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: 6823589
• 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/6823589
• 关键词: Primates; behavioral habituation /sensitization; brain morphology; caudate nucleus; clinical research; experimental brain lesion; frontal lobe /cortex; habits; hippocampus; human subject; memory; morphometry; neural information processing; neuroanatomy; putamen; short term memory; thalamus; visual cortex; visual stimulus

Summary: 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 new evidence obtained in Jon (one of the patients with 'developmental amnesia' described initially in Science 277: 376-380, 1997), who has seemingly selective bilateral hippocampal pathology induced by a neonatal hypoxic/ischaemic insult. On standardized memory tests allowing quantitative assessment, Jon's recognition scores were at or above the 50th percentile, whereas his recall scores fell below the 1st percentile. 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 obtained in monkeys. These 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. In the patients with developmental amnesia, however, relatively selective hippocampal damage did seem sufficient to impair memory for object-place associations. One potentially important difference between the two studies is that the patients were required to remember 20 object-place associations, presented as a single list for several successive trials, whereas the monkeys were required to remember only two such associations at a time, with each pair presented just once (i.e. one-trial memory for object-place associations). To approximate more closely the task given the patients, we used a 10-well board to train monkeys in successive steps to learn a set of 10 object-place associations. The final test consisted of randomly pairing each object in its correct (baited) place with a distracter (one of the other nine objects in an incorrect, unbaited, place). After acquisition, half of the animals received excitotoxic hippocampal lesions (Group HC), and half were kept as unoperated controls (Group N). All animals were then tested for retention of the preoperatively learned set and then trained on two additional sets. There was no impairment in Group HC at any stage of the experiment, suggesting that differences other than set size underlie the different outcomes in the human and animal studies. These other differences remain to be explored. We previously reported that hypoxic events sustained perinatally and those sustained in mid childhood can result in the same neuropsychological profile of developmental amnesia, i.e. markedly impaired episodic memory and relatively preserved semantic memory, in association with equivalent extents of hippocampal atrophy. Subsequent morphometric analyses of the whole brain revealed that, compared to age-matched controls, children with this syndrome whose pathology was incurred perinatally had bilateral reduction of grey matter in the putamen and ventral thalamus as well as the hippocampus. We have now compared the results of such analyses in two groups, the one with pathology sustained perinatally, and the other, between the ages of 6 and 13 years. Both showed bilateral abnormality in the hippocampus, putamen, and thalamus, as evidenced by conjunction analysis, which looks for common abnormalities across groups. The only other significant abnormality that was found in both groups by conjunction analysis was an area in the right posterior cingulate gyrus. The similarity of the amnesic and neuropathological patterns in the two groups suggests that, if the form of this memory disorder is a special syndrome related to the earliness of the hypoxia-induced damage, then the effective age at injury must extend from birth to puberty. Compared to age-matched controls, adolescents who were born preterm and required at least one week of ventilation showed a mean reduction in hippocampal volume on each side of approximately 10 percent (range, 0 to 25 percent), whereas adolescents who had suffered early hypoxic-ischaemic episodes showed a mean reduction on each side of approximately 40 percent (range, 30 to 55 percent). Both IQ scores and scores on immediate memory tasks were equivalent in the two patient groups. A wide variety of verbal and visual delay tasks, however, revealed marked group differences. The preterm group was significantly impaired relative to the controls on a few measures only: route following and prospective memory, including remembering an appointment and a belonging. The hypoxic-ischaemic group, by contrast, were impaired relative to both of the other groups on all delay tasks, a finding consonant with the diagnosis of developmental amnesia. Discriminant analysis indicated that the Rivermead Behavioural Memory Test classified the children into groups as accurately as the hippocampal volumes. Interestingly, on one non-delay measure, the numerical operations subtest of the Wechsler Objective Numerical Dimensions, the group with developmental amnesia was significantly superior to the preterm group. The results suggest that early hippocampal pathology leads to developmental amnesia only when the bilateral volume of this structure is reduced approximately 25-30 percent below normal on each side. To determine the extent to which the visual recognition impairment produced by perirhinal ablations might be due to subcortical fiber damage, we injected the neurotoxin, ibotenate, bilaterally into the perirhinal cortex of monkeys that had been trained in the rule for delayed nonmatching-to-sample (DNMS) with trial-unique objects. The postoperative performance of these animals (Group IBO) was compared with that of two previously studied groups, one with perirhinal aspiration lesions (Group ASP) and the other an intact control (Group NC), with an N of 4 in each group. The average relearning scores of Group IBO did not differ reliably from those of Group ASP, and both were impaired relative to Group NC. Group IBO was then given a performance test in which delays and lists were increased stepwise (to delays of 2 min. and to lists lengths of 10). Again, Group IBO's average scores on this performance test did not differ from those of Group ASP, and both were impaired relative to the controls. Although their memory deficits were thus of the same magnitude, Group IBO not only had damage restricted to grey matter but also sustained much smaller perirhinal lesions than Group ASP (about 50 and 90 percent, respectively). It may be concluded that the perirhinal cortex itself is the critical substrate for visual recognition and that there is very little safety factor within the area.

