||Functional Interaction between the Amygdala and Entorhinal Cortex in Modulating Cocaine Associated Learning and Memory
||Institute of Basic Medical Sciences
cocaine associated memory and cue-induced fear conditionings
在本論文的第一部分，本研究使用「古柯鹼制約場地偏好動物模型」來探討:杏仁核側底核區與內嗅皮質之間的互動在古柯鹼制約學習裡所扮演的角色。結果顯示，在古柯鹼制約學習之後，利用muscimol (一種GABAA受器的致效劑)加強杏仁核側底核區與內嗅皮質抑制性神經元的活性，會降低古柯鹼制約之場地偏好。此外，在古柯鹼制約場地偏好測試之後執行抑制或毀除杏仁核側底核區與內嗅皮質，也會減少之後古柯鹼制約場地偏好的表現。這些結果，皆指出杏仁核側底核區與內嗅皮質對於古柯鹼制約場地偏好的表現，是必要的。根據前述的發現，假設杏仁核側底核區與內嗅皮質互動進而調控古柯鹼制約場地偏好的再穩固歷程。因此，利用注射muscimol在同側單邊或對側單邊杏仁核側底核區與內嗅皮質，以檢驗兩核區之間的連結是否完整會有何影響。在古柯鹼制約場地偏好提取之後，於對側單邊杏仁核側底核區與內嗅皮質內注射muscimol，減少隨後古柯鹼制約場地偏好;然而，在古柯鹼制約場地偏好測試之後,於同側單邊杏仁核側底核區與內嗅皮質內注射muscimol，則不影響隨後古柯鹼制約場地偏好。最後，為了瞭解是否除了杏仁核側底核區與內嗅皮質外，仍有其他腦區參與古柯鹼制約場地偏好的形成。在提取古柯鹼制約場地偏好記憶之後，利用ibotenic acid毀除杏仁核側底核區與內嗅皮質,並不影響動物學習新的古柯鹼制約場地偏好。根據前述發現，假設應有其他腦區參與新的古柯鹼制約場地偏好的學習。為了檢驗這個假設，利用免疫組織方式檢測其他腦區Fos的表現。結果指出，在毀除杏仁核側底核區與內嗅皮質後，動物提取新的古柯鹼制約場地偏好，前額葉Fos蛋白質表現量有增加，而杏仁核中央核區Fos蛋白質表現量卻是減少的現象。
Emotional arousal events tend to be remembered vividly than neutral ones. Neuroanatomical studies have suggested that amygdala is involved in memory consolidation by facilitating or dampening emotional arousal level. It is well known that the amygdala modulates positively and negative emotional memory, including drug-cues associated memory and fear memory. The present study aims to elucidate the role of amygdala in the consolidation, reconsolidation of cocaine associated memory and in the formation of cued-fear memory.
In part 1, we used cocaine-induced conditioned place preference to examine the role of functional interaction between the basolateral nucleus of amygdala (BLA) and entorhinal cortex (EC) in cocaine-conditioned memory. First, to elucidate whether BLA and EC are involved in the consolidation of cocaine-conditioned memory, we transiently inactivated BLA or EC with muscimol, a GABAA agonist, immediately after training. To further understand whether BLA and EC are critical for the retrieval of cocaine conditioned place preference, intra-BLA or -EC muscimol infusion prior to the CPP test decreased cocaine-induced CPP. Furthermore, Inactivation of BLA or EC immediately after the CPP test decreased subsequent performance in cocaine-induced CPP. These results, taken together, suggest that BLA and EC are necessary for cocaine-induced CPP performance. Based on our findings, we hypothesized that BLA in together with EC may modulate the reconsolidation of cocaine-induced CPP. To test the hypothesis, BLA and EC were functionally disconnected from each other by using unilateral muscimol infusion method. Importantly, ipsilateral intra-BLA and -EC muscimol infusion immediately after the CPP retrieval did not affect subsequent cocaine induced CPP. However, contralateral intra-BLA and -EC muscimol infusion immediately after the CPP retrieval drastically decreased subsequent cocaine-induced CPP. Finally, to examine whether is there a BLA- or EC- independent neural circuit for the formation of cocaine-induced CPP. After the retrieval of cocaine conditioned memory, the animals with BLA or EC lesion by ibotenic acid underwent new cocaine conditionings expressed the new cocaine-induced CPP. According to the finding, we supposed that there are complementary brain regions for the formation of new cocaine-induced CPP. For testing the hypothesis, the Fos immunostaining technique was used. The results revealed that the rats receiving new cocaine conditioning following BLA, EC, or BLA and EC lesion exhibited higher numbers of Fos-positive nuclei in the prefrontal cortex and less numbers of Fos-positive nuclei in the central nuclei of amygdala than sham control group.
We, hereby, conclude that BLA and EC are necessary for the storage of cocaine-induced CPP. Ipsilateral reciprocal neural activity between BLA and EC is involved in modulating the reconsolidation of cocaine-induced CPP. The PFC and are
essential for the formation of new cocaine-induced CPP after BLA and EC lesion.
In part 2, we want to understand whether there are sex differences in the activation of the amygdala during cue-induced fear conditionings processing. After cued fear
conditioning procedure, female mice exhibited a more robust cued fear memory than male mice. Systemic testosterone administrations and an intra-LA testosterone infusion
eliminated the CS-induced freezing in gonadectomized male mice, while testosterone administrations did not affect the CS-induced freezing in intact or OVX female mice.
Hence, these findings suggest that there is sex difference in the effect of testosterone on cued fear conditioning.
