| 摘要: | 在許多神經精神疾病中，性別差異會造成的臨床表徵不同。其中思覺失調症是一個複雜的大腦心智疾病，主要病徵為妄想、幻覺、缺乏動機、情緒表達減少及認知功能異常。臨床觀察中發現女性發病年齡較男性晚，且女性較男性有高度幻覺及情緒問題，而男性則表現較多缺乏動機的表徵，但男女皆有認知功能異常問題。遺傳因子DTNBP1(dysbindin-1 蛋白)被列為影響思覺失調症的重要因子。過去研究顯示雄性的基因剔除小鼠(Dys-/-)有類似思覺失調症及認知功能失調的病徵，但是否雌性Dys-/-小鼠也具有同樣病徵仍是未知。而個人的初步研究結果顯示在DTNBP1基因剔除的小鼠中，在病理特徵上有性別上的差異存在。結果顯示在杏仁核內CaMKII 活性及Arc 蛋白有顯著減少現象，但在雌性的基因剔除小鼠中，杏仁核內的CaMKII活性相對於對照組並無改變，但Arc有顯著減少，AKT活性相對於對照組，則有顯著性增加。因此，此計畫主要結合生化學、行為學及腦區域性的消除dysbindin-1表達等實驗方法探討雌性Dys-/-小鼠的病理機制。透過本計畫的實驗結果可為未來在神經精神疾病性別差異上開創有益的方向。 ;Sex difference has been found in many neuropsychiatric disorders in terms of response, frequency, and severity. In the case of schizophrenia subjects, women present symptoms in the later age, while men develop symptoms during the earlier adolescent. Additionally, in the clinical observation, women exhibit symptoms in emotion and hallucination, while men display symptoms in lack of motivation as well as anhedonia. These clinical findings suggest that different gender could have distinct neuropathology in the brain to drive diverse symptoms and behaviors. Understanding the multiplicity of ways in which sex can alter physiological and/or behavioral response is essential to pinpoint therapeutic treatment in specific sex. The gene, dystrobrevin-binding protein 1 (DTNBP1), also known as dysbindin-1, has been associated with increased risk for schizophrenia. Dysbindin-1 mRNA and protein expression are decreased in the brains of subjects with this disorder. Male mice lacking dysbinidn-1 (Dys-/-) also display schizophrenic-like behavioral phenotypes and cognitive impairment. However, it remains unknown whether female Dys-/- mice also have similar functional as well as behavioral defects as observed in male mice. My preliminary results indicated that male and female Dys-/- shared common and distinct cellular signaling in the amygdala and hippocampus, the brain regions that is critical for emotional processing and learning and memory, which are disrupted in patients with schizophrenia. Specifically, in the amygdala and hippocampus, downregulation of CaMKII activity was observed in male Dys-/- mice, but not observed in female Dys-/- mice. While upregulation of AKT signaling was found in amygdala and hippocampus of female Dys-/- mice, but not observed in male Dys-/- mice. Lastly, both male and female Dys-/- mice showed a decrease of activity-regulated cytoskeleton-associated protein (Arc) in these brain regions. These results suggest that mutation of dysbindin-1 could results in different pathology in a sex-dependent manner. Thus, in this study, we aim to investigate the neuropathology in female Dys-/- mice. We will utilize biochemical as well as behavioral analysis, and brain region-specific deletion of dysbindin-1 to decipher the underlying mechanisms. In aim I, we will explore the cellular signaling pathways such as AKT-mTOR signaling that mediates autophagy in the amygdala and hippocampus of Dys-/- mice and their wild type (WT) littermates. In aim II, we will investigate fear conditioned behavior which is associated with dysregulation of autophagy in female Dys-/- mice as well as Dysflfl mice with specific deletion of dysbindin-1 in the amygdala. Finally, we seek to determine exogenous expression of dysbindin-1 in the amygdala of female Dys-/- mice will rescue the impairment of fear conditioned behavior. |