摘要：任何给定的感觉方式（或跨模态）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，内侧时间周围皮层组成丘脑。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电路，这是由乔恩（Jon）获得的新证据（一名最初在科学中描述的“发育性健忘症”的患者之一277：376-380，1997），他看似选择性双侧海马病理学，由新生儿低氧/异性疾病诱导。在允许定量评估的标准记忆测试中，乔恩的识别得分超过50％，而他的召回分数低于第一个百分点。在猴子中，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）得到了在猴子中获得的新证据的支持。这些结果表明，形成对象位置关联的能力不受选择性，兴奋性毒性损害对海马的影响，但由于消融下面的parahappocampal组织的消融严重损害了。然而，在发育性健忘症患者中，相对选择性的海马损害似乎足以损害对象位置关联的记忆。两项研究之间的一个潜在重要区别是，需要患者记住20个对象位置的关联，作为几个连续试验的一个单一列表，而猴子一次只记住两次这样的关联，每对仅呈现一次（即一次性的对象位置的一动物记忆，用于对象位置的关联）。为了更接近鉴于患者的任务，我们使用10孔板来训练猴子，以连续的步骤学习一组10个对象相关。最终测试包括在正确（诱饵）的位置将每个对象与干扰器（其他九个对象之一）随机配对。收购后，一半的动物接受了兴奋的海马病变（HC组），一半的动物被保存为无手术对照（N组）。然后，对所有动物进行了测试，以保留术前学习的集合，然后在另外两组中训练。在实验的任何阶段，HC组都没有损害，这表明除设定大小以外的其他差异是人类和动物研究中不同结果的基础。这些其他差异仍有待探索。我们先前报道说，低氧事件在围产期持续存在，而在童年中期持续的事件可能会导致发育性健忘症的神经心理学特征，即显着损害的情节记忆和相对保留的语义记忆，并与同等的海马萎缩相关。随后对整个大脑的形态分析表明，与年龄匹配的对照组相比，患有这种综合征的儿童的病理发生了围产期的病理学，其甲状腺肿和腹侧丘脑的灰质以及海马。现在，我们已经比较了两组此类分析的结果，一组具有围产期病理的持续性，另一组为6至13岁。两者均显示出海马，梭子鱼和丘脑的双侧异常，这是通过共同分析所证明的，该分析寻找整个组的常见异常。两组通过联合分析发现的唯一其他明显的异常是右后扣带回和的区域。两组中失忆症和神经病理学模式的相似性表明，如果这种记忆障碍的形式是与缺氧引起的损害的早期性有关的一种特殊综合征，则受伤时的有效年龄必须从出生到青春期。与年龄匹配的对照相比，天生的早产且需要至少一周的通风的青少年在每一侧的海马体积平均减少约为10％（范围为0至25％），而早期低氧期发作的青少年则平均降低了平均降低，每个面均平均减少，占每个范围约40％（范围为30％至55％）。在两个患者组中，立即记忆任务上的智商分数和分数都是等效的。然而，各种各样的口头和视觉延迟任务显示出明显的群体差异。相对于对控件的一些措施，早产组受到了严重损害：遵循的路线和前瞻性记忆，包括记住任命和归属。相比之下，低氧 - 缺血组相对于所有延迟任务上的其他两个组都受到了损害，这是与发育性失忆症的诊断相吻合。判别分析表明，瑞马德行为记忆测试将儿童分为群体与海马体积一样准确地分为组。有趣的是，在一项非延迟措施中，韦克斯勒客观数值维度的数值操作子测验，发育性健忘症的群体比早产组显着优于。结果表明，只有当这种结构的双边体积降低到两侧的正常约25-30％时，海马病理学才会导致发育性健忘症。为了确定周围消融造成的视觉识别障碍可能是由于皮层纤维下损伤引起的，我们将双侧的神经毒素，ibotenate，双侧注射到猴子的阴部皮层中，这些猴子受过训练，这些猴子受过训练，以延迟非匹配的非匹配样品（DNMS），以试用样品（DNMS）。将这些动物（IBO组）的术后性能与两个先前研究的组的术后性能，一个是围血抽吸病变（ASP组），另一组具有完整的对照（NC组），每个组中的N为4。 IBO组的平均重新学习分数与ASP组的平均分数没有可靠的差异，并且相对于NC组，两者均受到损害。然后，对IBO组进行了一项性能测试，其中延迟和列表逐步增加（延迟2分钟，列表长度为10）。同样，IBO组在此性能测试中的平均得分与组ASP的平均得分没有差异，并且相对于对照组，两者均受到损害。尽管它们的记忆缺陷幅度相同，但IBO组不仅限制了灰质的损害，而且比ASP组持有的周围病变要小得多（分别约为50％和90％）。可以得出的结论是，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。