Pharmacology Of Stimulus Memory And Habit Formation

刺激记忆和习惯形成的药理学

• 批准号: 6675602
• 负责人: MORTIMER MISHKIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6675602
• 关键词: AMPA receptors; Macaca mulatta; NMDA receptors; acetylcholine; dihydroxyphenylalanine; dizocilpine; dopamine; glutamate receptor; habits; laboratory rat; memory; methylphenyltetrahydropyridine; microdialysis; neuropharmacology; physostigmine; psychopharmacology; scopolamine; temporal lobe /cortex; visual stimulus

Evidence from our studies on the effects of systemic injections of pharmacological agents in behaving monkeys has led to the proposal that the formation of stimulus memories depends on interaction between the cholinergic and glutamatergic systems. More specifically, our evidence suggests that the critical event for storage of the trace or representation of a stimulus is the potentiation exerted by activation of the cholinergic muscarinic receptor on activity mediated by the glutamatergic NMDA receptor. To test this hypothesis, we have been examining the effects of infusing pharmacological agents directly into the perirhinal cortex, which is known from lesion studies to be the most critical area in the temporal lobe for stimulus recognition. Our results thus far have shown that, like systemic injections of a cholinergic muscarinic receptor antagonist (scopolamine), microinjecting this drug into perirhinal cortex impairs recognition memory. Preliminary results following cholinergic deafferentation of rhinal cortex indicate recognition memory deficits which complement our findings of those induced by blockade of perirhinal muscarinic receptors. By contrast, recognition memory is unaffected by either systemic or perirhinal injections of dopaminergic receptor antagonists (e.g. haloperidol). We have also demonstrated that, like systemic injections of an NMDA receptor antagonist (MK-801), perirhinal infusions of such an antagonist (D-AP5) impairs recognition memory. Again by contrast, recognition memory was unaffected by perirhinal injections of a kainate/AMPA receptor antagonist (CNQX). These results provide preliminary support not only for the hypothesis that stimulus memory depends on the interaction between muscarinic and NMDA receptor activation, but also for the notion that such interaction occurs within the neurons of the perirhinal cortex. Current experiments, involving perirhinal co-administration of muscarinic and NMDA receptor ligands, as well as selective immunolesioning of cholinergic afferents to rhinal cortex, will serve to refine our understanding of this interaction. The cholinergic/glutamatergic hypothesis of cognitive memory formation has been challenged on the basis of the finding that pretraining rats in the Morris water maze in one environment eliminates the impairing effects of muscarinic and NMDA receptor antagonists on learning the maze in another environment (for review, see Cain, Neuroscience and Biobehavioral Reviews 22: 181-193, 1998). In many of these studies, pretraining is used to familiarize animals with the procedural aspects of the task, and so it is commonly assumed that subsequent training in a novel environment should therefore be particularly sensitive to cognitive spatial processing. However, our recent behavioral findings in rats suggest that the pretraining promotes subsequent use in the novel environment of stimulus-response habits rather than cognitive memory. Therefore, corticostriatal habit circuits relying on intact nigrostriatal dopamine function may contribute to water maze performance following pretraining. Lesion and drug experiments will be conducted to test this hypothesis. Earlier findings in monkeys suggested that systemic injection of haloperidol, but not of scopolamine, retards the learning of a set of concurrent visual discriminations in which the stimulus pairs within the set are each presented just once every 24 hours. In a new study, using a version of this task in which the stimulus pairs of the set are each repeated a few times within each session, systemic injections of both drugs was found to retard learning. If confirmed, the differential results on the two versions of the task would support the notion that discrimination learning with pair-repetition just once every 24 hours can be mediated only by a dopaminergic-dependent corticostriatal habit system (and, hence, is susceptible to disruption only by haloperidol), whereas learning with pair-repetition within a session is mediated by both the latter system and a cholinergic-dependent cortico-limbic memory system (and, consequently, is susceptible to disruption by both pharmacological agents). The circuitry underlying the formation of stimulus memories is thought to involve a series of projections from the high-order sensory processing areas through structures in the medial temporal lobe, from there to the anterior group of thalamic nuclei and the magnocellular division of the medial dorsal nucleus (MDmc), and then to the ventral prefrontal and cingulate cortices. The parallel circuit underlying habit formation is thought to involve a series of projections from the neocortex through the basal ganglia, from there to thalamic nuclei within the ventral and intralaminar groups, and then to the premotor and supplementary motor areas. However, in the course of investigating medial thalamic efferents in macaques, we uncovered other thalamo-cortical routes that could contribute to stimulus memory and habit formation. The medial thalamic injection sites for anterograde tracers covered the midline nuclei, as well as MDmc, medial portions of the magnocellular ventral anterior nucleus (VAmc) and the intralaminar paracentral nucleus (Pc). These injections yielded terminal labeling in the outer half of layer I across an extremely large cortical expanse, sparing only the premotor and supplementary motor areas, precentral and postcentral gyri, and primary auditory cortex (the primary visual area in the occipital pole was not examined). In complementary studies, in which retrograde tracers were injected into various cortical areas, we searched for groups of neurons within the above medial thalamic region that were consistently labeled by the different injections and were therefore a potential source of the widespread projection to cortical layer I. Numerous retrogradely labeled neurons were seen in the midline group of thalamic nuclei after prefrontal, cingulate, and rhinal injections, suggesting that this particular thalamo-cortical projection could participate in the acquisition of stimulus memories. In addition, Pc and the medial portion of VAmc contained labeled cells from all the injected fields except rhinal cortex, suggesting that the widespread thalamo-cortical projections from these two nuclei, which belong to the ventral and intralaminar groups, might participate in habit formation.

