The proposed experiments will use cognitive and pharmacological manipulations coupled with functional MRI (fMRI) to test the modulatory regulation of memory formation. The experiments will test the hypothesis that acetylcholine enhances the sensory activation of cortical regions, and decreases interference from previously stored information during long term encoding and working memory. In Experiment #1, subjects will perform an encoding task using sequential lists of complex images in the fMRI scanner before and after iv injections of the centrally acting muscarinic cholinergic antagonist scopolamine, or after injections of the peripherally selective muscarinic antagonist glycopyrrolate. We predict that scopolamine, but not glycopyrrolate, will prevent an increase in fMRI activation during episodic encoding, and will be associated with a decrease in list-specific recognition. In Experiment #2, subjects will perform a delayed match to sample task in the scanner with either novel or familiar stimuli before and after scopolamine. We predict that activation of medial temporal lobe (MTL) regions will be stronger for novel stimuli relative to activation of prefrontal cortex (PFC) which will be stronger for familiar stimuli. Effects of scopolamine on task performance will be associated with changes in prefrontal cortex activation for the familiar task and changes in medial temporal activation for the novel task. In experiment #3, subjects will perform a two-back working memory task before and after infections of scopolamine. We predict that delay period activation will be stronger in PFC relative to MTL for this task, and scopolamine will decrease delay period activity and match enhancement. Experiment #4 will localize regions activated by face and house stimuli before and after encoding of paired associations. We predict that learning of associations will enhance the co-activation of these two regions, and that scopolamine will enhance this co-activation and proactive interference from associations learned before injections of scopolamine. The use of pharmacological manipulations provides an opportunity to test hypotheses by experimentally manipulating circuit level mechanisms important for cognitive tasks. This research is particularly relevant for understanding the cortical dynamics induced by cholinergic modulation, This isrelevant to the pathological states of low cholinergic innervation in Alzheimer's disease and Lewy-body dementia, and the potential therapeutic efficacy of different agents, including acetyleholinesterase inhibitors and other agents on selective processes involved in human memory.
