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：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）、腹内侧前额皮质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。 Jon（最早在 Science 277: 376-380, 1997 中描述的患有“发育性遗忘症”的患者之一）获得的新证据支持了该项目识别至少不依赖于高阶记忆回路，他似乎具有选择性新生儿缺氧/缺血性损伤引起的双侧海马病理学。在允许定量评估的标准化记忆测试中，乔恩的识别分数等于或高于第 50 个百分位数，而他的回忆分数则低于第 1 个百分位数。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），这一点得到了在猴子身上获得的新证据的支持。这些结果表明，形成物体-地点关联的能力不受海马选择性、兴奋性毒性损伤的影响，但会因底层海马旁组织的消融而严重受损。然而，在患有发育性遗忘症的患者中，相对选择性的海马损伤似乎足以损害物体与地点关联的记忆。这两项研究之间一个潜在的重要区别是，患者被要求记住 20 个物体-地点关联，并在多次连续试验中以单个列表的形式呈现，而猴子被要求一次只记住两个这样的关联，每对仅呈现一次（即物体-地点关联的一次尝试记忆）。为了更接近患者所承担的任务，我们使用 10 孔板来连续训练猴子，以学习一组 10 个物体与位置的关联。最终测试包括将正确（有诱饵）位置的每个物体与干扰物（其他九个物体之一在错误、无诱饵位置）随机配对。获得后，一半动物接受兴奋性毒性海马损伤（HC组），一半作为未手术对照（N组）。然后测试所有动物对术前学习的组的保留情况，然后进行另外两组的训练。 HC 组在实验的任何阶段都没有受到损害，这表明除了组大小之外的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讨。我们之前报道过，围产期持续的缺氧事件和童年中期持续的缺氧事件可导致相同的发育性遗忘症的神经心理学特征，即情景记忆显着受损和语义记忆相对保留，与同等程度的海马萎缩相关。随后对全脑的形态测量分析表明，与年龄匹配的对照组相比，围产期发生病理学的患有这种综合征的儿童的壳核、腹侧丘脑以及海马体的双侧灰质减少。我们现在比较了两组的此类分析结果，一组患有围产期持续的病理，另一组年龄在 6 至 13 岁之间。两者都显示出海马体、壳核和丘脑的双侧异常，这一点通过联合分析来证明，该分析寻找各组之间的共同异常。通过联合分析在两组中发现的唯一其他显着异常是右后扣带回区域。两组的遗忘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一种与缺氧引起的早期损伤相关的特殊综合征，那么有效损伤年龄必须从出生延伸到青春期。与年龄匹配的对照组相比，早产且需要至少一周通气的青少年每侧海马体积平均减少约 10%（范围为 0% 至 25%），而早期缺氧的青少年-缺血发作显示每侧平均减少约 40%（范围为 30% 至 55%）。两组患者的智商得分和即时记忆任务得分相当。然而，各种各样的言语和视觉延迟任务揭示了明显的群体差异。与对照组相比，早产组仅在以下几项指标上显着受损：路线跟踪和前瞻性记忆，包括记住约会和所有物。相比之下，缺氧缺血组在所有延迟任务上都比其他组受损，这一发现与发育性遗忘症的诊断一致。判别分析表明，Rivermead 行为记忆测试将儿童分组的准确度与海马体体积的准确度一样。有趣的是，在一项非延迟测量（韦克斯勒客观数字维度的数字运算子测试）中，发育性遗忘症组明显优于早产组。结果表明，只有当该结构的双侧体积减少至每侧低于正常值约 25-30% 时，早期海马病理学才会导致发育性遗忘。为了确定鼻周消融造成的视觉识别障碍在多大程度上可能是由于皮层下纤维损伤造成的，我们将神经毒素鹅膏酯双侧注射到猴子的鼻周皮层中，这些猴子已经接受了延迟不匹配样本规则的训练（DNMS）与试验独特的对象。将这些动物（IBO 组）的术后表现与之前研究的两个组进行比较，一组具有鼻周吸入性病变（ASP 组），另一组具有完整对照（NC 组），每组的 N 为 4。 IBO 组的平均再学习成绩与 ASP 组的平均再学习成绩没有可靠差异，并且相对于 NC 组均有所减值。然后对 IBO 组进行性能测试，其中延迟和列表逐步增加（延迟 2 分钟，列表长度 10）。同样，IBO 组在此性能测试中的平均分数与 ASP 组的平均分数没有差异，并且相对于对照组均有所下降。尽管他们的记忆缺陷程度相同，但 IBO 组的损伤不仅限于灰质，而且比 ASP 组的鼻周损伤小得多（分别约为 50% 和 90%）。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。