Scopolamine reduces persistent activity related to long-term encoding in the parahippocampal gyrus during delayed matching in humans

Abstract

Recent computational modeling and slice physiology studies have suggested that long-term encoding may depend on sustained spiking during brief memory delays in parahippocampal neurons, and that this persistent spiking activity is modulated by effects of acetylcholine at muscarinic receptors. Our recent functional magnetic resonance imaging (fMRI) study has shown that sustained parahippocampal delay period activity during delayed match-to-sample performance in healthy young individuals predicted subsequent memory of visual stimuli on a recognition memory assessment 20 min later (Schon et al., 2004). The current study combined this fMRI paradigm with a pharmacological manipulation to test whether this long-term encoding-related delay activity is reduced in subjects who receive the muscarinic cholinergic antagonist scopolamine before fMRI scanning. Subsequent memory was predicted by sustained activity during brief memory delays bilaterally in the perirhinal/entorhinal cortex, in the right posterior parahippocampal and mid-fusiform gyri, and in the hippocampal body in healthy young individuals without a scopolamine challenge. This activity was reduced in subjects receiving scopolamine. The results are consistent with computational modeling data and behavioral pharmacological studies, suggesting that long-term encoding-related activity may be reduced if cholinergic receptors are blocked by scopolamine.

Figure 1.

Behavioral tasks. A, Scanning tasks. Subjects saw the sample picture for 2 s, followed by a 10 s delay during which a gray box appeared, followed by a test picture presentation for 2 s, followed by a variable-length ITI (6-14 s) during which a fixation cross appeared. DMS and CON tasks differed only in instruction. The DMS task required the subject to indicate whether the test picture matched the sample picture, and the CON task required the subject to indicate whether the test picture was indoors or outdoors. B, Post-scan SMT. The subject saw all stimuli again from both DMS and CON tasks and an equal number of new stimuli. The task required the subject to indicate on a five-point rating scale their confidence on whether a given picture was old (previously seen) or new (never seen before). Stimuli were shown on black background.

Figure 2.

Behavioral results. A, The proportions of correct responses on DMS and CON task performance are depicted on the left, and the mean of the median RTs (in milliseconds) on DMS and CON task performance are depicted on the right. B, Response proportions on postscan subsequent memory rating for sample stimuli that were seen twice (match trials; top left), for sample stimuli that were seen once (nonmatch trials; top right), and for new stimuli (lures; bottom left) that were not seen before the postscan SMT was performed. The rating scale ranged from 1 (high confidence new) to 5 (high confidence old). Gray bars depict results for the NO DRUG group, and white bars depict results for the SCOP group.

Figure 3.

fMRI activation from the active maintenance analysis. Only activation within ROIs is superimposed on canonical average T1-weighted ICBM/MNI brain. A, NO DRUG group shows right mid-FG/PHG activity, y = -34, depicted on left, and left mid-FG/PHG, y = -48, depicted on right. B, Same as in A for SCOP group. C, Greater activation for the NO DRUG group compared with the SCOP group in the right mid-FG/PHG, y = -34, depicted on the left, and in the left mid-FG/PHG, y = -46, depicted on the right. D, Corrected signal intensities during sample presentation (S), delay period (DELAY), and test presentation (T) from the right mid-FG/PHG for the NO DRUG group, depicted on the left, and for the left mid-FG/PHG for the NO DRUG group, depicted on the right. E, Same as D but for the SCOP group. y-Axes, Signal intensity grand mean scaled to 100 and global calculation using mean voxel value (within per image full mean/8 mask). R, Right hemisphere; L, left hemisphere.

Figure 4.

fMRI activation from long-term encoding analysis. Only activation within ROIs is superimposed on canonical average T1-weighted ICBM/MNI brain. A, NO DRUG group, right posterior PHG, y = -26, depicted on left (arrow), and right (arrow) and left PRC/ERC, y = -10, depicted on right (from nonmatch trials). B, Same as in A for SCOP group. C, Greater activation for the NO DRUG group compared with the SCOP group in the right posterior PHG (across DMS trials), y = -30, depicted on the left, and in the right (and left) PRC/ERC (across DMS trials), y = -16, depicted on the right. D, Corrected signal intensities during sample presentation (S), delay period (DELAY), and test presentation (T) from the right posterior PHG for the NO DRUG group, depicted on the left, and for the right PRC/ERC for the NO DRUG group, depicted on the right (from nonmatch trials). E, Same as D but for the SCOP group. y-Axes, Signal intensity grand mean scaled to 100 and global calculation using mean voxel value (within per image full mean/8 mask). R, Right hemisphere; L, left hemisphere.

Figure 5.

fMRI activation from long-term encoding analysis. Only activation within ROIs is superimposed on canonical average T1-weighted ICBM/MNI brain. A, NO DRUG group, hippocampal body activation, bilateral, y = -26, for nonmatch trials (stimuli seen once), depicted on the left, and absence of hippocampal head activation, y = -2, for match trials (stimuli seen twice), depicted on the right. B, Opposite pattern as in A for SCOP group with absence of hippocampal body activation, y = -26, for nonmatch trials (stimuli seen once), depicted on the left, and presence of hippocampal head activation, y = -2, for match trials (stimuli seen twice), depicted on the right. C, Greater activation for the NO DRUG group compared with the SCOP group in the right and left hippocampal body, y = -26, for nonmatch trials (stimuli seen once), depicted on the left, and greater activation for the SCOP group compared with the NO DRUG group in the right (and left) hippocampal head/uncus, y = -4, for match trials (stimuli seen twice), depicted on the right. D, Corrected signal intensities during sample presentation (S), delay period (DELAY), and test presentation (T) from the right hippocampal body for nonmatch trials (stimuli seen once), in the NO DRUG group, depicted on the left, and for the left hippocampal body for match trials (stimuli seen twice), in the NO DRUG group, depicted on the right. E, Same as D but for the SCOP group. y-Axes, Signal intensity grand mean scaled to 100 and global calculation using mean voxel value (within per image full mean/8 mask). R, Right hemisphere; L, left hemisphere.