1、吗啡成瘾及吗啡对其他学习记忆的影响 2、老年猕猴初级视觉皮层细胞时间及空间特性的改变
文献类型：学位论文
| 作者 | 张洁 |
| 学位类别 | 博士 |
| 答辩日期 | 2008-06 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 马原野 |
| 关键词 | 吗啡 成瘾 学习记忆 Y-迷宫 水迷宫 条件化位置偏好 衰老 功能退化 初级视皮层 时间频率 空间频率 猕猴 |
| 其他题名 | 1.Morphine addiction and the effects of morphine treatment on other kinds of learning and memory 2.Spatial and Temporal Sensitivity Degradation of Primary Visual Cortical Cells in Senescent Rhesus Monkeys |
| 学位专业 | 动物学 |
| 中文摘要 | 一、 药物滥用是一种慢性、复发性脑疾病。药物滥用将导致药物成瘾（addiction），其主要表现有药物依赖、药物耐受、药物敏感化以及药物停用后的戒断症状（withdraw symptom）。药物成瘾的核心特征是强迫性觅药和用药行为。药物成瘾会导致药物滥用者认知功能的损伤和认知偏差，并会造成滥用者情绪异常。药物成瘾是一个复杂的生物学过程，有着及其复杂的机理。对药物成瘾机制的解释有很多种，主要认为成瘾过程是一种学习记忆过程，学习记忆的机制在药物成瘾过程中起到了非常重要的作用。首先，学习记忆和药物成瘾过程都受到了相似的神经营养因子以及神经递质系统的调控，例如：它们都受cAMP，CREB等调控因子的调控。其次，研究发现与成瘾相关的线索，如用药有关的人物、地点或暗示等，在药物戒断很长时间后都会恢复吸毒者的用药行为。并且，当把与成瘾相关的线索呈现给毒品戒断中的人时，这些人会出现心率、呼吸加快，血压升高等现象，甚至表现出明显的渴求行为。药物对学习记忆的影响是复杂的，虽然重复使用药物会导致药物成瘾，并且这个过程需要学习记忆机制的参与，但同时使用吗啡却会对其他类型的学习记忆（如：恐惧性学习记忆、一次性被动回避学习记忆和水迷宫空间学习记忆）造成破坏。学习前给予吗啡可以剂量及状态依赖地破坏被动回避试验以及空间辨别试验的记忆获取过程。学习过程结束后立即给予吗啡可以破坏一次性被动回避试验、主动回避试验和恐惧条件化试验的记忆巩固过程。测试前给予吗啡可以破坏空间辨别试验的记忆提取过程。本研究的目的在于更进一步地了解使用吗啡导致吗啡成瘾以及使用吗啡导致学习记忆的各个阶段受损的机制。为此我们采用了药理学以及多种行为学的方法，1、用PTZ诱发的癫痫持续状态干扰吗啡成瘾的学习记忆过程，进一步比较了吗啡成瘾的学习记忆与其他学习记忆，例如：空间学习记忆以及食物奖赏学习记忆的机制有何异同；2、研究了β-肾上腺素系统与阿片系统在空间记忆巩固过程中的相互作用；3、我们还研究了NMDA受体的激动剂和拮抗剂在吗啡破坏空间记忆提取过程中的作用。研究结果发现： 1．戊四唑诱发的癫痫持续状态，对吗啡建立的条件化位置偏好没有任何影响，动物仍然对阳性箱（吗啡匹配箱）表现出明显的偏好。但是癫痫持续状态破坏了食物建立的条件化位置偏好，并且还破坏了水迷宫和Y迷宫检测的空间记忆。癫痫持续状态破坏了食物建立的条件化位置偏好，原因不是由于其影响了动物的食欲。此外，癫痫持续状态也没有持续地破坏动物的活动能力，因此，对动物活动量的影响也不是造成其他学习记忆破坏的原因。这些结果说明，吗啡成瘾的学习记忆和普通的学习记忆在机制上可能存在不同之处。为了说明这个问题，我们还需要进行其他更深入的研究。 2、训练后立即单独注射吗啡（0.25和2.5 mg/kg）或心得安（2，10和20 mg/kg）都不会破坏动物Y-迷宫空间记忆的巩固过程，动物仍然能识别新异环境，并在里面停留较长时间。但是，训练后同时注射吗啡和心得安却可以破坏动物空间记忆的巩固过程。并且，较高剂量的吗啡（2.5 mg/kg）加上较高剂量的心得安（10和20 mg/kg）对记忆的破坏更严重，实验组动物在新异环境停留的时间显著低于对照组。这说明阿片系统和去甲肾上腺素系统在破坏记忆巩固的过程中可能有协同作用。 3、记忆提取前30分钟注射吗啡（1和10 mg/kg）可以剂量依赖地破坏Y-迷宫空间记忆的提取。单独注射NMDA受体的激动剂NMDA（1，2和4 mg/kg）对动物的空间记忆提取没有影响，但是，单独注射NMDA受体拮抗剂MK-801（0.05，0.1和0.2 mg/kg）剂量依赖地破坏了空间记忆的提取。同时注射吗啡（10 mg/kg）和NMDA（2 mg/kg）可以阻断吗啡对空间记忆造成的破坏作用。相反，共同注射吗啡（1 mg/kg）和MK-801（0.05 mg/kg）可以加重吗啡对空间记忆造成的破坏作用。这说明谷氨酸系统可以干扰吗啡对记忆提取过程的影响。 二、衰老严重地影响了人们的视觉功能，然而眼睛光学系统的老年性改变并不能完全解释清楚这种视觉功能衰退。一般认为是神经系统的退化导致了这种老年性功能降低。但是，研究显示视网膜（retina）和外膝体（dorsal lateral geniculate nucleus, dLGN）在衰老的过程中神经元的数量和体积以及神经元的功能特性，如对比度敏感性、空间分辨率等，都没有明显的变化，因此，人们推测老化导致的神经系统的变化发生在更高级的视觉皮层。过去几年的研究发现老年动物视觉皮层细胞发生了一系列反应特性的改变，如：老年动物皮层细胞的方向选择性和方位选择性降低以及细胞反应的潜伏期延长。这些细胞水平的变化被认为是老年性视觉功能衰退的神经机制。为了更全面地了解衰老过程对视觉皮层的影响以及细胞反应改变与整体功能降低之间的关系，本研究采用活体动物细胞外单位记录的方法，比较了青年和老年猕猴初级视觉皮层细胞时间反应特性和空间反应特性的差异。研究结果发现：老年动物初级视觉皮层细胞的时间频率和空间频率敏感性明显比年轻动物降低。表现为老年动物初级视觉皮层细胞的最优时间和空间频率、空间分辨率（spatial resolution, SR）和较高时间截至频率（high temporal frequency cut-off, TF50）都显著低于年轻动物初级视觉皮层细胞，同时伴随着这些功能的降低，老年动物初级视觉皮层细胞的自发放增加，对视觉刺激的反应增加，但是信噪比却显著降低。这些结果表明，老年动物初级视觉皮层细胞的功能在老化过程中都普遍降低。这可能是导致老年人视觉功能降低的原因。 |
