Molecular Structure and Catalytic Activity of Membrane-Bound Acetylcholinesterase from Electric Organ Tissue of the Electric Eel

The catalytic activity of membrane-bound acetylcholinesterase in electric organ tissue was shown to be governed by diffusion- controlled substrate and hydrogen ion gradients, generated by acetylcholinesterase-catalysed hydrolysis leading to a lower substrate concentration and pH in the vicinity of the particulate enzyme. Various solubilization procedures, including extraction with salts and detergents, chemical modification proteolysis showed that interaction of most of the acetylcholinesterase with the excitable membrane is primarily electrostatic, but that part of the enzyme seems to be more intimately associated with the membrane. \u27Native\u27 acetylcholinesterase, as isolated from fresh electric organ tissue, is a complex molecular structure in which a multisubunit head is connected to an elongated tail. Proteolytic digestion or autolysis leads to detachment of the tail and conversion of acetylcholinesterase to a globular tetramer containing four similar subunits in which each pair is connected by disulfide bonds. Further digestion leads to cleavage of the individual polypeptide chains of the subunits which are not, however, released unless the enzyme is denatured. The possible modes of attachment of the \u27native\u27 acetylcholinesterase molecule to the excitable membrane are discussed

Blockade of Cochlear NMDA Receptors Prevents Long-Term Tinnitus during a Brief Consolidation Window after Acoustic Trauma

Tinnitus, the perception of sound in the absence of external acoustic stimulation, is a common and devastating pathology. It is often a consequence of acoustic trauma or drug toxicity. The neuronal mechanisms of tinnitus are neither yet fully understood nor are effective treatments available. Using a novel behavioral paradigm for measuring tinnitus in the rat based on tone-guided navigation, we show here that the development of long-term noise-induced tinnitus, the most prevalent and clinically important form of human tinnitus, can be abated by local administration of the NMDA antagonist “ifenprodil” into the cochlea in the first 4 days following the noise insult but not afterwards. This suggests that long-term tinnitus undergoes a consolidation-like process, resembling the ontogeny of items in long-term memory. Furthermore, this finding paves the way to potential therapeutic strategies for the prevention of chronic tinnitus once the noise insult had taken place

Signatures of Memory: Brain Coactivations during Retrieval Distinguish Correct from Incorrect Recollection

Are specific distributed coactivations in the brain during memory retrieval a signature of retrieval outcome? Here we show that this is indeed the case. Widespread brain networks were reported to be involved in the retrieval of long-term episodic memories. Although functional coactivation among particular regions occurs during episodic memory retrieval, it is unknown to what extent it contributes to the accuracy and confidence of recollection. In this study we set out to explore this question. Participants saw a narrative documentary movie. A week later they underwent an fMRI scan during which they either accepted or rejected factual or fictitious verbal statements concerning the movie. Correct vs. incorrect responses to factual statements were more common and were provided with higher confidence than those made to fictitious statements. Whereas activity in the retrieval network correlated mostly with confidence, coactivations primarily correlated with memory accuracy. Specifically, coactivations of left medial temporal lobe regions with temporal and parietal cortices were greater during correct responses to factual statements, but did not differ between responses to fictitious statements. We propose that network coactivations play a role in recovering memory traces that are relevant to online retrieval cues, culminating in distinct retrieval outcomes

The Privileged Brain Representation of First Olfactory Associations

SummaryAuthors [1], poets [2], and scientists [3–6] have been fascinated by the strength of childhood olfactory memories. Indeed, in long-term memory, the first odor-to-object association was stronger than subsequent associations of the same odor with other objects [7]. Here we tested the hypothesis that first odor associations enjoy a privileged brain representation. Because emotion impacts memory [8–10], we further asked whether the pleasantness of an odor would influence such a representation. On day 1, we associated the same visual objects initially with one, and subsequently with a second, set of pleasant and unpleasant olfactory and auditory stimuli. One week later, we presented the same visual objects and tested odor-associative memory concurrent with functional magnetic resonance brain imaging. We found that the power (% remembered) of early associations was enhanced when they were unpleasant, regardless of whether they were olfactory or auditory. Brain imaging, however, revealed a unique hippocampal activation for early olfactory but not auditory associations, regardless of whether they were pleasant or unpleasant. Activity within the hippocampus on day 1 predicted the olfactory but not auditory associations that would be remembered one week later. These findings confirmed the hypothesis of a privileged brain representation for first olfactory associations

They saw a movie: Long-term memory for an extended audiovisual narrative.

