Neural Substrates Of Stimulus Recognition And Association Memory

我们在这个项目上的最新工作使用了两种记忆测量方法，都涉及对象。有一种记忆，称为配对联想学习，涉及两种不同视觉刺激之间的任意关联。记忆的第二种测量方法涉及视觉刺激和空间定向反应之间的任意关联，称为视觉条件学习。众所周知，痴呆症患者在获得任意联想方面很差，因此这些行为可以作为记忆功能的可靠指标。 在视觉条件学习中，受试者在触摸屏上看到三个图像中的一个，并学习三个相同的目标框中的哪一个是正确的。目标框显示在固定位置。如果受试者选择了图像提示的正确位置进行试验，就会获得奖励。从本质上讲，受试者了解到每个图像都与特定的空间定向目标或响应相关联。受试者在使用新刺激的会话中一次学习三个问题，称为新会话，因为他们使用新的刺激需要形成新的联想记忆。此外，行为可以与熟悉的记忆进行比较，这些记忆使用了良好的学习刺激。这些会议被称为熟悉的会议。在配对联想学习中，被试以与视觉条件学习相同的方式看到图像。不同的是，他们选择一个与之相关的目标图像，而不是一个固定位置的目标框。就像在视觉条件学习中一样，在新的和熟悉的会话中的行为可以被对比。 有证据表明，海马系统是不必要的配对联想学习。Murray等人（1993）发现，配对联想学习不受海马体完全移除的影响。这可能意味着，当关联的两个组成部分都没有相关的空间属性时，海马系统对于关联学习是不必要的。但最近对该项目的研究似乎排除了这种说法（Brasted等人，2002年、2003年、2005年）。这项研究表明，即使在视觉刺激和反应都是非空间分化的情况下，海马系统的损伤，特别是穹窿的横断，也会损害视觉条件性联想的快速学习。这一发现为Murray等人（1993）描述的结果指出了另一种可能性。根据我们对配对联想学习结果的解释，没有缺陷，因为受试者在之前的研究中学习配对联想很慢。这一假说预测，大脑皮层系统的损伤可能会导致成对联想者快速学习的缺陷。因此，我们正在从事测试的作用，海马在配对联想学习使用快速学习程序。这项研究测试了海马功能的一个更普遍的理论，该理论认为海马作为一个模式关联网络有助于快速获取信息，而新皮层获取类似的信息，但速度更慢。在配对联想学习的背景下，这一理论意味着，嗅周皮层（一个新皮层区域）支持较慢的学习形式，海马系统支持较快的学习形式。我们现在已经开发出了程序，允许受试者获得视觉条件和配对协会迅速，在一个单一的测试会话。该项目的结果可以解决有关海马和嗅周皮质功能的关键问题。 这个项目的第二个目的是确定海马系统的哪一部分对于快速视觉条件学习是必不可少的。为了确定海马体在这项任务中的作用，我们评估了向海马体中双侧注入神经抑制剂或生理盐水对行为的影响。我们的数据表明，相对于盐水输注或不输注，海马失活对视觉条件性学习没有影响。对于新的和熟悉的会议，海马失活并没有损害整体性能或跨块试验的学习速度。这些发现表明，海马体以外的区域，无论是单独还是与海马体一起，都有助于完成这项任务。候选者包括下托复合体和内嗅皮层。因此，我们评估了视觉条件学习和表现的MTL，内嗅皮层的另一个结构的贡献。内嗅皮层不仅是海马体输入的主要来源，而且还广泛投射到与记忆有关的其他皮层区域，包括内侧前额叶皮层。内嗅皮质的双侧失活会损害熟悉和新奇会话的表现，并减慢新奇会话期间的会话内学习率。 这个项目的未来目标是研究MTL-前额叶互动在快速联想学习中的作用。我们预测，直接和间接的前额叶-海马连接，分别通过穹窿和内嗅皮层，是快速，任意的联想学习的两种类型在这个项目中研究的关键。如果得到证实，这一假设可能会促进治疗干预措施的发展，目的是在损伤或疾病破坏另一个途径时促进一个途径。

Our most recent work on this project has made use of two measures of memory, both involving objects. One type of memory, known as paired associate learning, involves the arbitrary association between two different visual stimuli. A second measure of memory involves the arbitrary association between visual stimuli and spatially-directed responses, known as visuomotor conditional learning. Amnesic patients are notoriously poor in acquiring arbitrary associations, and so these kinds of behavior serve as reliable indicators of memory function. In visuomotor conditional learning, subjects are presented with one of three images on a touch screen and learn which one of three identical target boxes is correct on that trial. The target boxes appear in fixed locations. If the subject chooses the correct location cued by the image for that trial, a reward is delivered. In essence, the subjects learn that each image is associated with a particular spatially directed goal or response. Subjects learn three problems at a time in sessions with novel stimuli, called novel sessions, which because they use new stimuli require the formation of new associative memories. In addition, behavior can be compared for familiar memories, which use well learned stimuli. These sessions are called familiar sessions. In paired associate learning, subjects see images in the same way as in the visuomotor conditional learning. The difference is that they choose a target image associated with it rather than a target box in a fixed location. As in visuomotor conditional learning, behavior on novel and familiar sessions can be contrasted. There is evidence that the hippocampal system is not necessary for paired associate learning. Murray et al. (1993) found that paired associate learning was unaffected by complete removal of the hippocampus. This could mean that the hippocampal system is unnecessary for associative learning