2010-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/681430摘要：研究中發現基因遺傳在精神分裂症上扮演重要角色，但從同卵雙生子的研究中也發現雙生子的共病率從未超過百分之五十，這些證據顯示表觀遺傳扮演一定的調控角色。從精神分裂症通常好發於青春期可以推測青春期階段的心理與社會壓力可能促成精神分裂症之症狀的出現，特別好發於有基因缺損的群體中。為了進一步測試這個假說，在這個子計畫中使用了DISC1與NRG1基因缺損小鼠為模式，去探討壓力與賀爾蒙對於小鼠在與精神分裂症症狀相關之行為測驗中的行為表現，包括了前脈衝抑制、痕跡恐懼制約與社會記憶等作業。這幾項作業可以作為測試精神分裂症的三個重要症狀，即注意力、認知能力以及社會能力不良的模式。在心理壓力的部分，將給予電擊與中性聲音或環境連結的制約學習後並用該中性刺激的重複呈現作為心理壓力源；在賀爾蒙調控的部分，將利用手術閹割及睪固酮注射的方式來調控小鼠體內雄性激素含量，將利用這些壓力與賀爾蒙的操弄去研究是否會在基因缺損小鼠中有促發或舒緩精神分裂症相關症狀的效果。在這個子計畫中將利用DISC1與NRG1基因缺損小鼠為模式去探討四個主要的目標：(1)評量心理與社會壓力對於精神分裂症成因的影響；(2)評估賀爾蒙睪丸酮對於精神分裂症的促發所 扮演的角色；(3)研究壓力及賀爾蒙兩種因素對於神經生理活動影響；(4)用電生理的方法去研究壓力及賀爾蒙對於神經突觸活動的影響。 <br> Abstract: While evidence indicates a genetic basis for schizophrenia, the concordance rate in homozygotic twins inflicting schizophrenia never reaches 50%, suggesting epigenetic involvement in this disease. In view of appearance of major schizophrenic symptoms after the juvenile stage, it is conjectured that psychological or social stress encountered at the puberty may be a factor of precipitating the symptoms in a genetic prone population. To test this hypothesis, matured DISC1 or NRG1 mutant mice and the wild-type controls will be subjected to stress or hormonal manipulations and then tested on pre-pulse inhibition, trace fear conditioning and social memory tests, which are used to model the attention, cognitive and social or emotional impairments in schizophrenic patients. Psychological stress will be induced by pairing an otherwise neutral stimulus with a foot shock, while social stress will be induced by group housing of the subjects. It is expected that psychological or social stress will either precipitate or aggravate behavioral deficits in the mutant mice which are sexually matured. Further, sex hormones may play an enabling role in these deficits, thus gonadectomy before stress should be able to attenuate the effects of stress on the various behavioral indices. Findings from this project should contribute to our understanding of how external factors in the environment or internal milieu in the body interact with genetic endowment to induce symptoms of schizophrenia. This subproject is expected to achieve four specific aims: (1) To assess the behavioral effects of psychological or social stress on pre-pulse inhibition, trace fear conditioning and social memory in DISC1 and NRG1 mice. (2) To evaluate the effects of gonad hormone depletion and supplement on pre-pulse inhibition, trace fear conditioning and social memory and involvement of these hormones in influences of stress in DISC1 and NRG1 mice. (3) To study the neurophysiological correlates of the stress or hormonal effects on pre-pulse inhibition, trace fear conditioning and social memory in behaving DISC1 and NRG1 mice. (4) To study the synaptic mechanisms underlying neurophysiological correlates of the stress and hormonal effects in brain slices or reduced preparation of DISC1 and NRG1 mice.精神分裂症生殖賀爾蒙心理或社會壓力DISC1基因缺損小鼠NRG1基因缺損小鼠schizophreniagonad hormonespsychological/social stressDISC1 deficient miceNRG1 deficient mice