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.

Cholinergic Stimulation Enhances Neural Activity Associated with Encoding but Reduces Neural Activity Associated with Retrieval in Humans

“…Under placebo, there was no such effect, resulting in a significant interaction effect between pharmacological condition and spatial context encoding. These data provide direct evidence for an enhancing effect of cholinergic stimulation on encoding at the neural level in humans and complement previous findings that cholinergic inhibition by administration of the muscarinic receptor antagonist scopolamine reduces neural activity during encoding in the hippocampus and parahippocampal gyrus (Sperling et al, 2002;Schon et al, 2005). It is important to note that the application of physostigmine generally elevated ACh-levels and thus affected both nicotinic and muscarinic receptors.…”

Working Memory for Social Cues Recruits Orbitofrontal Cortex and Amygdala: A Functional Magnetic Resonance Imaging Study of Delayed Matching to Sample for Emotional Expressions

“…In addition to sustained activity in the OFC and amygdala, we also found sustained activity within the hippocampus. Previous fMRI data has demonstrated a role for MTL structures, including the hippocampus and surrounding parahippocampal cortex, in the short term maintenance of novel information (Ranganath and D'Esposito, 2001;Stern et al, 2001;Ranganath et al, 2003Ranganath et al, , 2005Schon et al, 2004;Schon et al, 2005). Based on the rich connections between the hippocampus, amygdala, and OFC (Barbas, 2000;Insausti and Munoz, 2001;Munoz and Insausti, 2005), we suggest that together these areas form a circuit that binds together and actively maintains emotion and identity information in WM.…”

“…Analysis of BOLD activity during the delayed match-to-sample task was assessed with multiple regression with near orthogonal regressors using the SPM2 software package. This approach has been successfully used to assess delay period activity in fMRI studies with delayed-match-to-sample tasks (Courtney et al, 1997(Courtney et al, , 1998Postle and D'Esposito, 1999;Schon et al, 2004;Schon et al, 2005). As originally proposed by Courtney et al (1997), and similar to Postle et al (2000) and previous work in our laboratory (Schon et al, 2004;Schon et al, 2005), we created six regressors that reflected the comparisons of interest and convolved them with a Gamma hemodynamic response function (HRF) (Boynton et al, 1996) in Matlab 6.5 (MathWorks, Natick, MA).…”

“…This approach has been successfully used to assess delay period activity in fMRI studies with delayed-match-to-sample tasks (Courtney et al, 1997(Courtney et al, , 1998Postle and D'Esposito, 1999;Schon et al, 2004;Schon et al, 2005). As originally proposed by Courtney et al (1997), and similar to Postle et al (2000) and previous work in our laboratory (Schon et al, 2004;Schon et al, 2005), we created six regressors that reflected the comparisons of interest and convolved them with a Gamma hemodynamic response function (HRF) (Boynton et al, 1996) in Matlab 6.5 (MathWorks, Natick, MA). The regressors consisted of the following comparisons: regressor 1 assessed activation caused by nonspecific visual stimulation, regressor 2 assessed the difference between DMS stimuli and CON stimuli, regressor 3 assessed the difference between the sample stimulus and the test stimulus for CON trials, regressor 4 assessed the difference between the sample stimulus and the test stimulus for DMS trials, regressor 5 assessed differences in activity during task delays (across tasks) versus during the ITI, and regressor 6 assessed the difference between activity during the DMS delay versus activity during the CON delay (see Fig.…”

Grid cell mechanisms and function: Contributions of entorhinal persistent spiking and phase resetting

“…The mechanisms of intrinsic persistent firing in single neurons could contribute to persistent spiking shown with unit recording during the delay period of delayed matching to sample tasks in awake, behaving rats (Young et al, 1997) and monkeys (Suzuki et al, 1997). Persistent spiking could also underlie persistent fMRI activation appearing during delay periods in human memory tasks, which can be reduced by muscarinic cholinergic blockade (Schon et al, 2004(Schon et al, , 2005Hasselmo and Stern, 2006).…”