when neither component of the association has a relevant spatial attribute. But recent work on this project appears to rule out that account (Brasted et al., 2002, 2003, 2005). This research showed that hippocampal-system damage, specifically a transection of the fornix, impaired fast learning of visuomotor conditional associations even when both the visual stimuli and the responses were nonspatially differentiated. This finding points to another possibility for the results described by Murray et al. (1993). According to this explanation of our paired associate learning results, there was no deficit because subjects learned the paired associates slowly in that prior study. This hypothesis predicts that hippocampal-system damage might cause deficits in the fast learning of paired associates. Accordingly, we are engaged in testing the role of the hippocampus in paired associate learning using a fast learning procedure. This research tests a more general theory of hippocampal function, which holds that it subserves rapid acquisition, as a pattern-associator network, whereas the neocortex acquires similar information, but more slowly. In the context of paired associate learning, this theory implies that the perirhinal cortex, a neocortical area, subserves the slower form of learning and that the hippocampal system subserves the faster form. We have now developed procedures that allow subjects to acquire both visuomotor conditional and paired associations rapidly, within a single testing session. The results from this project could resolve crucial issues about hippocampal and perirhinal cortex function. A second aim of this project is to determine what part of the hippocampal system is essential for fast visuomotor conditional learning. To determine the role of the hippocampus in this task, we assessed the effects on behavior of bilateral infusions into the hippocampus of a neural inhibitor or saline. Our data indicate that there is no effect of hippocampal inactivation on visuomotor conditional learning relative to saline infusion or no infusion. For both novel and familiar sessions, hippocampal inactivation did not impair the overall performance or the rate of learning across blocks of trials. These findings suggest that regions outside the hippocampus proper, either alone or together with the hippocampus, contribute to performance on this task. Candidates include the subicular complex and the entorhinal cortex. Accordingly, we assessed the contribution to visuomotor conditional learning and performance of one other structure in the MTL, the entorhinal cortex. The entorhinal cortex is not only a major source of inputs to the hippocampus, but also has widespread projections to other cortical fields implicated in memory, including the medial prefrontal cortex. Bilateral inactivation of the entorhinal cortex impaired performance on both familiar and novel sessions, and slowed the within-session learning rate during novel sessions. A future aim of this project is to examine the role of MTL-prefrontal interactions in fast associative learning. We predict that both direct and indirect prefrontal-hippocampal connections, via the fornix and entorhinal cortex, respectively, are critical for rapid, arbitrary associative learning of both types studied in this project. If confirmed, this hypothesis could promote the development of therapeutic interventions aimed as facilitating one pathway when damage or disease disrupts the other.