal care behaviors, and would be different in genders and would be overcome byfish oil supplementation.We will use pregnant rats fed n-3 fatty acid-adequate or -deficient diet with orwithout fish oil supplementation during pregnancy and lactation. The maternal carebehaviors will be observed. The postpartum rats and the adult offspring will be used toexamine the plus-maze anxiety-like and the forced swimming depression-like behavior.Physiological responses, HPA axis hormone release, neurotransmitters secretion,serotonin signaling on GR expression, GABA circuits in rats before, during or after therestrain- or GABA antagonist-induced stress will be measured.This work should contribute the understanding the mechanism of a maternal n-3fatty acid-deficient diet during pregnancy and lactation on postpartum depression inpostpartum rats and the effect of DHA on fetal origins of stress related adult behavioralindices of depression and anxiety.

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Maternal N-3 Fatty Acid-Deficient Diet on Hypothalamic-Pituitary-Adrenal Axis Responses and Feedback Regulation to Stress in Postpartum Rats and in the Offspring( I )

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