Working memory for social cues recruits orbitofrontal cortex and amygdala: a functional magnetic resonance imaging study of delayed matching to sample for emotional expressions.

During everyday interactions, we continuously monitor and maintain information about different individuals and their changing emotions in memory. Yet to date, working memory (WM) studies have primarily focused on mechanisms for maintaining face identity, but not emotional expression, and studies investigating the neural basis of emotion have focused on transient activity, not delay related activity. The goal of this functional magnetic resonance imaging study was to investigate WM for two critical social cues: identity and emotion. Subjects performed a delayed match-to-sample task that required them to match either the emotional expression or the identity of a face after a 10 s delay. Neuroanatomically, our predictions focused on the orbitofrontal cortex (OFC) and the amygdala, as these regions have previously been implicated in emotional processing and long-term memory, and studies have demonstrated sustained OFC and medial temporal lobe activity during visual WM. Consistent with previous studies, transient activity during the sample period representing emotion and identity was found in the superior temporal sulcus and inferior occipital cortex, respectively. Sustained delay-period activity was evident in OFC, amygdala, and hippocampus, for both emotion and identity trials. These results suggest that, although initial processing of emotion and identity is accomplished in anatomically segregated temporal and occipital regions, sustained delay related memory for these two critical features is held by the OFC, amygdala and hippocampus. These regions share rich connections, and have been shown previously to be necessary for binding features together in long-term memory. Our results suggest a role for these regions in active maintenance as well.

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

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.

Persistence of parahippocampal representation in the absence of stimulus input enhances long-term encoding: a functional magnetic resonance imaging study of subsequent memory after a delayed match-to-sample task.

Recent theoretical models based on cellular processes in parahippocampal structures show that persistent neuronal spiking in the absence of stimulus input is important for encoding. The goal of this study was to examine in humans how sustained activity in the parahippocampal gyrus may underlie long-term encoding as well as active maintenance of novel information. The relationship between long-term encoding and active maintenance of novel information during brief memory delays was studied using functional magnetic resonance imaging (fMRI) in humans performing a delayed matching-to-sample (DMS) task and a post-scan subsequent recognition memory task of items encountered during DMS task performance. Multiple regression analyses revealed fMRI activity in parahippocampal structures associated with the active maintenance of trial-unique visual information during a brief memory delay. In addition to a role in active maintenance, we found that the subsequent memory for the sample stimuli as measured by the post-scan subsequent recognition memory task correlated with activity in the parahippocampal gyrus during the delay period. The results provide direct evidence that encoding mechanisms are engaged during brief memory delays when novel information is actively maintained. The relationship between active maintenance during the delay period and long-term subsequent memory is consistent with current theoretical models and experimental data that suggest that long-term encoding is enhanced by sustained parahippocampal activity.

Sp and GATA factors are critical for Apolipoprotein AI downstream enhancer activity in human HepG2 cells.

The factors that bind to the hepatic-specific human apolipoprotein AI (apoAI) 48-bp downstream enhancer (DSE) were identified and characterized by electrophoretic mobility shift assays. A significant homology was shown between the histone 4 (H4) promoters and the hepatic-specific human apoAI DSE at Sp1 and H4TF2 binding sites. Human HepG2 nuclear extracts were used to form four specific complexes with the DSE (referred to as apoAI DSE-1, -2, -3, and -4). The apoAI DSE-1 and -2 complexes showed similar binding specificity to the Sp/H4TF1 consensus site within the apoAI DSE. The apoAI DSE-1 complex was predominantly recognized by anti-Sp1 and Sp3 sera in gel shift assays, indicating that the DSE was recognized by multiple Sp family members. Nuclear extracts that were prepared from retinoic acid treated HepG2 cells showed increased levels of Sp factors in gel shift and Western blot assays. The apoAI DSE-2 complex was identified as H4TF1 and formed in the absence of magnesium chloride. The apoAI DSE-3 complex bound to a consensus GATA element within the DSE that was recognized by recombinant human GATA-6 as well. The apoAI DSE-3 complex was completely disrupted by a GATA-4 antibody in EMSA. GATA-4 and -6 were detected in nuclear extracts prepared from retinoic acid treated HepG2 cells using Western blot assays. The highest apoAI DSE-3 levels were observed with retinoic acid treated HepG2 cell nuclear extracts in EMSA. ApoAI DSE-4 is a multi-factor complex that includes an Sp/H4TF1 factor and either H4TF2 or apoAI DSE-3. Because apoAI DSE mutations revealed transcription defects in transient transfection assays, we conclude that the entire DSE sequence is required for full apoAI transcriptional activity in HepG2 cells.