| 英文摘要 | Part 1. Drug abuse is a problem of complex, compulsive drug administration. It will lead to drug addiction which is characterized by drug dependence, drug resistance, drug sensitivity and withdraw symptom. The most important character of drug addiction is compulsive pattern of drug-seeking and drug-taking behavior. That is, addicts loss of control in drug seeking and taking behavior. Accumulated studies have demonstrated that repeated exposure to certain drugs can produce deleterious sequelae, especially cognitive impairments, cognitive biases and emotion dysfunction, which may be the reason for drug abuse and relapse. However, the mechanisms underlying drug addiction are still unclear. Most evidences have indicated that the neural circuitry and molecular mechanisms of drug addiction and of learning and memory have converged. First, drug addiction and learning and memory are modulated by the similar neurotrophic factors, share certain neurotransmitters transmission and intracellular signaling cascades, and depend on activation of the transcription factor cAMP-response element-binding protein (CREB). Second, evidence is presented that in the process of drug addiction, memory about the environmental cues which are associated with the hedonic experiences of drug taking plays a critical role in drug craving. Clinical efforts have found that recovering addicts seemed to respond abnormally to drug-associated contextual cues represented by autonomic responses such as increased heart rate and blood pressure as well as subjective feelings of craving. Although drug abuse can lead to drug addiction and this process involved the mechanisms of learning and memory, injection of morphine impaired other kinds of learning and memory, such as one-trial inhibitory avoidance task, Morris water-maze spatial memory and fear conditioning memory. Pre-training administration of morphine impaired the learning process of passive avoidance task and spatial recognition memory. Post-training immediately injection of morphine impaired memory consolidation of fear conditioning and avoidance task. In addition, pre-retention administration of morphine blocked memory retrieval of spatial recognition memory. The purpose of the present study is to further investigate the mechanisms underlying morphine addiction and the impairing effects of morphine on spatial recognition memory. To this end, we used a series of behavior paradigms, including Morris water-maze (MWM), Y-maze and conditioning place preference (CPP), and neuropharmacological paradigm to study 1) the effects of PTZ induced status epilepticus on morphine-induced CPP and food-induced CPP. Moreover, we compared these effects with the effects of SE on MWM and Y-maze; 2) the effects of combined injection of morphine and propranolol (a beta-adrenergic receptor antagonist) on consolidation of spatial recognition memory; 3) the effects of NMDA system on morphine induced impairment of memory retrieval. We found that 1) SE had no effects on the formation of morphine CPP, however, the formation of food CPP was blocked by SE. Meanwhile, spatial memory assayed in the Morris water maze and Y-maze was impaired by SE. In addition, the data demonstrated that SE did not cause a lasting disturbance of motor activity nor a change in the mice’s appetite. These results suggested that although SE had no effects on morphine CPP, there was impaired food CPP and spatial memory in both the Morris water maze and the Y-maze; 2) post-training administration of morphine (0.25 and 2.5 mg/kg) or PROP (2, 10 and 20 mg/kg) alone did not impair