記憶相關的蛋白質及表觀基因印記

高國勝

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高國勝 , Ph.D　　Advisor：游一龍　　

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Abstract │ Reference (63) │ Altmetrics

Abstract 〈TOP〉

長期記憶的形成，需合成所體驗對應相關的蛋白質。利用二維凝膠電泳與液相層析質譜學的分析方法，鑑別提取利用古柯鹼建立的小鼠制約場地偏好(CPP)時，表現在伏隔核(nucleus accumbens, NAc)的相關記憶候選蛋白質群。其中，經由西方墨點分析以及活體內質體轉殖蛋白表現系統證實，14-3-3ζ蛋白表現會影響提取古柯鹼建立的制約場地偏好記憶。在蛋白質體學分析所得到的記憶候選蛋白質中，針對記憶提取為負調控的14-3-3ζ蛋白，分析它在古柯鹼制約場地偏好記憶的功能。結果顯示，在小鼠伏隔核區表現14-3-3ζ蛋白(14-3-3蛋白亞型之一)時，制約線索調節的古柯鹼相關記憶會受到不可逆的削減。然而，這種在伏隔核表現14-3-3ζ蛋白質方式所得到的結果，並不影響小鼠的活動能力或改變局部多巴胺(dopamine)的新陳代謝。相反的，在小鼠伏隔核區表現14-3-3ε蛋白(另一種14-3-3蛋白亞型)時，制約線索調節的古柯鹼相關記憶提取並不會受到影響。意味著，伏隔核內的14-3-3ε蛋白質無論在儲存古柯鹼誘發的制約場地偏好記憶，或提取相對應的記憶，都比較次要。綜合以上的實驗結果，過多的14-3-3ζ蛋白表現在伏隔核會降低提取制約線索所主導的古柯鹼相關記憶。此外，在生命早期所遭受的壓力經驗，會透過表觀基因體機制影響爾後的學習和記憶。以恐懼增益的驚嚇方式模擬受創傷的過程，藉由所記取的恐懼程度，評估幼年時遭受壓力事件的母鼠，於成年後再次遭遇創傷，其反應程度會有何種改變。結果發現，在出生後連續八天 (D2-9PP)，每天經歷一小時隔離程序的母鼠，會降低成年後的恐懼增益驚跳反應；但仍保有正常的聽覺驚嚇反應。檢測後評估實驗中所建立的隔離方式並不影響Corticosterone (CORT) 的基準值及面臨壓力時的分泌量，卻會造成血液中Estradiol(E2) 濃度的增加；經由表觀基因體印記分析，此隔離方式並未改變母鼠前額葉皮質組織內組蛋白3離胺酸9 位置 (Histone 3 lysine 9, H3K9)的乙醯化(acetylation)，取而代之的是降低該位置的單-及三-甲基化程度(mono- and tri-methylation)。在隔離過程中給予幼鼠二種不同劑量的5-aza-2’-deoxycytidine (AZA)治療，無影響隔離造成的成年恐懼增益驚跳反應程度降低。但分別給予幼鼠高、中及低劑量的 valproic acid (VPA)，卻可回復因隔離造成的成年恐懼增益驚跳反應降低的現象。在不影響幼鼠體重的VPA劑量治療下，成年後的母鼠，並不會改變因幼時隔離所增加的血清Estradiol分泌量，但可回復因隔離所降低的前額葉皮質組織內H3K9位置的單-及三-甲基化程度。然而，當幼時經歷隔離的母鼠，成熟後(D28PP)再接受連續八天的VPA或AZA的治療；對隔離所降低的恐懼增益驚跳反應、血液中增加的Estradiol濃度、以及前額葉皮質組織內組蛋白3離胺酸9 位置的單-及三-甲基化成度的降低，並沒有實質的效果。所以，前額葉皮質組織內組蛋白3離胺酸9 位置的單-及三-甲基化程度降低，可能與幼時隔離所造成的恐懼記憶形成減退有關。早期立即給予VPA 的治療，對於幼時受壓力抑制的線索恐懼制約會比後期有效果。

Parallel Abstract 〈TOP〉

The formation of long term memories requires de novo protein synthesis shortly after the relevant experience.  Two-dimensional gel electrophoresis was used to identify accumbal candidate proteins involved in the retrieval of a cue-mediated memory. Among the identified candidate proteins, a downregulated 14-3-3ζ protein was chosen and confirmed by Western immunoblotting. A polymer-mediated plasmid DNA delivery system was then used to overexpress 14-3-3ζ protein in the mouse nucleus accumbens before the CPP retrieval tests. Overexpression of accumbal 14-3-3ζ protein was found to diminish conditioned cue/context-mediated cocaine-induced CPP. Overexpression of accumbal 14-3-3ζ protein did not produce motor activity-impairing effect or alter local dopamine metabolism. Moreover, overexpression of accumbal 14-3-3ζ protein did not affect food-induced CPP. These results indicated that overexpressed accumbal 14-3-3ζ protein specifically decreased conditioned cue/context-mediated cocaine memory. In addition, epigenetic processes influence stress effects of early-life experience on learning and memory. In this study, a fear-potentiated startle was used to model the acquisition of traumatic event-related memory in female rats experiencing early life stress. We found that a 1 hr/day maternal and sibling separation throughout day 2-9 postpartum (D2-9PP) caused a decrease in the fear-potentiated startle, but not acoustic startle baseline, in female adult rats. The separation procedure did not affect baseline and acute stress-stimulated corticosterone (CORT) secretion but produced an increase in serum estradiol concentration. Moreover, the separation procedure did not affect histone 3 lysine 9 (H3K9) acetylation but decreased H3K9 mono- and tri-methylation in frontal cortices. Treatment with 5-aza-2’-deoxycytidine (AZA), an H3K9 acetylation enhancer, at 2 variant dosing regimens did not affect the separation-decreased fear-potentiated startle. Treatment with valproic acid (VPA), a histone deacetylase inhibitor, at 3 dosing regimens prior to daily separation reversed such a decrease in fear-potentiated startle. An effective VPA dosing regimen did not affect early life separation-produced increase in serum E2 secretion but reversed separation-decreased H3K9 mono- and tri-methylation in frontal cortices. Eight consecutive days of VPA and AZA treatments starting at D28PP were ineffective in altering the separation-decreased fear-potentiated startle, -increased E2 concentration, or -decreased frontal cortical mono-, tri-methylation. We suggest that decreased H3K9 mono- and tri-methylation in frontal cortex may be involved in early life separation-decreased fear memory formation. Early, but not late, VPA treatment is effective in treating early life stress-produced decrease in cued fear conditioning.

Reference ( 63 ) 〈TOP〉

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連結：
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連結：
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連結：
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連結：
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連結：

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