One of the first indications of the importance of the cholinergic system in memory function was that the memory impairment associated with Alzheimers disease was associated with the loss of large cholinergic neurons of the basal forebrain and pathophysiology of the entorhinal/perirhinal, or rhinal cortex. 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 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 recognition memory performance was impaired by microinfusing scopolamine directly into rhinal cortex. More recently we made infusions of a selective cholinergic immunotoxin, which lead to cholinergic deafferentation of the infused cortex and 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 of visual representations and thereby enabling their later recognition. This past year we began a series of experiments to assess the effects on recognition memory of selective blockade of muscarinic receptor subtypes. We infused either the m1-selective antagonist pirenzepine, or the m2-selective antagonist methoctramine directly into the perirhinal cortex (PRh) of monkeys performing one-trial visual recognition, and compared these scores with those following infusions of equivalent volumes of saline. Animals received a series of bilateral intra-PRh microinfusions. Compared with control performance following saline infusions, injections of pirenzepine, but not of methoctramine (at concentrations that afford selectivity for the m2 receptor), significantly impaired recognition accuracy. These findings support the view that m1 and m2 receptor subtypes in the perirhinal cortex have functionally dissociable roles, and that visual recognition memory is critically dependent on the m1 receptor subtype. Previously we 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. We have now extended this dissociation to neuromodulatory function by comparing the effects on performance of systemic administration of muscarinic (scopolamine) vs dopaminergic (haloperidol) receptor antagonists on object recognition and object discrimination learning (S-R habit formation). 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. An important variable that differed between the two tasks used to uncover this double dissociation of deficits, and that may have been just as critical as the type of learning process tested, was the duration of the retention interval. In the recognition task (delayed nonmatching-to-sample with list lengths of 20 trial-unique stimuli), the interval between sample presentation and choice test lasted only about 10 minutes, whereas in the discrimination task (concurrent discrimination learning of 20 stimulus pairs), the interval between successive trials on a given pair lasted 24 hours. To investigate the role of this large difference in retention interval, monkeys were trained on a short inter-trial interval form of concurrent visual discrimination learning, one in which a set of stimulus pairs is repeated not only across daily sessions but also several times within each session (in this case, at about 4-min intervals). Asymptotic discrimination learning rates in the non-drug condition were reduced by half, and this faster learning was impaired by systemic injections of either haloperidol or scopolamine. The results suggest that the short-ITI version of the concurrent discrimination task recruits both the visuorhinal and visuostriatal circuits, and that the relatively quick learning is therefore enabled by cognitive memory and habit formation working in concert.