memory consolidation after a 2 h inter-trial interval (ITI). However, co-administration of ineffective doses of morphine (0.25 and 2.5 mg/kg) and ineffective doses of PROP (2, 10 and 20 mg/kg) disrupted memory consolidation after a 2 h ITI. Moreover, the relatively higher dose of morphine (2.5 mg/kg) plus the relatively higher doses of PROP (10 and 20 mg/kg) more seriously disrupted memory consolidation after a 2 h ITI. Locomotor activity was not affected by any of the drug treatments; 3）pre-retention administration of morphine (1 and 10 mg/kg) and MK-801 (0.05, 0.1 and 0.2 mg/kg) dose dependently impaired memory retrieval, but administration of NMDA (1, 2 and 4 mg/kg) had no effects on memory retrieval. Co-administration of ineffective low dose of morphine (1 mg/kg) and ineffective low dose of MK-801 (0.05 mg/kg) impaired memory retrieval. In addition, co-administration of high dose of morphine (10 mg/kg) and middle dose of NMDA (2 mg/kg) blocked the impairing effects of morphine on memory retrieval Part 2. Studies of visual perception have indicated that human visual abilities decline with age. The mechanisms underlying these age-related changes are unclear. Previous studies indicate that age related changes in the retina and dorsal lateral geniculate nucleus (dLGN). Those results, however, cannot explain the declines of senescence. It has been suggested that the deficits in visual function that accompany old age result from a degradation of function in the visual cortex. In previous studies, we have found that both the orientation and direction selectivity of primary visual cortex (V1) cells are decreased in senescent monkeys and cats. These decreases are accompanied by increased visual responsiveness, increased spontaneous activity (baseline) and decreased signal to noise ratios. We also found that the visual response latencies of V1 cells were greater in old than in young monkeys. In addition, Mendelson and Wells have found the degradation of temporal sensitivity of cells in areas 17 and 18 of visual cortex in aged rats. Here we compared the spatial and temporal sensitivities of primary visual cortical (V1) cells in young and old paralyzed macaque monkeys, using extracellular single-unit in vivo recordings. Our results show that cortical neurons of old monkeys exhibit lower optimal spatial and temporal frequency, lower spatial resolution and lower high temporal frequency cut-offs than do cells in young adult monkeys. These changes of old monkeys were accompanied by increased visually evoked responses, increased spontaneous activities and decreased signal-to-noise ratios. The increased excitability of cells in old animals is consistent with an age-related degeneration of intracortical inhibition. A significant degradation of neural spatial and temporal function in striate cortex should contribute to the declines in visual function that accompany old age. |
| 语种 | 中文 |
| 公开日期 | 2010-10-15 |
| 源URL | [http://159.226.149.42:8088/handle/152453/6280]  |
| 专题 | 昆明动物研究所_认知障碍病理学 |
| 推荐引用方式 GB/T 7714 | 张洁. 1、吗啡成瘾及吗啡对其他学习记忆的影响 2、老年猕猴初级视觉皮层细胞时间及空间特性的改变[D]. 北京. 中国科学院研究生院. 2008. |
入库方式： OAI收割
来源：昆明动物研究所
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