The memory impairment associated with Alzheimers disease has been associated with a loss in acetylcholine function and pathophysiology of the entorhinal/perirhinal, or rhinal cortex. We first demonstrated a cholinergic contribution to visual recognition memory in a series of studies showing that this function could be enhanced and impaired, respectively, by systemic administration of the cholinergic agonist, physostigmine, and the cholinergic antagonist, scopolamine. More recently we made infusions of a selective cholinergic immunotoxin, which lead to cholinergic deafferentation of the rhinal cortex and yielded recognition deficits of the same magnitude as those produced by excitotoxic lesions of this region. Substantial recognition memory deficits have been found following local infusions of the non-selective muscarinic antagonist scopolamine into the rhinal cortex. Scopolamine, however, includes antagonists of both m1 and m2 receptor subtypes. To assess the effects of selective blockade of muscarinic receptor subtypes, we infused either the m1-selective antagonist pirenzepine, or the m2-selective antagonist methoctramine directly into the rhinal cortex. Compared with control performance following saline infusions, injections of pirenzepine, but not of methoctramine, significantly impaired recognition accuracy. These findings suggest 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. In contrast to what we know about recognition memory and the importance of the rhinal cortex and cholinergic activity, we know much less about habit formation, the visuo-striatal processing stream and the responsible neuromodulator(s). The monkeys ability to learn a set of visual discriminations presented concurrently just once a day on successive days is based on habit formation and the visuo-striatal system. We recently found that performance on this 24-h ITI task is impaired by a striatal-function blocking agent, the dopaminergic antagonist haloperidol, and not by the rhinal-function blocking agent, the muscarinic cholinergic antagonist scopolamine. In a follow-up study we trained monkeys on a short-ITI 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. The number of trials to learn a discrimination list was reduced by half, from about 11 trials/pair on the 24-h ITI task to about 5 trials/pair on the short-ITI task. Learning on this faster discrimination task was impaired by systemic injections of either haloperidol or scopolamine. The results suggest that learning discriminations with the short ITIs within a session could be driven by both cognitive memory and habit formation working in concert. We then compared the effects of local, bilateral, microinfusions of the dopamine D2-selective antagonist eticlopride into the tail of caudate nucleus and ventral putamen, combined with microinfusions of scopolamine into the perirhinal cortex, with the effects of infusing equivalent volumes of saline into these same targets. The results suggest that while learning rates were similarly rapid following local saline infusions to these regions, the combined local drug administration impeded learning. Suggesting these different visuo-striatal and visuo-rhinal circuits operate in tandem during on some forms of learning.

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U.S. National Institute of Mental Health
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Turchi, Janita; Buffalari, Deanne; Mishkin, Mortimer (2008) Double dissociation of pharmacologically induced deficits in visual recognition and visual discrimination learning. Learn Mem 15:565-8