Neural Mechanisms Of Stimulus Memory And Habit Formation

刺激记忆和习惯形成的神经机制

• 批准号: 7135725
• 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/7135725
• 关键词: Primates; apraxias; association learning; behavioral /social science research tag; behavioral genetics; brain mapping; brain morphology; cerebral ischemia /hypoxia; clinical research; developmental disease /disorder; experimental brain lesion; family genetics; functional magnetic resonance imaging; hippocampus; human subject; memory; memory disorders; neural information processing; neurogenetics; visual stimulus

(1) The essential circuit for both item and associative stimulus recognition in any given sensory modality (or across modalities) consists of the relevant cortical sensory processing stream(s), the medial temporal periallocortex (i.e. parahippocampal, perirhinal, and entorhinal cortices), the ventromedial prefrontal cortex, and the magnocellular division of the medial dorsal nucleus of the thalamus. Associative recall, on the other hand, appears now to be organized hierarchically; thus, whereas context-free recall, or fact memory, also seems to depend primarily on the above basic memory circuit, context-rich recall, or event memory, seems to depend in addition on a higher-order circuit superimposed on the basic one and consisting of the hippocampus, mamillary body, anterior thalamic nuclei, and, possibly, cingulate cortex. That item recognition at least does not depend on the higher-order memory circuit is supported by evidence obtained in previous studies of children conducted at the Developmental Cognitive Neuroscience Unit (DCNU) in the Institute of Child Health/University College London. In these experiments we discovered that hypoxic?ischemic events sustained within the first year of life can result in a form of amnesia that appears to differ from the global anterograde amnesia commonly reported in adult-onset cases. The early-onset form, which we labeled 'developmental amnesia' (DA), is characterized by markedly impaired episodic (or event) memory combined with relative preservation of both semantic (or fact) memory and familiarity-based recognition memory, and is associated with medial temporal pathology that seems to be restricted to the hippocampus. In a follow-up study, we found the same selective disorder in children who had sustained hypoxia-induced pathology between the ages of 6 and 14, indicating that the effective age-at-injury for DA to result from hypoxic-ischemic episodes extends from birth to puberty. (2) In a second follow-up study we found that early hippocampal pathology leads to DA only when the volume of this structure is reduced below normal by 20?30% on each side. (3) To measure incidental nonverbal recall in DA, we also studied deferred imitation of action sequences with objects. Like cases of adult-onset amnesia, DA patients performed normally in the spontaneous production of such sequences prior to watching them being modeled but, after seeing them modeled, recalled fewer target actions and action pairs than their matched controls after a 24-hour delay. However, the degree of impairment was less than that reported for the adult-onset cases. (4) That associative recognition in monkeys also does not depend on the higher-order memory circuit (but does require the basic circuit) is supported by new evidence on spatial memory. The new results indicate that the ability to form object-place associations is unaffected by selective, excitotoxic damage to the hippocampus, and yet is severely impaired by ablation of the underlying parahippocampal tissue, revealing the first known mnemonic role for this area. (5) In a follow-up experiment, parahippocampal lesions made with ibotenic acid, which spared the underlying fibers of passage, still yielded a significant impairment in postoperative performance (71% correct compared with 82% correct preoperatively), but this impairment was significantly less than that following the original parahippocampal ablations (60% correct), despite the comparable extent of damage to the parahippocampal cortex in both studies. (6) This result suggests that although the parahippocampal cortex contributes significantly to object-place associations, other areas of the medial temporal lobe, such as the perirhinal and entorhinal cortex, possibly deafferented by undercutting the white matter in parahippocampal-ablation group, might also contribute to that group?s more severe impairment. Preliminary results indicate that ibotenic acid lesions to either perirhinal or entorhinal cortices, both of which receive projections from the parahippocampal cortex, result in an impairment of equal magnitude as that following ibotenic lesions of parahippocampal cortex alone. Thus, multiple cortical areas of the parahippocampal gyrus appear to contribute to the object-place associations, presumably each of them to a different component of this complex task. (7) In an earlier study we examined the extent to which the visual recognition impairment produced by perirhinal cortical ablations might be due to subcortical damage. In that study perirhinal lesions made with ibotenic acid resulted in memory deficits of the same magnitude as that observed after aspiration lesions, even though the amount of damage to the perirhinal cortex was substantially less than that after aspiration lesions (about 50 and 90 percent, respectively); thus it can be concluded that the perirhinal cortex itself is the critical substrate for visual recognition and that there is very little safety factor within this area. (8) More recently we found that monkeys with bilateral removals of the perirhinal cortex failed to relearn one-trial object-reward associations even after 1500 trials, suggesting that the rhinal cortex may also subserve this type of memory. (9) Studies performed earlier at the DCNU and Oxford University demonstrated that half the 30 members of the 3-generational KE family suffer from a speech and language disorder characterized by misarticulation associated with orofacial dyspraxia, which is due in turn to structural brain abnormalities caused by a mutation in the FOXP2 gene. To locate the functional brain abnormalities associated with this mutation, we used both overt and covert verb generation and word repetition during fMRI. The results indicated that whereas the unaffected family members showed the typical left-dominant pattern of activation involving Broca?s area and the neostriatum, among other brain regions, the affected members showed an abnormal distribution of activation located more posteriorly and bilaterally, suggesting that the FOXP2 gene plays a critical role in the development of the frontostriatal system that normally mediates speech.

