腦創傷 (traumatic brain injury, TBI) 為全球創傷導致死亡和殘疾的主要原因，研究顯示全世界每年約有5000至6000萬人受到腦創傷的影響，據統計其中輕度腦創傷 (mild traumatic brain injury, mTBI ) 約佔75至90%，且因診斷差異以及只有少部分的傷患會去醫院接受醫療，所以普遍認為其數目被低估，然而mTBI的研究文獻數量，約只佔TBI全數研究的八分之一。並且mTBI患者在創傷後常併發注意力缺失 (attention deficit)、記憶受損 (memory impairment)與情緒障礙 (emotional disorders)，如：憂鬱症(depression disorder) 、焦慮症 (anxiety disorder)，與嚴重腦創傷相比，輕度腦創傷反而更容易引起焦慮症與憂鬱症，並且有報導指出在創傷恢復的五至十年後，還是可以觀察到認知(cognitive)以及情緒上(emotional)的影響。
人類腦部灰質發育於七歲達到高峰，並透過生活經驗進行突觸修飾(synaptic modification)直至青少年期 (juvenile stage)，然而部分腦區如：前額葉皮質(prefrontal cortex)、海馬體(hippocampus)和杏仁核(amygdala) 的突觸修飾甚至可持續至成年，而這些腦區均與憂鬱症和焦慮症有高度相關，足見青少年期的不良經驗，為成年期是否產生情緒障礙的關鍵因素。本研究利用動物模式，探討青少年期輕度腦創傷處理後 (juvenile mild TBI treatment, mTBI-J) 導致成年期情感異常之病理變化及神經機轉。
研究中探討輕度腦創傷所產生的精神異常現象，主要針對憂鬱症以及焦慮症進行研究設計，探討腦創傷程度、行為變化、分子機轉之影響。研究由四個面向進行分析，實驗結果顯示，(一) 青少年期大鼠 (六週齡) 接受於mTBI-J 後24小時，使用氯化四唑染色 (triphenyl tetrazolium chloride stain, TTC stain) 與蘇木素-伊紅染色 (hematoxylin and eosin stain, HE stain) 觀察腦創傷程度，和控制組相比，mTBI-J組未發現明顯腦損傷，但有輕微腦水腫 (brain edema)。(二) 青少年期接受 mTBI-J 處理的大鼠，於成年後 (九週齡) 自發性運動行為偵測 (locomotor activity test, LAT) 之結果顯示自發性運動和運動功能相對於控制組並沒有明顯改變；類憂鬱行為明顯增加，糖水之攝取量 (amount of sucrose intake) 明顯較低，且不掙扎時間百分比 (percent time of immobility) 明顯變少；類焦慮行為相對於控制組沒有明顯變化，在恐懼所促進的驚跳反應(fear-potentiated startle, FPS) 結果顯示，mTBI-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，合併開放空間實驗 (open field test, OFT) 觀察進出中央次數與高架十字迷宮(elevated plus maze, EPM) 觀察開放臂與封閉臂的停留時間，推估mTBI-J組的類焦慮行為無明顯改變，但在聲音誘發的驚跳反應 (acoustic startle response, ASR)顯著增加，代表 mTBI-J 的處理會增加基礎驚跳值。(三) qPCR 結果顯示，背側海馬迴 (dorsal hippocampus, dHip) 與、腹側海馬迴 (ventral hippocampus, vHip) 中腦源性神經生長因子 (brain-derived neurotrophic factor , BDNF) 表現量下降，但其受體 (tropomyosin receptor kinase B, TrkB) 的表現量卻沒有明顯變化。西方墨點結果顯示，vHip的TrkB表現量下降，此結果與先前觀察到的mTBI-J組類憂鬱行為增加相互契合，然dHip的TrkB 和BDNF表現量並無顯著差異，顯示 mTBI-J 的處理影響到腹側海馬迴的功能。此外杏仁核處磷酸化ERK2 (phosphorylated-extracellular signal-regulated kinase 2, P-ERK2) 之表現明顯下降，電生理結果顯示，杏仁核中高頻刺激誘導長期增強作用(high frequency stimulation induced long-term potentiation, 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，與ERK2的磷酸化改變，進而影響到杏仁核的神經神經傳遞功能之假設相互契合。 (四) 進行機轉驗證：透過投與TrkB之促進劑7,8-二羥基黃酮 (7,8-DHF)，發現可以改善mTBI-J組的類憂鬱行為。
本研究之結果顯示mTBI-J處理雖然沒有造成明顯運動功能與組織學損傷，卻會增加成年期的類憂鬱與基礎驚跳值上升，在mTBI-J所引起的類憂鬱行為中，腹側海馬迴的 BDNF 表現量在其中扮演關鍵腳色。而mTBI-J所引起的基礎驚跳值上升則影響到杏仁核的突觸傳遞，可嘗試使用降低神經興奮性藥物進行改善，可以提供相關治療藥物的開發提供所需的方向及基礎。

Traumatic brain injury (TBI) is a significant cause of death and disability worldwide; population-based studies showed that 50–60 million people worldwide (including at least 3.5 million in the United States and 2.5 million in Europe) are affected by a new TBI each year. The great majority of cases (75–90%) are mild TBI (mTBI). Estimates of mTBI incidence often involve diagnostic and selection biases. It is widely acknowledged that incidence is underestimated because only a minor proportion of cases are admitted to hospitals. However, the number of studies in mTBI was only about one-eighth relative to the reported in TBI. mTBI patients are often complicated by attention deficit, memory impairment, and emotional disorders (depression and anxiety), interestingly mTBI is more likely to cause anxiety and depression than severe TBI, and cognitive and emotional effects have been reported five to ten years after mTBI recovery.
