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.

我们研究的证据表明，药理学剂在行为猴子中的影响的作用导致了这样的建议，即刺激记忆的形成取决于胆碱能和谷氨酸能体系之间的相互作用。更具体地说，我们的证据表明，储存刺激的痕量或表示的关键事件是通过激活胆碱能毒蕈碱受体对谷氨酸能NMDA受体介导的活性的增强作用。为了检验这一假设，我们一直在研究直接将药理学剂直接注入周围皮质的影响，从病变研究中知道，这是颞叶中最关键的刺激识别区域。到目前为止，我们的结果表明，就像全身注射胆碱能毒蕈碱受体拮抗剂（Scopolamine）一样，将这种药物显微注射到周围的皮层中会损害识别记忆。 rhinal皮层胆碱能脱落后的初步结果表明识别记忆缺陷，这补充了我们对封闭前毒蕈碱受体诱导的发现的发现。相比之下，识别记忆不受多巴胺能受体拮抗剂（例如氟哌啶醇）的全身或周围注射的影响。我们还证明，就像全身注射NMDA受体拮抗剂（MK-801）一样，这种拮抗剂（D-AP5）的周围输注会损害识别记忆。同样，相比之下，识别记忆不受海藻酸盐/AMPA受体拮抗剂（CNQX）的周围注射影响。这些结果不仅为刺激记忆取决于毒蕈碱和NMDA受体激活之间的相互作用的假设提供了初步支持，而且还为这种相互作用发生在周围皮质神经元内发生的观点。当前涉及毒蕈碱和NMDA受体配体的周围共同给药的实验，以及将胆碱能传入的选择性免疫对鼻皮层的免疫，将有助于我们完善我们对这种相互作用的理解。 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).在许多研究中，预处理用于使动物熟悉任务的过程方面，因此通常假定在新型环境中随后的训练应对认知空间处理特别敏感。但是，我们最近在大鼠中的行为发现表明，预处理促进了随后在刺激反应习惯而不是认知记忆的新型环境中的随后使用。因此，依靠完整的黑质纹状体多巴胺功能的皮质乳化习惯回路可能有助于训练后的水迷宫性能。将进行病变和药物实验以检验该假设。猴子的早期发现表明，全身注入氟哌啶醇，但不是scopolamine，它阻碍了一组并发的视觉区分的学习，其中每24小时只会出现一次集合中的刺激对。在一项新的研究中，使用此任务的一个版本，在该任务中，该任务在每个会话中分别重复几次刺激对，发现两种药物的全身注射都会阻碍学习。如果得到确认，则在任务的两个版本上的差异结果将支持以下观点：仅每24小时一次歧视每24小时进行歧视学习一次，只能通过多巴胺能依赖性的皮质性皮质习惯系统来介导（因此，仅由卤素内部的散热器都易于破坏），同时又易于破坏），同时将其放置在综合上）胆碱能依赖性的皮质 - 纤维膜记忆系统（因此，两种药理学剂都容易受到破坏的影响）。认为刺激记忆形成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中的结构，从那里到丘脑前核的结构，以及丘脑前部的大组和内侧背侧核（MDMC）（MDMC）的大量细胞分裂，然后再到ventral prefrant和cortal和cort cortculte cortculte cortculte cortculte cortculte cortrontice。据认为，基本习惯形成的平行回路涉及从新皮层到基底神经节的一系列投影，从那里到腹侧和腔内组内的丘脑核，然后再到运动前和补充运动区域。但是，在研究猕猴中内侧丘脑传出的过程中，我们发现了其他丘脑皮层途径，这些路线可能有助于刺激记忆和习惯形成。前进示踪剂的内侧丘脑注射部位覆盖了中线核，以及MDMC，大细胞腹侧前核（VAMC）的内侧部分（VAMC）和腔内内核核（PC）。这些注射在I层的外侧产生了末端标记，穿过极大的皮质膨胀，仅保留前前和补充运动区域，中心和后中侧和后式听觉皮层（未检查枕骨中的主要视觉区域）。在互补的研究中，将逆行示踪剂注入各个皮质区域，我们在上述内侧丘脑区域内搜索了一组神经元，这些神经元被不同的注射始终被标记为不同的注射，因此在皮层层中广泛投射的潜在投影。注射剂表明，这种特殊的丘脑 - 皮质投影可能参与刺激记忆的获取。此外，PC和VAMC的内侧部分包含来自除鼻皮层以外的所有注射领域的标记细胞，这表明属于腹侧和腔内组的这两个核的广泛的丘脑 - 皮层投影可能参与习惯形成。