(1) 在任何给定的感觉模式（或跨模式）中，项目和联想刺激识别的基本电路由相关的皮质感觉处理流、内侧颞周皮质（即海马旁皮质、鼻周皮质和内嗅皮质）组成，腹内侧前额叶皮层和丘脑内侧背核的大细胞分裂。另一方面，联想回忆现在似乎是按等级组织的。因此，上下文无关回忆或事实记忆似乎也主要依赖于上述基本记忆回路，而上下文丰富回忆或事件记忆似乎还依赖于叠加在基本记忆回路上的高阶回路，并且由海马、乳头体、丘脑前核和可能的扣带皮层组成。伦敦大学学院儿童健康研究所发育认知神经科学中心（DCNU）之前对儿童进行的研究中获得的证据支持了该项目识别至少不依赖于高阶记忆回路。在这些实验中，我们发现生命第一年内持续的缺氧缺血事件可能导致某种形式的遗忘症，这种遗忘症似乎与成人发病病例中常见的整体顺行性遗忘症不同。我们将这种早发性遗忘症称为“发育性遗忘症”（DA），其特征是情景（或事件）记忆明显受损，同时语义（或事实）记忆和基于熟悉性的识别记忆相对保留，并且与内侧颞叶病变似乎仅限于海马体。在一项后续研究中，我们在 6 岁至 14 岁之间持续缺氧引起的病理学的儿童中发现了相同的选择性障碍，表明缺氧缺血发作导致 DA 的有效损伤年龄为出生至青春期。 (2) 在第二项后续研究中，我们发现，只有当该结构的体积每侧减少至低于正常值 20% – 30% 时，早期海马病理学才会导致 DA。 (3) 为了测量 DA 中的附带非语言回忆，我们还研究了对象动作序列的延迟模仿。与成人失忆症的病例一样，DA 患者在观看这些序列被建模之前，在自发产生此类序列时表现正常，但在看到它们被建模后，在 24 小时延迟后，与匹配的对照组相比，回忆起的目标动作和动作对要少。然而，损伤程度小于成人发病病例的报告。 (4) 空间记忆的新证据支持猴子的联想识别也不依赖于高阶记忆回路（但确实需要基本回路）。新结果表明，形成物体-地点关联的能力不受海马体选择性、兴奋性毒性损伤的影响，但会因海马旁组织的消融而严重受损，这揭示了该区域第一个已知的助记作用。 (5) 在后续实验中，用鹅膏蕈酸造成的海马旁损伤，保留了下面的通道纤维，仍然对术后表现产生显着损害（正确率为 71%，术前正确率为 82%），但这种损害是显着的。尽管两项研究中海马旁皮层的损伤程度相当，但仍低于最初的海马旁消融后的结果（正确率为 60%）。 (6) 这一结果表明，虽然海马旁皮层对物体-地点关联有显着贡献，但内侧颞叶的其他区域，例如嗅周和内嗅皮层，可能因海马旁消融组中的白质削弱而​​导致传入神经阻滞，也可能导致该群体遭受更严重的损害。初步结果表明，鼻周或内嗅皮质（两者均接受海马旁皮质的投射）的鹅膏菌酸损伤，导致与仅海马旁皮质的鹅膏菌酸损伤同等程度的损害。因此，海马旁回的多个皮质区域似乎对物体-地点关联做出了贡献，大概每个区域都参与了这项复杂任务的不同组成部分。 (7) 在一项早期研究中，我们研究了鼻周皮质消融造成的视觉识别障碍在多大程度上可能是由于皮质下损伤造成的。在那项研究中，用鹅膏菌酸造成的鼻周损伤导致的记忆缺陷与误吸损伤后观察到的记忆缺陷程度相同，尽管对鼻周皮质的损伤程度远小于误吸损伤后的损伤程度（分别约为 50% 和 90%） ）；因此可以得出结论，鼻周皮层本身是视觉识别的关键基质，并且该区域内的安全系数非常小。 (8) 最近我们发现，双侧鼻周皮层被切除的猴子即使经过 1500 次试验也未能重新学习一次试验的物体-奖励关联，这表明鼻皮层也可能有助于这种类型的记忆。 (9) DCNU 和牛津大学早期进行的研究表明，3 代 KE 家族的 30 名成员中有一半患有言语和语言障碍，其特征是与口面部运动障碍相关的发音错误，而这是由于大脑结构异常引起的FOXP2 基因突变。为了定位与这种突变相关的功能性大脑异常，我们在功能磁共振成像期间使用了显性和隐性动词生成以及单词重复。结果表明，虽然未受影响的家庭成员表现出典型的左侧主导激活模式，涉及布罗卡区和新纹状体以及其他大脑区域，但受影响的家庭成员表现出位于更后部和两侧的异常激活分布，这表明FOXP2 基因在正常介导言语的额纹状体系统的发育中发挥着关键作用。