Pharmacology Of Stimulus Memory And Habit Formation

National Institute Of Mental Health

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Abstract

(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.