男女有別?男性與女性在大腦與行為上存在著相當的差異性。此等差異的發生除了源自於生物個體原有遺傳背景的性別差異外，也可能是在生長發育過程中男女專屬的性賀爾蒙波動所造成的影響。根據前人文獻報導與流行病學統計結果指出，女性罹患壓力所造成的情感障礙比例高出男性許多，女性罹患憂鬱症比例為男性的兩倍。這樣的差異可能與兩性在遭遇壓力事件後引發不同程度的下視丘-腦下垂體-腎上腺 (hypothalamus-pituitary-adrenal axis, HPA axis) 內分泌軸線的活化作用有關，已知下視丘-腦下垂體-腎上腺之內分泌軸線的活化為壓力系統的重要表徵，而血液中之皮質醇 (cortisol) 濃度，則為臨床上可測知此壓力系統的標記之一，其可透過直接或間接作用於中樞神經系統訊息傳導分子，進而改變神經元活性及個體行為表現。本論文主要的研究目的係去探討是否壓力所誘發的生理和心理反應上會有性別上的差異，此外雌激素 (estrogen) 在此之中所扮演的角色為何？利用藥理、生化及生理行為模式的策略，我們發現處於不同生理週期的雌性大鼠海馬迴 CA1 區長期增益現象表現的大小程度會隨著體內不同賀爾蒙濃度高低而產生波動，處於雌激素含量較高的 proestrus 和 estrus 時期的雌性大鼠海馬迴 CA1 區域的長期增益現象表現程度明顯大於體內雌激素濃度較低的 diestrus 雌性大鼠與雄性大鼠。此外我們也發現血清中的雌激素含量與海馬迴 CA1 區域的長期增益現象表現程度呈現正相關。再者，量測壓力暴露對於不同性別及不同週期的雌性大鼠所造成的神經突觸塑性影響時，我們發現雄性大鼠遭受壓力時較易產生海馬迴 CA1 區域的長期增益現象表現受損的作用，而當體內處於較高雌激素濃度的雌性大鼠，此一受損情形則較不明顯；另外，在恐懼記憶表現的行為模式上，我們發現雄性大鼠較容易形成恐懼記憶的連結。當生物體暴露在相同場景卻沒有出現前述之危險事件時，恐懼記憶會逐漸消除。我們發現雌性大鼠恐懼記憶消除的速度明顯較雄性大鼠快，而且體內含有較高濃度雌激素的雌性大鼠其恐懼記憶消除的速度也較體內低濃度的雌性大鼠來的快，顯示雌激素可能參與恐懼記憶消除作用中。在卵巢切除的雌性大鼠腹腔注射雌激素受體 ß 亞型的致效劑 diarylpropionitrile (DPN) 也可以加速恐懼記憶消除的作用，然而雌激素受體 α 亞型的致效劑 propyl-pyrazole-triol (PPT) 則與控制組在恐懼記憶消除的作用相當，因此我們認為雌激素所調控的母鼠恐懼記憶消除加速的作用需要活化雌激素受體 ß 亞型。此外，利用卵巢切除母鼠組埋管注射雌激素於海馬迴 CA1 區域相較於注射溶劑組也可以快速消除恐懼記憶，更進一步證實雌激素係直接作用在海馬迴 CA1 區域來產生加速恐懼記憶消除的作用。然而，雌性大鼠並不會因處於不同生理週期而有明顯的活動力改變或是焦慮的現象發生。有趣的是，兩性恐懼記憶形成及消除上的差異在尚未性成熟和青春期時期並未出現。綜合上述實驗結果，揭示了雌激素扮演調控壓力所造成神經突觸塑性改變以及對於恐懼行為表現程度不同的重要角色。個體對於同樣壓力卻有反應程度上的落差，往往決定不同個體罹患壓力相關精神疾病與否，本篇研究除了從分子神經科學及行為科學上顯示性別差異與雌激素含量多寡可造成不同壓力感受與反應，並提供罹患因壓力所造成精神疾病的高危險族群可能有效預防治療的面向。

Females and males are different in brain and behavior. Differences begin early during development due to a combination of genetic and hormonal events and continue throughout the lifespan of an individual. Females are more susceptible than males to stress-induced affective disorders and twice as likely to experience depression. These differences are probably underlined by sexual dimorphisms observed in the hypothalamic-pituitary-adrenal (HPA) axis activity/response to stress and its interaction with the central neurotransmitter systems. In this study, we investigated whether sex alters behavioral and physiological responses to stress and estrogen exerts both organizational and activational influence on the sex differences in response to stress. Using pharmacological, biochemical and behavioral techniques, we have found that levels of hippocampal CA1 long-term potentiation (LTP) induction vary across the estrous cycle and estrogen contributes greater amount of LTP in proestrus and estrus females. A significant positive linear correlation is evident between the plasma estradiol levels and the magnitude of LTP expression in females. Male rats exhibited significantly higher levels of contextual fear freezing and stress-induced impairment of LTP than female rats. The sexually dimorphic extinction of contextual fear conditioning is mediated, at least in part, through an estrogen-dependent mechanism. An estrogen receptor (ER)  agonist diarylpropionitrile (DPN) but not an ER  agonist propyl-pyrazole-triol (PPT) also facilitataes the extinction of contextual fear memory in ovariectomized female rats, suggesting that estrogen-mediated facilitation of fear extinction involves the activation of ER. Intrahippocampal injection of estradiol one hour before extinction training in ovariectomized female rats remarkably reduced the duration of freezing responses during the extinction training and test, compared with the vehicle-injected control rats. In addition, the locomotion or the anxiety state of female rats does not vary across the estrous cycle. We found no significant difference in acquisition and extinction of contextual fear memory between male and female at juvenile and adolescent ages. Taken together, these experiments reveal an important role for estrogen in modulating both sexually dimorphic contextual fear conditioning and hippocampal synaptic plasticity in response to stress. Understanding why individuals exhibit differential responses to stress-induced affective disorders is important to further the basic science of stress vulnerability as well as to effectively treat and perhaps prevent stress-related affective disorders in at-risk individuals.

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