Pharmacology Of Stimulus Memory And Habit Formation

刺激记忆和习惯形成的药理学

• 批准号: 7594495
• 负责人: MORTIMER MISHKIN
• 金额: $ 87.24万
• 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/7594495
• 关键词: 6-Cyano-7-nitroquinoxaline-2,3-dione; AMPA Receptors; Acetylcholine; Address; Amnesia; Anterior; Area; Auditory; Auditory area; Basal Ganglia; Behavioral; Brain; Cell Nucleus; Cells; Cerebral cortex; Cerebrum; Child; Cholinergic Agents; Cholinergic Agonists; Cholinergic Antagonists; Cognitive; Complement; Complex; Corpus striatum structure; Deafferentation procedure; Denervation; Development; Discrimination; Discrimination Learning; Disruption; Dopamine; Event; Excitotoxic lesion; Familiarity; Funding; Habits; Haloperidol; Hippocampus (Brain); Hour; Hypoxia; Immunotoxins; Impairment; Incidence; Infusion procedures; Injection of therapeutic agent; Knowledge; Label; Learning; Macaca; Medial; Medial Dorsal Nucleus; Mediating; Memory; Metabolic; Methods; Monkeys; Motor; Muscarinic Acetylcholine Receptor; Muscarinics; Neocortex; Neurobiology; Neuromodulator; Neurons; Neurotoxins; Outcome; Paracentral Nucleus; Pathology; Pathway interactions; Performance; Perinatal; Pharmaceutical Preparations; Pharmacology; Physostigmine; Process; Property; Receptor Activation; Research; Rewards; Risk; Route; Sampling; Scopolamine; Sensory Process; Series; Site; Source; Stimulus; Structure; Structure of postcentral gyrus; Synapses; Syndrome; System; Techniques; Temporal Lobe; Thalamic Nuclei; Thalamic structure; Thinking; Time; Tissues; Tracer; Ventral Anterior Thalamic Nucleus; Visual; Work; basal forebrain; base; cholinergic; cingulate cortex; cohort; extrastriate visual cortex; forgetting; injured; kainate; magnocellular; memory process; memory recognition; multidisciplinary; neuroimaging; paired stimuli; receptor; visual memory; 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. However, 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). We have extended the immunolesion approach to investigate cholinergic versus dopaminergic contributions to one-trial object-reward associative memory. Like recognition memory the medial temporal cortex and in particular the perirhinal cortex is critical for the associative memory processing. In addition dopamine in the perirhinal cortex is thought to be critical for some reward learning processes. Therefore in two groups of monkeys we injected perirhinal cortex with the immunotoxins ME20.4SAP or anti-DAT-SAP to produce cholinergic and dopaminergic deafferentations respectively. The results suggest that cholinergic system may be critical for reward associative memory processes as well as recognition memory in the perirhinal cortex. (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. (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. The differential results on the two versions of the task 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）在研究中首先证明了对猴子中的单次视觉识别的胆碱能贡献，该研究表明，通过系统地给药胆碱能激动剂，Physostigmine和胆碱能拮抗剂Scopolamine，可以分别增强和损害该功能。 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。但是，没有令人信服的证明，即通过消除对鼻皮质的胆碱能输入来破坏新的视觉记忆的形成。试图通过将神经毒素注入基底前脑来实现猴子，这是胆碱能投射的主要来源，这是对视觉识别中最多适度且短暂损害产生的大脑皮层的主要来源。但是，这种温和的作用不能直接归因于颞叶组织的胆碱能神经化。 （2）在猴子中重新检查这个问题，我们将猴子的视觉识别性能进行了比较，鉴于选择性胆碱能免疫毒素ME20.4-SAP的鼻皮层输注与将猴子的对照输液输注到同一组织中。免疫毒素导致注入皮层的胆碱能脱落，其识别缺陷与该区域的兴奋性病变所产生的胆碱性缺陷相同，从而提供了迄今为止最直接的证明，迄今为止，最直接的证明是Rhinal Cortex的胆碱能激活对于存储新的视觉刺激的代表，并在其上识别了新的视觉刺激的代表。这些结果在胆碱能脱落后补充了我们对周围毒蕈碱受体阻断引起的发现的结果。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。我们已经扩展了对胆碱能和多巴胺能对一试对象奖励联想记忆的贡献进行研究的免疫方法。 像识别记忆一样，内侧时间皮层，尤其是周围皮层对于关联内存处理至关重要。 另外，据认为对某些奖励学习过程至关重要的多巴胺被认为至关重要。因此，在两组猴子中，我们分别为免疫毒素ME20.4SAP或抗DAT-SAP注射周围皮质，分别产生胆碱能和多巴胺能脱生。 结果表明，胆碱能系统对于奖励联想记忆过程以及周围皮质中的识别记忆至关重要。 （3）我们还证明，就像全身注射N-甲基-D-甲基-D-A甲酸（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。 （4）我们以前在猴子中的发现表明，氟哌啶醇的全身注入（但不是scopolamine）减弱了学习一组并发视觉区分的学习，其中每24小时每24小时都会出现一次刺激对。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。任务的两个版本的差异结果支持以下概念，即仅每24小时一次进行歧视学习一次，只能通过多巴胺能依赖性的皮质乳化性习惯系统来介导一次（因此，仅在卤素中仅由haloperidol中的颠覆和对haloperition进行中的限制范围，lyeasection the celepine the theeles oper-Repetient op-repetient op-repetition均在loperip的情况下进行。 Cortico-Limbic存储系统（因此，两种药理学剂都容易受到破坏的影响）。 （5）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进行的一系列投影，从那里，从那里到丘脑前核和丘脑前核的群和内侧背核（MDMC）的内侧核（MDMC），然后再进行通风孔和ccatter和ccatter cactal和cccatter cact。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。前生示踪剂的内侧丘脑注射部位覆盖了中线核以及MDMC，MDMC，大细胞腹侧前核的内侧部分（VAMC）和内膜内心核核（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。