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）在任何给定的感觉形式（或跨跨模态）中，项目和联想刺激识别的必要电路由相关的皮质感觉处理流，内侧颞外膜皮层组成丘脑。另一方面，联想召回现在似乎是在层次上组织的。因此，尽管无上下文的回忆或事实记忆似乎也主要取决于上述基本内存电路，上下文富含的回忆或事件记忆似乎还取决于叠加在基本的高级电路上，并由海马，乳房乳房，乳房前体，前丘脑前核核以及可能的，可能，可能，可能，可能是含水的。该项目的识别至少不取决于高阶记忆回路，这是在伦敦儿童健康学院/大学学院在发育认知神经科学单元（DCNU）进行的先前研究中获得的证据。在这些实验中，我们发现在生命的第一年内进行的缺血性缺血事件可能导致一种失忆症，似乎与成人发病病例中通常报道的全球顺行性健忘症不同。我们标记为“发育性健忘症”（DA）的早期发作形式的特征是显着受损（或事件）记忆，结合了语义（或事实）记忆和基于熟悉度的识别记忆的相对保留，并且与内侧时间病理学有关，并且似乎限制在海马室。在一项后续研究中，我们发现在6至14岁之间持续缺氧引起的病理学的儿童中存在相同的选择性障碍，这表明DA对DA的有效年龄发作是由于缺氧 - 缺血性发作导致的，从出生到青春期。 （2）在第二次随访研究中，我们发现，只有当该结构的体积在正常上降低20？30％时，早期海马病理才会导致DA。 （3）为了衡量DA中的偶然非语言召回，我们还研究了使用物体对动作序列的延期模仿。像成人发作性健忘症的病例一样，DA患者在观看建模之前自发产生的自发产生，但在看到它们建模后，召回了目标动作和动作对比在延迟24小时后匹配的对照组更少。但是，损害程度少于成人发作病例的损害程度。 （4）猴子中的关联识别也不取决于高阶记忆电路（但确实需要基本电路）得到了空间内存的新证据的支持。新结果表明，形成对象的关联的能力不受选择性的，兴奋性毒性损害的影响，但由于消融基础寄生虫组织的消融而严重损害，这表明该区域的首次已知Mnemonic作用。 (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两项研究的皮质。 （6）这一结果表明，尽管帕拉希普帕克皮层对对象相关性有很大贡献，但内侧颞叶的其他区域，例如周围和内嗅皮层，可能会导致在Parahippocampal-ablation Group中削弱白质组，这可能会给该组造成更严重的Implymment吗？初步结果表明，对周围或内嗅皮层的依替酸病变，这两者都从偏头皮皮质中接受投影，从而导致与单独的帕拉皮马接管皮质的伊比尼型病变相同。因此，帕拉希公共回合的多个皮质区域似乎有助于对象位置关联，大概是每个复杂任务的不同组成部分。 （7）在较早的研究中，我们研究了周围皮质消融产生的视觉识别障碍可能是由于皮层下损伤所致。在这项研究中，用依靠尼酸制造的周围病变导致与抽吸病变后观察到的记忆缺陷，即使对疗养损伤的损伤量大大低于抽吸病变后的记忆力（分别为50％和90％）；因此可以得出结论，周围皮质本身是视觉识别的关键底物，并且该区域内的安全因子很少。 （8）最近，我们发现，双侧去除皮质的猴子即使在1500次试验后也无法重新学习一试对象 - 奖励关联，这表明Rhinal Cortex也可以提供这种存储器。 （9）在DCNU和牛津大学之前进行的研究表明，三代KE家族的30名成员的一半遭受了语音和语言障碍，其特征在于与口面异性障碍相关的错误，这反过来归因于FOXP2基因突变引起的结构性脑异常。为了找到与该突变相关的功能性脑异常，我们在fMRI期间使用了明显的动词产生和秘密动词重复。结果表明，尽管不受影响的家庭成员表现出涉及broca区域和新纹状体的典型左派激活模式，除其他大脑区域外，受影响的成员表现出异常位置的激活分布更加向后和双侧，这表明FOXP2基因在portecteral术中发挥了至关重要的作用。