頭部外傷(traumatic brain injury, TBI) 為全世界青壯年人口中，發生率(morbidity)及死亡率(mortality)雙高的意外傷害，患者在創傷後常併發癱瘓(paralysis)、癲癇(epilepsy)、重度憂鬱(major depression)以及焦慮症(anxiety disorder)等一系列後遺症(sequelae)，使得患者在其最具生產力的人生階段，必須接受長期的醫療照護及藥物治療。
頭部外傷的病理變化可簡分為初始傷害(primary injury)及繼發性傷害(secondary injury)兩大類。初始傷害發生在受傷當時，而繼發性傷害如:血腫(hematoma)、腦缺血(ischemia)、腦缺氧(hypoxia)及腦水腫(brain edema)，前人研究多專注於成年期的頭部外傷，缺乏青少年期的研究。本研究將利用動物模式，探討青少年期頭部外傷處理後(juvenile TBI treatment, TBI-J)導致成年期情感異常之病理變化及神經機轉。
主要採用的行為實驗方法包括強迫游泳實驗(forced swimming test, FST)、糖水偏好實驗(sucrose preference test, SPT)，FST和SPT為測量類憂鬱行為(depression-like behavior)；測量類焦慮行為(anxiety -like behavior)的方法，則包括高架十字迷宮(elevated plus maze, EPM)和恐懼所促進的驚跳反應(fear-potentiated startle, FPS)；而開放空間實驗(open field test, OFT)和平衡桿(rotarod)則用以測量自發性運動(locomotor activity)及運動能力。部分動物被犧牲取腦，並以即時聚合酶連鎖反應分析(real-time PCR, qPCR)或西方墨點法(western blot, WB)分析杏仁核(amygdala)、中央前額葉皮質(medial prefrontal cortex, mPFC)及伏隔核(nucleus accumbens, NAcc)中特定基因之表現，以作為分析憂鬱症的分子生物學依據。同時將會有另一平行組別(parallel group)，用於離體胞外電生理(in vitro extracellular recording)實驗，觀察TBI-J大鼠海馬迴(hippocampus)及杏仁核中，經高頻率電刺激(high-frequency stimulation, HFS)誘發之長期增益效應(long-term potentiation, LTP)之變化。
實驗結果顯示，於青少年期(六週齡)曾接受頭部外傷處理的大鼠(TBI-J rats)，於成年後(十週齡)類憂鬱行為明顯增加，在FST實驗中，其不掙扎時間(immobility)明顯較少；在SPT實驗中，糖水之攝取量(sucrose intake) 明顯較低，但其自發性運動和運動功能並沒有明顯改變。此外，在FPS結果顯示，TBI-J組的基礎驚跳反應(basal startle)明顯增加，但促進的驚跳反應百分比(percent potentiated startle)則無顯著變化，合併EPM的數據，推估TBI-J組的類焦慮行為無明顯改變。在手術恢復期投予新興抗藥物7,8-DHF，對TBI-J組成年期類憂鬱行為亦無改善。西方墨點法分析杏仁核表現之磷酸化p42-ERK以及TrKA 明顯下降，而BDNF 則在兩組之中表現無差異。以即時聚合酶連鎖反應分析中央前額葉皮質BDNF的RNA表現量明顯下降，伏隔核中的CRH及Slc6a4有明顯上升的趨勢。最後，電生理結果顯示，杏仁核中HFS-LTP明顯增強，而海馬迴中HFS-LTP無顯著變化。此結果與先前觀察到的基礎驚跳值增加相互契合，顯示TBI-J的處理會影響到杏仁核的功能。
本研究之結果顯示青少年期頭部外傷，會增加成年期的類憂鬱行為，而對類焦慮行為則無明顯影響，電生理的實驗結果也與行為實驗結果相符合。但是意外地在機轉上，卻與大多數研究者認定的BDNF表現量減少，引發類憂鬱行為的機制不甚相同，且7,8-DHF的投藥也無法改善TBI-J組的類憂鬱行為，此結果暗示成年期與青少年期頭部外傷引發行為異常之神經機轉可能不盡相同，故在採用相關治療藥物時需做進一步的思考。總結本研究之結果，對於青少年期頭部外傷引發行為異常之機轉進行初步的探討，希望能對相關藥物治療的開發提供所需的方向及基礎。

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity among global youth and commonly results in paralysis, epilepsy, and/or a host of mental disorders. In such cases, long-term hospitalization and medication become necessities for those who should otherwise be living active, productive lives. TBI can also lead to secondary injury such as hematoma, ischemia, hypoxia, cerebral edema, or other conditions that resemble mental illnesses like anxiety and depression. While previous studies mainly focus on TBI as it occurs in adults, this thesis explores the long-term effects of TBI in adolescents.
In the present study, I employ a juvenile traumatic brain injury animal model (TBI-J) that involves subjecting juvenile rats to head injury that mimics TBI. Once reaching adulthood, rats underwent behavioral, biochemical, and electrophysiological experimentation. The forced swimming test (FST) and sucrose preference test (SPT) were used to measure depression-like behavior, while anxiety-like behavior was measured using the elevated plus maze (EPM) and fear-potentiated startle (FPS) tests. An open field test (OFT) and rotarod test were additionally used to evaluate the non-specific effects of juvenile TBI. Adult rat hippocampus, amygdala, medial prefrontal cortex (mPFC), and nucleus accumbens (NAcc) were later dissected for Western blot (WB) and real-time PCR (qPCR) analysis to screen for expression of genes associated with depression. Finally, hippocampus and amygdala brain slices were tested using in vitro extracellular recording to reveal long-term potentiation (LTP) induced by high frequency stimulation (HFS).
Results revealed an increase in depression-like behavior among adult TBI-J rats. FST revealed a decrease in mobility, SPT revealed a decrease in sucrose consumption, and no differences were seen between TBI and control groups for total distance traveled during either the locomotion or rotarod test. Basal startle response, but not percent potentiated startle, was found to be elevated in TBI-J rats, which is consistent with EPM data. We therefore concluded no significant difference in anxiety-like behavior between TBI-J and sham control rats. Furthermore, we found no significant therapeutic benefit with 7,8-DHF, a novel antidepressant, for TBI-J rats exhibiting depression-like behavior. Extracellular recording revealed elevated HFS-LTP in the amygdala but not the hippocampus, which supports our hypothesis that juvenile TBI induces elevated basal startle response in adults. Amygdaloid p42-ERK phosphorylation and TrKA were significantly reduced, but BDNF activity did not vary greatly between groups. Finally, RT-PCR revealed a low brain-derived neurotrophic factor (BDNF) expression in the mPFC and high CRH and Slc6a4 expression in the NAcc.
Overall, we found that juvenile TBI rats exhibited long-term depression–like but not anxiety-like behavior. Administration of 7,8-DHF, a TrkB agonist, does not appear to lessen depression-like symptoms in adulthood.. It is widely accepted that BDNF plays an essential role on the pathogenesis of major depression, and BDNF receptor quantity/activation state are also central to depression pathology. In summary, these results suggest a difference in the mechanism of TBI-induced behavioral abnormalities among adult and juvenile animals. Further research is required to elucidate specific disease mechanisms as well as to devise new therapies for depression resulting from juvenile TBI.

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