我们对行为猴子全身注射药物效果的研究证据表明，刺激记忆的形成取决于胆碱能系统和谷氨酸能系统之间的相互作用。更具体地说，我们的证据表明，刺激痕迹或表示的存储的关键事件是胆碱能毒蕈碱受体的激活对谷氨酸能 NMDA 受体介导的活性所产生的增强作用。为了检验这一假设，我们一直在研究将药物直接注入鼻周皮层的效果，根据病变研究可知，鼻周皮层是颞叶中刺激识别最关键的区域。迄今为止，我们的结果表明，与全身注射胆碱能毒蕈碱受体拮抗剂（东莨菪碱）一样，将该药物显微注射到鼻周皮层会损害识别记忆。鼻皮质胆碱能传入神经阻滞后的初步结果表明识别记忆缺陷，这补充了我们对鼻周毒蕈碱受体阻断引起的缺陷的发现。相比之下，识别记忆不受全身或鼻周注射多巴胺能受体拮抗剂（例如氟哌啶醇）的影响。我们还证明，与全身注射 NMDA 受体拮抗剂 (MK-801) 一样，鼻周注射此类拮抗剂 (D-AP5) 也会损害识别记忆。再次相比之下，鼻周注射红藻氨酸/AMPA受体拮抗剂（CNQX）不会影响识别记忆。这些结果不仅为刺激记忆取决于毒蕈碱受体激活和 NMDA 受体激活之间的相互作用这一假设提供了初步支持，而且还为这种相互作用发生在鼻周皮层神经元内的观点提供了初步支持。目前的实验涉及毒蕈碱和 NMDA 受体配体的鼻周共同给药，以及胆碱能传入鼻皮质的选择性免疫损伤，将有助于完善我们对这种相互作用的理解。认知记忆形成的胆碱能/谷氨酸假说受到了挑战，因为发现在一种环境中在莫里斯水迷宫中对大鼠进行预训练可以消除毒蕈碱和 NMDA 受体拮抗剂对在另一种环境中学习迷宫的损害作用（供审查，参见 Cain，神经科学和生物行为评论 22：181-193，1998）。在许多此类研究中，预训练用于使动物熟悉任务的程序方面，因此通常认为在新环境中的后续训练应该对认知空间处理特别敏感。然而，我们最近对大鼠的行为发现表明，预训练促进了随后在新环境中使用刺激反应习惯而不是认知记忆。因此，依赖于完整的黑质纹状体多巴胺功能的皮质纹状体习惯回路可能有助于预训练后的水迷宫表现。将进行病变和药物实验来检验这一假设。早期在猴子身上的研究结果表明，全身注射氟哌啶醇（而非东莨菪碱）会阻碍一组并发视觉辨别的学习，其中该组中的刺激对每 24 小时仅出现一次。在一项新的研究中，使用该任务的一个版本，其中该组刺激对在每个会话中重复几次，发现全身注射两种药物会阻碍学习。如果得到证实，该任务的两个版本的差异结果将支持这样的观点，即每 24 小时一次的成对重复的辨别学习只能由多巴胺能依赖的皮质纹状体习惯系统介导（因此，很容易受到干扰）仅通过氟哌啶醇），而在一个会话中进行成对重复学习是由后一个系统和胆碱能依赖性皮质边缘记忆系统介导的（因此，很容易受到影响）被两种药理学试剂破坏）。刺激记忆形成背后的电路被认为涉及一系列从高阶感觉处理区域通过内侧颞叶结构的投射，从那里到丘脑核前群和内侧背核的大细胞分裂（MDmc），然后到腹侧前额叶和扣带皮层。习惯形成背后的并行回路被认为涉及从新皮质到基底神经节的一系列投射，从那里到腹侧和层内组内的丘脑核，然后到前运动区和辅助运动区。然而，在研究猕猴内侧丘脑传出神经的过程中，我们发现了其他可能有助于刺激记忆和习惯形成的丘脑皮质路径。顺行示踪剂的内侧丘脑注射部位覆盖中线核以及 MDmc、大细胞腹侧前核 (VAmc) 的内侧部分和板内旁中央核 (Pc)。这些注射在第一层的外半部分产生了终端标记，跨越了极大的皮质区域，仅保留了前运动区和辅助运动区、中央前回和中央后回以及初级听觉皮层（未检查枕极的初级视觉区域） 。在补充研究中，将逆行示踪剂注射到各个皮质区域，我们在上述内侧丘脑区域内寻找神经元组，这些神经元被不同的注射一致标记，因此是广泛投射到皮质 I 层的潜在来源。前额叶、扣带回和鼻部注射后，在丘脑核的中线组中看到许多逆行标记的神经元，表明这种特殊的丘脑皮质投射可能参与刺激的获取回忆。此外，Pc 和 VAmc 的内侧部分包含来自除鼻皮质外的所有注射区域的标记细胞，表明这两个核（属于腹侧和层内组）的广泛丘脑皮质投射可能参与习惯形成。