Pharmacology Of Stimulus Memory And Habit Formation

刺激记忆和习惯形成的药理学

基本信息

批准号：
7735107
负责人：
MORTIMER MISHKIN
金额：
$ 79.19万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/7735107
关键词：
6-Cyano-7-nitroquinoxaline-2,3-dione AMPA Receptors Acetylcholine Address Animals Area Auditory Behavioral Brain Cerebrum Child Cholinergic Agents Cholinergic Agonists Cholinergic Antagonists Cognitive Complex Corpus striatum structure Deafferentation procedure Discrimination Discrimination Learning Dissociation Dopamine Dose Excitotoxic lesion Habits Haloperidol Hour Immunotoxins Infusion procedures Injection of therapeutic agent Learning Length Mediating Memory Metabolic Methods Modification Monkeys Muscarinic Acetylcholine Receptor Muscarinics N-Methyl-D-Aspartate Receptors Neostriatum Neurobiology Neuromodulator Neurons Pathway interactions Performance Pharmaceutical Preparations Pharmacology Physostigmine Property Receptor Activation Research Role Sampling Scopolamine Site Stimulus Stream Synapses System Techniques Testing Time Training Visual Work base cholinergic forgetting injured kainate memory recognition memory retention multidisciplinary neuroimaging object recognition touchscreen visual memory visual stimulus

项目摘要

(1) A cholinergic contribution to 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) this recognition memory performance was impaired by microinfusing scopolamine directly into rhinal cortex, and (ii) this performance is impaired after eliminating the cholinergic input to rhinal cortex after infusions of a selective cholinergic immunotoxin, ME20.4-SAP into the rhinal cortex. This 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. By contrast, recognition memory was unaffected by perirhinal injections of a kainate/AMPA receptor antagonist (CNQX). These results provide preliminary support 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. (2) We have demonstrated that visual object recognition, a form of cognitive memory, depends on a circuit connecting the ventral visual stream with the rhinal cortex, whereas acquisition of object discrimination habits requires a circuit connecting the ventral visual stream with the ventrocaudal neostriatum. To determine whether this dissociation also extends to neuromodulator function, we tested separate groups of animals on two different touch-screen tasks, examining the effects on performance of systemically administered dopaminergic vs. muscarinic receptor antagonists. The group trained in object recognition were tested on the one-trial object recognition task delayed nonmatching-to-sample with list lengths of 20 stimuli. The group trained in S-R habit formation learned sets of concurrent 20 object-pair discriminations with 24-h intertrial intervals. Whereas scopolamine produced a dose-dependent deficit in object recognition, it had no effect on the formation of object discrimination habits. Conversely, whereas haloperidol produced a dose-dependent deficit in the formation of object discrimination habits, it had no effect on object recognition. These differential drug effects point to differences in synaptic modification induced by the two neuromodulators that parallel the contrasting properties of the two types of learning, namely, fast acquisition but weak retention of memories within the visuorhinal circuit vs. slow acquisition but durable retention of habits dependent on the visuostriatal circuit. (3) The object recognition and the 24 hr object-pair discrimination tasks that yielded this pharmacologically induced, double dissociation of deficits differed in several ways. One variable that might have been as important as the type of learning and memory tested was the length of the retention intervals. In the recognition task the interval between sample presentation and choice test lasted only several min. By contrast, in the discrimination task the interval between successive trials on a given pair lasted 24 hrs. To investigate the role of this large difference in retention interval, we made use of another, more common form of concurrent discrimination learning, one in which a set of discrimination problems is presented several times within a session as well as across sessions, such that the retention interval between successive trials within a session lasts only a few minutes. Unlike visual recognition at retention intervals of several minutes, which was impaired only by systemic scopolamine and also unlike visual discrimination learning at retention intervals of 24 hours, which was impaired only by systemic haloperidol visual discrimination learning at within-session retention intervals of several minutes was impaired by both of these drugs. The results indicate that the effects of the pharmacological agents depend not only on the type of acquisition being tested but also on the retention intervals used.

（1）在研究中首先证明了猴子对视觉识别的胆碱能贡献，表明该功能可以通过全身性胆碱能激动剂，Physostigmine和胆碱能拮抗剂Scopolamine，分别增强和损害。后来，当发现皮质是识别记忆证据的关键基板时，获得了对这种记忆的贡献的关键位置，这也是对这种记忆贡献的关键位置，因为（i）（i）（i）将这种识别记忆力直接造成了这种识别的障碍，但这种识别的记忆力直接使脊髓磷在这种识别中受到了影响。在选择性胆碱能免疫毒素输注后，输入了鼻皮层，将ME20.4-SAP输入到Rhinal Cortex中。这种免疫毒素导致注入皮层的胆碱能脱落，产生了与该区域兴奋性毒性病变所产生的识别量相同的大小，从而提供了迄今为止最直接的证明，即迄今为止，Rhinal Cortex的胆碱能激活对于存储新的视觉刺激的代表和该新的视觉刺激的代表是必不可少的。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。这些结果为刺激记忆的假设提供了初步支持，即刺激记忆取决于毒蕈碱和NMDA受体激活之间的相互作用，同时也是这种相互作用发生在周围皮质神经元内的概念。（2）我们已经证明，视觉对象识别是一种认知记忆的形式，取决于将腹侧视觉流与鼻皮层连接起来的电路，而对物体歧视习惯的获取需要将腹侧视觉流与腹膜新植物连接起来。为了确定这种解离是否还扩展到神经调节剂功能，我们在两个不同的触摸屏任务上测试了单独的动物组，研究了对系统施用的多巴胺能与毒蕈碱受体拮抗剂的性能的影响。对对象识别进行培训的组对单审对象识别任务进行了测试，该任务延迟了非匹配样本，列表长度为20个刺激。经过S-R习惯形成的小组以24小时的间隔学习了一组并发的20个对象对歧视。 Scopolamine在对象识别中产生了剂量依赖性的缺陷，但它对物体歧视习惯的形成没有影响。相反，尽管氟哌啶醇在形成对象歧视习惯时产生了剂量依赖性的缺陷，但它对物体识别没有影响。这些差异药物作用指出了由两个神经调节剂引起的突触修饰的差异，这些神经调节剂与两种类型的学习类型的对比特性相似，即快速获取，但在视觉回路中对记忆的保留较弱，而在缓慢的习得中，但依赖于依赖于耐粘性电路的海比特的保留。（3）对象识别和24小时的对象对歧视任务产生了这种药理诱导的，缺陷的双重分离在几种方面有所不同。一个可能与测试的学习类型和记忆类型一样重要的变量是保留间隔的长度。在识别任务中，样本演示和选择测试之间的间隔仅持续了几分钟。相比之下，在歧视任务中，给定对的连续试验之间的间隔持续了24小时。为了调查这种巨大的保留间隔差异的作用，我们利用了另一种更常见的并发歧视学习形式，其中一组歧视问题在一个会话中和整个会话中几次呈现，以便在会话中连续试验之间的保留间隔仅持续几分钟。与几分钟的保留间隔内的视觉识别不同，这仅受到全身性骨pol碱的损害，并且与在24小时的保留间隔内的视觉歧视学习不同，只有在几分钟内，这些药物都会损害几分钟的全身性氟哌啶醇视觉歧视学习，从而损害了这两种药物。结果表明，药理学剂的作用不仅取决于要测试的采集类型，还取决于所使用的保留间隔。