We measured long-term memory for a narrative film. During the study session, participants watched a 27-min movie episode, without instructions to remember it. During the test session, administered at a delay ranging from 3 h to 9 mo after the study session, long-term memory for the movie was probed using a computerized questionnaire that assessed cued recall, recognition, and metamemory of movie events sampled ∼20 sec apart. The performance of each group of participants was measured at a single time point only. The participants remembered many events in the movie even months after watching it. Analysis of performance, using multiple measures, indicates differences between recent (weeks) and remote (months) memory. While high-confidence recognition performance was a reliable index of memory throughout the measured time span, cued recall accuracy was higher for relatively recent information. Analysis of different content elements in the movie revealed differential memory performance profiles according to time since encoding. We also used the data to propose lower limits on the capacity of long-term memory. This experimental paradigm is useful not only for the analysis of behavioral performance that results from encoding episodes in a continuous real-life-like situation, but is also suitable for studying brain substrates and processes of real-life memory using functional brain imaging. Experimental protocols that probe brain correlates of episodic memory formation commonly use paradigms in which memoranda are presented as individual items devoid of continuous context outside of the laboratory setting Movies are capable of simulating aspects of real-life experiences by fusing multimodal perception with emotional and cognitive overtones Here, we describe the use of a 27-min narrative movie to investigate long-term cued recall and recognition as well as metamemory judgments. We measured memory performance of several groups of participants, each at a different delay ranging from 3 h to 9 mo after watching the movie, by probing memory for events occurring in the movie ∼20 sec apart. Participants remembered many events in the movie that they had seen only once without prior instructions to remember it, even months after watching it. We have dissected multiple facets of memory and metamemory as a function of time and type of occurrence in the movie. Our analysis also suggests lower limits on the capacity of long-term memory for a real-life-like situation. Results Memory of the movie persists for months The first set of experimental groups watched the movie and answered the questionnaire ( Heuristic subdivisions in long-term memory Pairwise comparisons among all groups, corrected for multiple comparisons, reveal superior performance of the 3-h, 1-wk, and 3-wk groups compared with the 3-mo and 9-mo groups ( Recall attempts over time Participants made fewer attempts at recall as more time passed between study and test sessions ( Memory confidence over time The proportions of all answers made at different levels of confidence were compared across time-interval groups, revealing a surprisingly stable proportion of high-confidence recognition (HCR) answers over time, and a significant decrease in the use of recall over time. In contrast, the proportion of low-confidence recognition (LCR) and guess answers significantly increased over time ( One might expect a smaller proportion of correct answers as confidence declines with the passage of time. To test this assumption, the proportion of correct answers was calculated from all answers made in each level of confidence Furthermore, the main group effect suggests that distribution of correct answers between the four possible levels of confidence is uneven among time-interval groups. The interaction between these two main effects, time and confidence-level, was further explored by performing pairwise contrasts, revealing performance differences that further support differentiation of ST and LT groups. As can be seen in The findings described above indicate that confidence measures of memory are time-sensitive: more high-confidence answers (using recall and HCR) are used after short time durations, while more lower-confidence answers (LCR and guessing) are used after longer time durations. We further sought to characterize the temporal dynamics of metamemory measures using analysis of answers by confidence level. We find that on the one hand, proportion of overall use of recall declines over time Memory density The availability of memory performance scores that sample events every 20 sec in a 27-min episode renders it tempting to attempt tapping into long-term memory capacity per unit time, or density (Dudai 1997). Any such attempt is bound to yield only rough estimates. First, formal units that might be used for quantifying the stored memory, such as bits Using the algorithm specified in the Materials and Methods, we estimate that 56% of information in the movie is remembered after 3 h, while 53%, 39%, 25%, and 19% are remembered after 1 wk, 3 wk, 3 mo, and 9 mo, respectively. Equating for the sake of calculation a memory unit as a questionnaire item to be answered correctly and assuming independence among items, Long-term memory of a movie Learning & Memory 459 www.learnmem.org Cold Spring Harbor Laboratory Press on December 7, 2007 -Published by www.learnmem.org Downloaded from hence, 77 items that could be potentially encoded over 27 min, this implies retrievability ranging from 1.6 items per minute movie after 3 h to 1.4 and 1.0 items per 2 min after 3 and 9 mo, respectively. The robustness of the assumptions involved and the relevance to previous estimates of long-term memory capacity are discussed below. Recall and recognition as function of memory content Six independent raters were asked to classify the questions into eight predetermined categories (while allowing overlap of categories). Questions were then grouped into nonoverlapping clusters based on 66% agreement among raters. Clusters