Pharmacology Of Stimulus Memory And Habit Formation

刺激记忆和习惯形成的药理学

• 批准号: 7136222
• 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/7136222
• 关键词: Macaca; acetylcholine; anticholinergic agent; behavioral /social science research tag; brain mapping; cholinergic agents; denervation; entorhinal cortex; habits; haloperidol; immunoconjugates; memory; neuronal transport; neuropharmacologic agent; neurophysiology; neurotoxicology; neurotoxins; scopolamine; thalamocortical tract; visual pathways; visual perception; visual stimulus

(1) A cholinergic contribution to one-trial visual recognition in the monkey was first demonstrated in studies showing that this function could be enhanced and impaired, respectively, by systemic administration of the cholinergic agonist, physostigmine, and the cholinergic antagonist, scopolamine. Later, when the entorhinal/perirhinal, or rhinal, cortex was found to be a critical substrate for recognition memory, evidence was obtained that this cortex was also a critical site for the cholinergic contribution to such memory, based on the demonstration that (i) visual recognition performance was accompanied by efflux of acetylcholine in the rhinal cortex and (ii) this performance was impaired by microinfusing scopolamine directly into rhinal cortex. However, there has not been a convincing demonstration that the formation of new visual memories can be disrupted by eliminating the cholinergic input to rhinal cortex. Attempts to achieve this outcome in monkeys by injecting a neurotoxin into the basal forebrain, the major source of cholinergic projections to the cerebral cortex produced at most only modest and transient impairment in visual recognition. and even this mild effect could not be attributed directly to cholinergic denervation of temporal lobe tissue. (2) To reexamine this issue in the monkey we compared the visual recognition performance of monkeys given rhinal cortex infusions of a selective cholinergic immunotoxin, ME20.4-SAP, with that of monkeys given control infusions into this same tissue. The immunotoxin, which leads to cholinergic deafferentation of the infused cortex, yielded recognition deficits of the same magnitude as those produced by excitotoxic lesions of this region, providing the most direct demonstration to date that cholinergic activation of the rhinal cortex is essential for storing the representations of new visual stimuli and thereby enabling their later recognition. These results following cholinergic deafferentation 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). (3) We have also demonstrated that, like systemic injections of an N-methyl-D-asparate (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. (4) Our previous 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). (5) 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. 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.

(1) 胆碱能对猴子一次性视觉识别的贡献首次在研究中得到证实，研究表明，通过全身施用胆碱能激动剂毒扁豆碱和胆碱能拮抗剂东莨菪碱，可以分别增强和损害这种功能。后来，当发现内嗅/鼻周或鼻皮质是识别记忆的关键基质时，获得的证据表明该皮质也是胆碱能对此类记忆贡献的关键部位，基于以下证明：视觉识别性能伴随着鼻皮质中乙酰胆碱的流出，并且（ii）将东莨菪碱直接微量输注到鼻皮质中会损害这种性能。然而，目前还没有令人信服的证据表明，通过消除鼻皮质的胆碱能输入可以扰乱新视觉记忆的形成。试图通过向猴子的基底前脑注射神经毒素来达到这一结果，基底前脑是大脑皮层胆碱能投射的主要来源，最多只会产生适度和短暂的视觉识别障碍。即使这种轻微的影响也不能直接归因于颞叶组织的胆碱能去神经支配。 (2) 为了重新检查猴子的这个问题，我们比较了鼻皮质注射选择性胆碱能免疫毒素 ME20.4-SAP 的猴子与注射同一组织对照的猴子的视觉识别性能。免疫毒素会导致输注皮质的胆碱能传入神经阻滞，产生与该区域的兴奋性毒性损伤产生的识别缺陷相同程度的识别缺陷，这提供了迄今为止最直接的证据，表明鼻皮质的胆碱能激活对于存储表征至关重要新的视觉刺激，从而使他们以后能够被识别。胆碱能传入神经阻滞后的这些结果补充了我们通过阻断鼻周毒蕈碱受体诱导的结果。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。 (3) 我们还证明，与全身注射 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂 (MK-801) 一样，鼻周输注这种拮抗剂 (D-AP5) 也会损害识别记忆。相比之下，识别记忆同样不受鼻周注射红藻氨酸/AMPA受体拮抗剂（CNQX）的影响。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。 (4) 我们之前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）。 (5) 刺激记忆形成的基础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丘脑大细胞分裂。内侧背核（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) 的内侧部分和层内旁中央核 (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。