TABLE OF CONTENTS
CHINESE ABSTRACT.......... II-III
ENGLISH ABSTRACT.......... IV-IV
Chapter 1 ............ 1
Chapter 2 ............7
Functional Interaction between Amygdala and Entorhinal Cortex in Modulating Cocaine Associated Learning and Memory
INTRODUCTION ............ 8-12
MATERIALS AND METHODS .........13-25
Drug preparation and administration ....13
Stereotaxic Surgery and Cannula Implantation..14
Cocaine-induced CPP pretest, training, retest Pretest, training, test and retest protocol for cocaine-induced CPP experiments ............14
Procedures of Experiment 1.........16
Procedures of Experiment 2.........16
Procedures of Experiment 3.........19
Procedures of Experiment 4.........19
Procedures of Experiment 5.........20
Procedures of Experiment 6.........21
Procedures of Experiment 7.........22
Experiment 1: Inhibition by infusing muscimol into bilateral BLA or EC immediately after cocaine-induced CPP training diminished cocaine-induced CPP....26
Experiment 2: The BLA and EC are associated with retrieval of cocaine-conditioned memory........27
Experiment 2.1: The current conditioning protocol rendered reliable Cocaine-CPP memory and performance.27
Experiment 2.2: Cocaine-CPP memory reactivation enhanced Fos expression in BLA and EC........28
Experiment 2.3: Cocaine-CPP memory reactivation did not affect Fos expression in the dorsal striatum....29
Experiment 3: Infusion of muscimol BLA or EC immediately before the test diminished the expression of cocaine-induced CPP.................30
Experiment 4: Bilateral infusion of muscimol into BLA and EC after the retrieval diminished cocaine-conditioned memory................30
Experiment 5: Contralateral intra-BLA and intra-EC muscimol infusion significantly attenuated cocaine-induced CPP.................31
Experiment 6: Role of the BLA and EC in Overtrained cocaine memory................32
Experiment 7: The BLA- or EC-independent neural circuit for cocaine associated learning.......34
Experiment 7.1: The animals with BLA, EC or both BLA and EC lesion underwent excessive alternation conditionings displayed new cocaine-induced CPP.......34
Experiment 7.2: mPFC may be a candidate complementary site after BLA or EC lesion for the formation of new cocaine-induced CPP...............35
Chapter 3 ..............74
Sex Differences In Cued Fear Conditioning
MATERIALS AND METHODS..........78-83
Drug preparation and administration.....78
Stereotaxic Surgery and Cannula Implantation..78
Determination of the Estrous Phase, Gonadectomy, and Gonadal Hormone Treatment.........79
Acoustic Stimulus (tone)- and Footshock-induced Freezing Responses...............81
Cued Fear Conditioning and Test.......82
Experiment 1: Tone- and Footshock-induced Freezing Response in the Male and Female Mice......84
Experiment 2: Cued Fear Conditioning in the Male and Female Mice...............85
Experiment 3: Gonadectomy and the Cued Fear Conditioning in the Male and Female Mice.........85
Experiment 4: Modulating Effects of E And 4-OHT on Cued Fear Conditioning in Ovariectomized Female and Male Mice.86
Experiment 5: Modulating Effects of T and Flu on Cued Fear Conditioning in Female and Gonadectomized Male Mice..87
Figure 1-1. Involvement of the amygdala in emotional memory..................5
Functional Interaction between Amygdala and Entorhinal Cortex in Modulating Cocaine Associated Learning and Memory
Figure 2-1. Effects of intra-BLA and intra-EC muscimol infusions on the consolidation of cocaine-induced CPP.61
Figure 2-2. The development of a preference for the environment previously paired with cocaine....62
Figure 2-3. Schematic representation of coronal sections selected for quantification of Fos-positive nuclei..63
Figure 2-4. Numbers of Fos positive nuclei/0.36 mm2 in brain regions...............64
Figure 2-5. Effects of intra-BLA and intra-EC muscimol infusions on expression of cocaine-induced CPP. ..65
Figure 2-6. Effects of intra-BLA and intra-EC muscimol infusions on the reconsolidation of cocaine-induced CPP. ..................66
Figure 2-7. Effects of contralateral and ipsilateral intra-BLA and -EC muscimol infusion on the reconsolidation of cocaine-induced CPP.............67
Figure 2-8. Effects of intra-BLA and intra-EC ibotenic acid infusion after cocaine memory retrieval on subsequent cocaine conditionings...........68
Figure 2-9. Effects of intra-BLA and intra-EC ibotenic acid infusion after cocaine memory retrieval on new cocaine conditionings...............69
Figure 2-10. Schematic representations of coronal sections for lesion in the basolateral nucleus of amygdala (BLA) and entorhinal cortex (EC)............70
Figure 2-11. Schematic representation of coronal sections selected for quantification of Fos-positive nuclei..71
Figure 2-12. Numbers of Fos positive nuclei/0.36 mm2 in brain regions...............72
Figure 2-13. Schematic diagram of the possible outputs and functions of these connections among the basolateral nucleus of amygdala and entorhinal cortex.......73
Sex Differences In Cued Fear Conditioning
Figure 3-1. Tone- and footshock-induced freezing responses in male and female mice............100
Figure 3-2. Cued fear conditioning in male and female mice.................101
Figure 3-3. Gonadectomy and the Cued Fear Conditioning in the Male and Female Mice...........102
Figure 3-4. The modulating effects of Estradiol (E) and 4-hydroxytamoxifen (4-OHT) on the cued fear conditioning in ovariectomized (OVX) female and gonadectomized (TX) male mice.................103
Figure 3-5. The modulating effects of testosterone (T) and flutamide (F) on the cued fear conditioning in female and gonadectomized male mice...........104
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