在本實驗室過去的研究中已經知道出生後早期動物的聽覺經驗會改變其中腦聽神經元對聲音反應的敏感度。但是，對於中腦神經可塑性的發生時間，其變化的詳細情形，與此一幼年期的神經可塑性是否可以維持至更長的時間則仍不清楚。因此，此實驗分別探討：(一)瞭解早年的聽神經可塑性是否可以持續到老年；(二)在發育早期的不同時段中給予長期的聲音刺激對於下丘核聽神經的發育影響，及此聽神經元之神經可塑性起源；(三)探討此一早年的長期聲音刺激是否會改變下丘核的抑制性神經系統的發育。

　　在第一部份的實驗採用一種具有早衰特性的小白鼠，以電生理細胞外單細胞紀錄技術來探討早年的聲音刺激對於在老年時的下丘核聽神經細胞的影響。實驗結果發現下丘核聽神經細胞可塑性的改變可以持續到老年。此外，也發現早年的長期聲音刺激可能會加速聽覺系統的老化。在第二部份的實驗分別採取兩種不同的聲音刺激流程來找出大白鼠下丘核聽神經元可塑性的關鍵期。第一種刺激流程是在出生的第一到第四周分別給予為期一周的單音(4 kHz, 65 dB SPL)刺激；第二種則是分別再在出生後的第一到四周或是從第二到五周分別給予為期四周的單音刺激。在結束聲音刺激的一周內，以電生理細胞外記錄技術來探討下丘核聽神經元對聲音反應特性的變化情形。結果發現，在單周的聲音刺激中，在第二周給予聲音刺激的實驗大白鼠下的丘核中最敏感的頻率為4-5kHz的聽神經元數目均增加最多，此一群的細胞其閾值也明顯的提高。此一結果僅只在第二周給予刺激的大白鼠下丘核中發現，其他時期給予聲音刺激並未發現類似的變化。在出生後的第一周給予聲音處理的大白鼠下丘核中可記錄到對聲音反應的聽神經元增多，但是，由於能計錄的細胞數實在太少，故此部分結果無法確定第一周的聲音處理確實是否有作用。在另外之時驗中，經過四周的聲音刺激後，兩組實驗組大白鼠下丘核中最敏感的頻率為4-5kHz的聽細胞數目均明顯的增加，同時，以第一到四周聲音刺激後增加的比率較高。第二到五周聲音刺激後，下丘核聽神經元增加的比率則與只在第二周給予聲音刺激的結果相似。此外，此二組增加的聽神經元對聲音頻率選擇性也有所不同；在第一到四周接受聲音刺激組中最敏感的頻率為4-5kHz的聽細胞對頻率的選擇範圍比較窄。另一方面，從第二到五周接受聲音刺激組大白鼠則與只在第二周經聲音處理的大白鼠相似，對頻率的選擇性比較寬廣。綜合此部分的實驗結果，影響下丘核聽神經元發育的‘關鍵期’應是出生後的第一到二周。在第三部份的實驗我們則是用抑制性神經傳導物質GABA的免疫染色方式來探討在出生後第二周給予聲音刺激對於下丘核的抑制性神經細胞的影響。結果發現在出生後第二周的控制組，下丘核只有少量的神經元含有GABA。但是，若給予三十分鐘短暫的聲音刺激後含有GABA的神經元數目顯著的增加；而此一現象並未在三周大的控制組老鼠出現。在出生後第二周內給予為期一周的聲音刺激後，下丘核神經元含有GABA的數目在沒有聲音環境下有明顯增加，但是，GABAA受體卻明顯減少。此外，這些含有GABA的神經元並不同時表現細胞活性標的蛋白-Fos。在犧牲動物前若再給予三十分鐘短暫的聲音刺激，則含有GABA神經元則明顯減少，但是，GABAA受體卻明顯增加。

　　由實驗結果發現，在出生的第一與第二周中下丘核的神經可塑性仍相當高，在此一時期給予長期的聲音刺激可改變下丘核的聽神經細胞對聲音的反應特性，且此一改變是持久的。此外，在此一時間給予長期的聲音處理也會改變下丘核中含有GABA此一抑制性神經元與GABAA受體的表現。

　　Response characteristics of central auditory neurons can be altered by early acoustic experience but details are not clear. Previous studies in young rats showed that the tonotopic representation and response properties of midbrain neurons can be shaped following sound exposure during the first three weeks after birth. Aims of this following-up study are to determine (a) the longer-term effects of neonatal sound exposure; (b) details of time-dependent functional changes following sound exposure at different stages and (c) changes of GABAergic system following sound exposure at the critical period.

　　The first part of experiment is to determine if such experience-dependent changes at the inferior colliculus (IC) could last into old ages. A mutant strain of senescence accelerated mice (SAM) was for this study. At the old age of 15 months, an apparent cell clustering of best frequencies of cells towards the frequency of the exposing tone was still found at the IC after sound exposure during the first month. In addition, there was an increase of spontaneous activity and loss of high frequency sensitivity. Results suggested that the early sound exposure has a long-lasting effect on IC neurons and that the early acoustic over- stimulation also accelerates the senescence of the auditory system.

　　The second part of experiment adopted two exposure protocols (weekly: from week-1 to week-4 or monthly: week-1to -4 and week-2 to-5). Extracellular single unit recordings and activity labeling with Fos-immunohistochemistry were used to characterize functional changes at the IC and cochlear nucleus (CN) respectively. After weekly exposures, only the week-2 exposed group showed a significant over-representation of best frequencies at the exposing frequency. In addition, only the week-2 exposed rats showed more Fos-positive labels when re-exposed to a tone with frequency modulated across the exposing tone. The fact that the aforementioned results were not found at the CN suggested that the changes occurred locally at the IC. After monthly exposures, both the week-1 to -4 and week-2 to -5 rats showed over-representation at the exposing frequency. These cells showed a narrowed frequency tuning in the week-1 to -4 exposed groups. But those in either the week-2 to -5 or week-2 exposed groups showed broadened frequency tuning. Results suggested that both tuning properties and tonotopic representation of collicular neurons are sensitively altered by acoustic over-stimulation during the first two weeks, which likely represent the critical period.

　　The third part of experiment is to determine changes in the GABAergic system in the IC following the neonatal sound exposure using immunohistochemistry. In control animals, GABA-immunoreactivity increased in the IC after brief acoustic stimulation in the week-2 but not week-3 old rats. Following weekly sound exposures, more GABA-containing neurons were found in the whole IC of rats put in a silent room before sacrifice. The increased GABA-containing neurons did not express Fos protein simultaneously in their nuclei. These GABA-containing neurons disappeared after a brief acoustic stimulation. On the other hand, neonatal sound exposures down regulated the expression of GABAA receptor under a silent condition and they can be elevated by acoustic re-stimulation. Results suggested the neonatal sound exposures can shape the GABAergic inhibition in the IC.

　　Findings suggested that IC is particularly plastic during the first two weeks after birth. Rats exposed to tones during this critical period have time-dependent changes on tonotopic representations and tuning properties. Such plastic changes last into old ages. In addition, the neonatal sound exposure also had effects on altering the GABAergic system in the IC.

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