活化海馬迴-內嗅皮質路徑內第一型大麻受體延長時間估計而非衝動性

Abstract

解密腦部各區域之間的溝通對於理解大腦如何處理如情緒、溝通、學習和記憶神經功能極為重要，腦部各區的神經振盪被認為與這些認知功能的執行有關。當執行不同行為試驗時，海馬迴及內嗅皮質迴路中的theta及gamma波會展現顯著的活性，這些腦波之間同步化的精確性被視為神經元興奮後節律變化的結果，並可能為解剖迴路進行有效溝通的機制，其中一種不同頻率腦波同步化的現象為theta相位與gamma振幅的Cross-frequency coupling (CFC)，也就是gamma波的振幅大小會受theta波調控而較常承載在theta波特定的相位上，此種theta與gamma波之間的藕連現象在學習後會增強並與維持工作記憶相關，然而目前仍不清楚海馬迴和內嗅皮質中神經振盪對於行為表現的詳細作用。 區別性增強低頻率行為（DRL）可用於評估在操作如衝動抑制、時間感知和工作記憶行為時腦波的特性。我們假設操作DRL試驗時，由於需要維持工作記憶，因此海馬迴CA1區域及內嗅皮質腦波的溝通性是重要的。結果數據顯示按壓槓桿前一秒鐘CA1中theta波的強度可預測內在時間感；另外在衝動事件中，海馬迴CA1 theta對於調節內嗅皮質gamma振幅的能力較低。我們推測由於老鼠沒有仔細思考，使得海馬迴及內嗅皮質的溝通無效而導致了衝動，而此可能促使工作記憶的障礙，最後造成DRL行為試驗不佳的結果。 此外由於內生性大麻系統大量存在於大鼠的海馬迴-內嗅皮質迴路，也有多篇文獻指出時間感的改變可能使海馬迴內生性大麻系統無法累積時間相關的工作記憶。因此為了進一步瞭解此迴路之間CFC與時間感的關係，我們假設海馬迴和內嗅皮質彼此間的溝通對於傳遞時間相關的工作記憶是重要的。我們使用DRL十秒試驗來評估在大麻致效劑arachidonylcyclopropylamide (ACPA)作用下反應時距(inter-response-time, IRT)的分布，由於此行為試驗需要老鼠表現最佳的時間感知能力。我們的結果顯示活化內嗅皮質內突觸前CB1受體後，CA1 theta波相位調節內嗅皮質高頻率gamma振幅的能力下降，此現象可能是由於CA1迴路中的中間神經元受到干擾，而此種只出現於特定的反應時距的無效溝通可能因為損害時間相關的工作記憶，最終延長了時間感估計，也就是老鼠腦內認為的一秒比實際的一秒來得長(time overproduction)。 在我們的實驗之中，我們的結果顯示許多認知行為障礙皆與海馬迴及內嗅皮質迴路中的CFC受到干擾有關，如CFC的下降會導致衝動，此外在大麻藥物作用影響CB1受體後，神經的藕連現象受到改變也促使時間感低估。最後，我們的數據可能有助於破解DRL試驗時大腦的功能，並有助於理解海馬迴與內嗅皮質迴路如何對時間記憶和衝動產生影響。

Unveiling how each brain regions communicate is crucial for understanding how the brain processes emotion, timing, learning and memory. Neural oscillation within and across brain regions have been proposed to correlate to these cognitive processes. While performing distinct behavioral tasks, the entorhinal and hippocampal circuitries display prominent theta and gamma activities. Their precision of synchronization is served as a mechanism for the rhythmical changes in neuronal excitability and provides effective functional communication. One of the synchronized phenomenon known as theta phase to gamma amplitude cross-frequency coupling (CFC) is depicted gamma amplitudes often entrain in specific phases of the theta frequency. The theta-gamma oscillatory coupling is thought to be strengthened during learning and maintain in working memory. However, it is still unclear what the function role of neural oscillation in hippocampus and medial entorhinal cortex (MEC) in the behavioral performance. Differential-reinforcement-of-low-rate (DRL) schedules are used to evaluate the brain wave properties in modulating behavioral functions such as impulse inhibition, temporal perception and working memory processes. We hypothesized that communication between the hippocampal CA1 region and the MEC is critical for executing the DRL procedure because working memory refers to the instant system that holds and manipulates operational information over short periods of time. Our data show theta power in the CA1 one seconds prior to lever pressing may predict internal times. Also, the CFC in CA1 theta phases to MEC fast gamma amplitudes was low during impulsive behavior. Thus, these results suggest that subjects may not think carefully and the poor communication between the CA1 and MEC results in impulsivity. We speculate the working memory impairment in the hippocampal formation accounts for the poor performance on the DRL. In addition, because the endogenous cannabinoid system is predominant in the rat CA1-MEC network, several previous research has also suggested that the alternation in timing perception is through the failure of accumulation temporal information of possessing working memory in the hippocampal endocannabinoid system. To further understand the role of CFC in timing behavior, we hypothesized that the communication between the CA1 and MEC is essential for the transmission of temporal associated working memory. We use the DRL-10 tasks to examine the inter-response-time (IRT) distributions under the effects of cannabinoids, arachidonylcyclopropylamide (ACPA), because the task requires subjects performing at the optimal timing. Our results depict after activation CB1 receptors from MEC presynapses, the CFC in CA1 theta phases to MEC fast gamma amplitudes declines and is possibly influenced by interfering with the interneurons in CA1 circuitries. Then, this inefficient communication leads to impairment in temporal working memory during critical IRT and eventually led to the time overproduction, in which subjects generate longer time intervals than predetermined. In our study, we have found several cognitive impairments are associated with disturbances in CFC in the hippocampal entorhinal pathway in our results. A decrease in cross-frequency coupling leads to impulsivity. Additionally, under the effects of cannabinoids on CB1 receptors, the alternation in these oscillation activities result in time underestimation. To sum up, our data may help decipher the brain functions during DRL and benefit in understanding how the hippocampal entorhinal circuitries work on the temporal memory and impulsivity. overproduction, in which subjects generate longer time intervals than predetermined. In our study, we have found several cognitive impairments are associated with disturbances in CFC in the hippocampal entorhinal pathway in our results. A decrease in cross-frequency coupling leads to impulsivity. Additionally, under the effects of cannabinoids on CB1 receptors, the alternation in these oscillation activities result in time underestimation. To sum up, our data may help decipher the brain functions during DRL and benefit in understanding how the hippocampal entorhinal circuitries work on the temporal memory and impulsivity.