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研究生:廖婉廷
研究生(外文):WAN-TING LIAO
論文名稱: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
論文名稱(外文):Activation of type 1 cannabinoid receptor in hippocampal entorhinal circuit prolongs time estimation but not impulsivity
指導教授:蕭逸澤
指導教授(外文):Yi-Tse Hsiao
口試委員:張芳嘉賴文崧姚皓傑
口試委員(外文):Fang-Chia ChangWen-Sung LaiHau-Jie Yau
口試日期:2019-07-12
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:獸醫學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:英文
論文頁數:110
中文關鍵詞:大麻素時間知覺工作記憶衝動行為操作制約行為海馬迴內嗅皮質Theta波Gamma波
DOI:10.6342/NTU201901051
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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.
中文摘要 i
Abstract iii
General Introduction 1
Chapter 2 5
Poor intrahippocampal communication increases impulsive responses during a differential-reinforcement-of-low-rate (DRL) task 5
2.1 Abstract 5
2.2. Introduction 7
2.3. Materials and methods 10
2.3.1 Animals 10
2.3.2 Pretraining 11
2.3.3 Surgery 12
2.3.4 Experimental procedures and data collection 13
2.3.5 Histology 14
2.3.6 Data analysis 15
2.3.7 Statistics 19
2.4. Results 19
2.4.1 Comparison of LFP properties of the non-reinforced and reinforced events in the CA1 and MEC 19
2.4.2 High power LFPs in the CA1 region of the hippocampus during impulsive states 22
2.4.3 High coherence, but low causality, in the LFP signals from the CA1 to MEC during the impulsive events 24
2.4.4 Cross-frequency coupling between CA1 theta phases and MEC fast gamma amplitudes decreases during impulsive events. 25
2.5. Discussion 27
2.5.1 Hippocampal formation controls impulsive behaviors 27
2.5.2 Poor memory processing results in impulsive behaviors 28
2.5.3 Information from CA1 to MEC is important for DRL 30
2.6 Graphical conclusion 31
Chapter 3 41
Activation of hippocampal endocannabinoid system prolongs time estimation in rats 41
3.1 Abstract 41
3.2 Introduction 43
3.3 Materials and methods 47
3.3.1 Subjects 47
3.3.2 Pretraining 47
3.3.3 Surgery 49
3.3.4 Drugs and microinjections 50
3.3.5 Experimental procedures and data collection 51
3.3.6 Histology 52
3.3.7 Data analysis 52
3.3.8 Statistics 54
3.4 Results 55
3.4.1 Comparison of DRL behavior performance under local infusion ACPA in the CA1 and MEC. 55
3.4.2 Comparison of LFP properties under local infusion of PFS and ACPA in the CA1 and MEC during DRL. 57
3.4.3 Antagonistic effects of CB1 agonist against time overproduction in the MEC during DRL behavior 58
3.4.4 High phase synchronization in the LFP signals from the CA1 to MEC and intrahippocampus circuitry under the effects of high dose of ACPA. 60
3.4.5 Cannabinoid disrupts cross-frequency coupling between CA1 theta phases and MEC fast gamma amplitudes. 62
3.5 Discussion 63
3.5.1 Effects of cannabinoids on the consequence of time overproduction 64
3.5.2 Distort of timing perception under cannabis effects by impairment of oscillation from CA1 to MEC 66
3.6 Graphical conclusion 70
Chapter 4 87
Overall conclusions 87
References 89
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