內側前額葉皮質投射至藍斑核之突觸傳遞特性

Abstract

在2005年，Aston-Jones與Cohen，以及Bouret與Sara，提出假說認為在獎勵導向目標(reward-oriented targets)或顯著刺激(salient stimuli)出現時，藍斑核(locus coeruleus, LC)會產生短暫高頻率活性(phasic activity)並調節下游迴路的刺激增益(gain)或重整(reset)下游迴路以最佳化行為結果。根據他們的假設，負責高等認知功能的皮質區域(cortical region)，尤其是內側前額葉(medial prefrontal cortex, mPFC)，會負責辨認行為效益並直接影響LC活性以達成此目的。然而過往研究所提出mPFC投射至LC的突觸傳遞(synaptic transmission)的生理證據在許多方面都不一致。其中一個衝突是兩篇研究提出mPFC會透過釋放γ-氨基丁酸的局部前LC細胞(LC-GABA)來對釋放正腎上腺素(Norepinephrine, NE)的LC細胞(LC-NA)達到前饋抑制(feedforward inhibition)，而兩篇研究提出mPFC對LC-NA細胞只有興奮性(excitatory)效果。另一個衝突是兩篇研究認為mPFC活化對LC-NA細胞的整體效果是興奮性的，而兩篇則認為是抑制性的。為了調和這些不一致，我們透過結合對離體LC細胞的全細胞紀錄(ex vivo whole cell recording)與mPFC纖維的光遺傳學活化(optogenetic stimulation)來對此神經連結提供更全面的數據。我們發現63%被記錄到的LC-NA神經元會透過AMPA和NMDA受體的活化來對mPFC的光遺傳學活化做出反應。印防己毒素(picrotoxin)與馬錢子鹼(strychnine)的使用並沒有顯著影響突觸活性，顯示LC-GABA神經元沒有被招募。然而，我們發現39%被記錄的LC-GABA神經元也會透過AMPA受體的活化來對mPFC的光遺傳學活化做出反應。在電流鉗紀錄(current-clamp recording)中，模仿生理條件下 mPFC 神經元放電的輸入光刺激(2 Hz 下的 600 個偽隨機脈衝(pseudo-random pulses))顯著增加了LC-NA細胞放電間隔的變異度，但沒有增加平均頻率。因此我們在此報告，在生理條件下，mPFC 的活化可以透過增加突觸雜訊來顯著改變 LC 神經元的輸出模式，而不影響輸出強度。這種活化必須與其他 LC 輸入整合，以引發如活體實驗所示的前饋抑制，並誘導行為任務中所示的 LC phasic activity。

In 2005, Aston-Jones and Cohen, along with Bouret and Sara, suggested that in response to reward-oriented targets or salient stimuli, the locus coeruleus (LC) shows phasic activity and modulates the gain or resets the downstream cortical networks to optimize behavioral outcomes. Accordingly, cortical regions of high cognitive function, specifically the medial prefrontal cortex (mPFC), are thought to identify task utility and directly influence LC output for this purpose. However, physiological evidence for the properties of the synaptic transmission of mPFC inputs to LC provided by previous studies is inconsistent in several aspects. One of the conflicts presented is that 2 studies reported feed-forward inhibition of mPFC activation to norepinephrine-releasing LC (LC-NA) neurons that may be mediated by GABA-releasing LC (LC-GABA) neurons located in peri-LC regions, while 2 studies reported that mPFC only causes excitatory effect to LC-NA neurons. The other conflict is that the overall effect of mPFC activation is activating LC-NA neurons in 2 groups and inhibiting LC-NA neurons in 2 other groups. To reconcile these inconsistencies, we provide further comprehensive data on this connection by combining whole-cell recording in LC neurons with optogenetic activation of mPFC fibers ex vivo. We found that 63% of recorded LC-NA neurons responded to optogenetic activation of the mPFC with activation of both AMPA and NMDA receptors. Applying picrotoxin and strychnine did not significantly affect synaptic activity, suggesting that local inhibitory pre-LC neurons were not recruited. However, we discovered that 39% of recorded LC-GABA neurons responded to optogenetic activation of the mPFC with activation of AMPA receptors. In current-clamp recordings, photostimulation of mPFC inputs that mimicked mPFC neuron firing under physiological conditions (600 pseudo-random pulses at 2 Hz) significantly increased the variance of the inter-spike interval but not the mean frequency of LC firing. Accordingly, we report here that under physiological conditions, activation of the mPFC can significantly alter the output pattern, without affecting the output strength, of LC neurons by increasing synaptic noise. Such activation has to be integrated with other LC inputs to elicit feed-forward inhibition as shown in vivo, and induce LC phasic activity as shown in behavioral tasks.