The brain was increased in grey matter that peaks at around seven years of age in humans. The experience-dependent synaptic pruning occurs mainly during childhood and juvenile but can extend into adulthood in the prefrontal cortex, hippocampus, and amygdala. Therefore, the juvenile experience was a critical and sensitive stage for developing emotional disorders in adulthood. This study was used animal models to study the pathological changes and emotional abnormalities in adulthood after juvenile mild TBI treatment (mTBI-J). This study was aimed to investigate the long-term adverse effect of mTBI-J treatment on behavior and its neural mechanism using animal models.
The study was analyzed from four perspectives. The experimental results showed that (1) mTBI-J treated rats in 24 hours after the 2,3,5,-triphenyltetrazolium chloride monohydrate stain (TTC stain) and hematoxylin and eosin stain (HE stain) were used to observe the degree of brain injury. Compared with the control group, no apparent neural damage was found in the mTBI-J group, but slight brain edema occurred in mTBI-J treated animals. (2) The results of locomotor activity test (LAT) in adult stage rats (nine-week-old) with mTBI-J treated showed the spontaneous motor activity and motor function was not significantly different compared with the control group; The depression-like behavior was significantly increased compared with the control group, the amount of sucrose intake and the percentage time of immobility were significantly reduced; In the fear-potentiated startle (FPS) test, that results revealed an increase in the basal startle response, but not percent potentiated startle, and the extinction of conditioned fear remains intact in the mTBI-J treated rats. In addition, there was no significant change in the mTBI-J group in the elevated plus maze (EPM) and the open field test (OFT) compared with the control group. Results were suggested that was not exhibited in anxiety-like behavior in the mTBI-J group, but there was a significant increase in acoustic startle response (ASR), indicating that mTBI-J processing increased basal startle response. (3) The qPCR results showed that the expression of brain-derived neurotrophic factor (BDNF) decreased in the dorsal hippocampus (dHip) and ventral hippocampus (vHip). However, the expression of the BDNF receptor (tropomyosin receptor kinase B, TrkB) did not change significantly compared with the control group. The western blotting results showed a decrease in the expression of BDNF in vHip, which is consistent with the previously observed increase in depression-like behavior in the mTBI-J group. In addition, the expression of phosphorylated-extracellular signal-regulated kinase 2, P-ERK2 in the amygdala was significantly decreased. Brain slice extracellular recording results showed that HFS-LTP in the amygdala was significantly enhanced, and there was no significant change in HFS-LTP in the hippocampus. . This result is consistent with previous observations that increased basal startle value and altered phosphorylated P-ERK2 affect neuroplasticity in the amygdala. (4) Verifying the mechanism through the BDNF analog, that mTBI-J treatment-induced depression-like behavior was lessened after the TrkB agonist (7,8-dihydroxyflavone hydrate, 7,8-DHF) administration.
In summary, we successfully established the mTBI-J animal model to induce behavioral and neural abnormalities in adult and juvenile rats. These results indicate that even a mild juvenile TBI treatment that did not produce motor deficits or significant histological damage could have a long-term adverse effect that could be sustained to adulthood, which increases the depression-like behavior and enhances the basal and contextual startle responses in the adult age. The BDNF-TrkB pathway in the ventral hippocampus plays a critical role in mTBI-J induced depression-like behavior. The anxiety-like behavior induced by mTBI-J treated that showed an increase in HFS-LTP in the amygdaloid suggested that it could be improved with drugs that reduce nerve excitatory. This study could provide new insight for the mTBI-J induce mental illness treatments.

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