included plot themes, social interactions, couple relationship, and jokes and minor details (13, 19, 6, 5, and 14 questions, respectively). "Social interactions" is a nonoverlapping broader category than "couple relationship," and did not include questions relating to interactions between the central character and his partner, which were included in the "couple relationship" cluster. Twenty of 77 items in the memory questionnaire were not entered into analysis, as the agreement criterion was not reached. For each content cluster, we examined proportion of recall and recognition attempts We find that narrative elements and social interactions between characters are remembered best ("plot themes" questions elicited close to 100% accuracy in all ST groups). Questions about "jokes" and "details" elicit less recall attempts and answer accuracy declines more rapidly and drastically than for all other question clusters. Better performance of ST groups relative to LT groups is established for all content clusters, while comparison of time-dependent performance decline (i.e., curve slope) between content clusters approached significance only for correct recall performance. Significant main effects of content and time-interval group were found (recall attempts: content F (4,3224) = 62.27, P < 0 . 0 0 0 1 , t i m e -i n t e r v a l g r o u p F (4,44.13) = 4.96, P < 0.002; correct recall: content F (4,874) = 8.02, P < 0.0001; timei n t e r v a l g r o u p F ( 4 , 7 5 . 5 4 ) = 8 . 4 9 , P < 0.0001). The interaction between these effects (difference in performance between content clusters as a function of time-interval group, or comparison of slopes) was insignificant for both analyses, but approached significance for correct recall (recall attempts: F (16,3224) = 1.1, P < 0.35; correct recall: F (16,874) = 1.52, P < 0.09). In order to further explore main effects, pairwise contrasts were performed separately according to time-interval groups It is noteworthy that the division of LTM performance into ST and LT groups, introduced above on the basis of analysis of correct and incorrect answers, is also supported by the analysis of content-based correct recall answers, and is partially supported by analysis of content-based recall attempts. Subjects in the ST groups made significantly more recall attempts and more correct recall answers, per content cluster, than subjects in the LT groups. (Two exceptions are the "couple relationship" question cluster, which elicited a high proportion of correct recall answers throughout the tested span, and proportion of recall attempts of the 3-wk group that did not differ from both LT groups; Tables 1, 3.) While superior performance across content clusters is found Cold Spring Harbor Laboratory Press on December 7, 2007 -Published by www.learnmem.org Downloaded from for the ST groups, different content clusters elicited significantly different performance profiles over time. This is illustrated by observing that the starting point of maximal value for forgetting curves varies between plots of different content clusters We should qualify our finding that memory performance can be differentiated according to content elements, as it seems that time since encoding is also an important factor in rendering this differentiation evident. Further examination of correct recall data, where interaction between content and group effects was found to only approach significance, was performed using post hoc comparisons. When examining content effects within timeinterval groups, significant differences between content clusters were found in all but the 3-h and 1-wk groups Manipulation of movie and questionnaire did not diminish memory We further tested whether certain manipulations of the movie during the study session, or of the questionnaire in the test session, or both, will affect memory performance. A separate set of experimental groups all participated in the test session 3 wk after watching the movie, but were subjected to manipulated study or test material. Manipulations were either in the order of content material (scrambling the order of scenes in the movie or the questions in the test) or in perceptual attributes (eliminating color from the movie). One experimental group performed an interference protocol, in which subjects watched a different episode from the same sitcom at the beginning of the test session, and immediately afterward completed the original computerized questionnaire. No significant differences were found in performance (correct answers, collapsing confidence levels) between manipulation protocols and the original 3-wk group (unaltered movie and test, n = 8, 78.79 ‫ע‬ 2.02% correct; scrambled version of the movie followed by regular test, n = 10, 79.87 ‫ע‬ 2.38% correct; unaltered movie followed by scrambled test, n = 6, 73.81 ‫ע‬ 2.97% correct; scrambled movie followed by scrambled test, n = 7, 73.1 ‫ע‬ 2.76% correct; interference protocol, n = 7, 73.28 ‫ע‬ 2.39% correct; regular movie in black and white and regular test using black and white frames as visual cues, n = 6, 70.35 ‫ע‬ 2.99% correct; F (5,40.25) = 2.24, P < 0.07). It is noteworthy that although some of the manipulations did show a trend for decreased performance, scrambling of the order of the scenes in the movie itself had no effect whatsoever. The potential implication of this finding to the encoding of the study material is discussed below. Discussion We describe a memory paradigm in which the study material is a 27-min narrative movie. This paradigm was intended to mimic aspects of "real-life" learning and memory under controlled experimental settings. We tested the memory once, in delays ranging from 3 h to 9 mo after the study session. The test targeted events that occur in the movie every ∼20 sec. We found that details from the movie, which the participants watched only once without prior instruction to remember it, were remembered well over several months. Multiple performance measures indicate that long-term memory after hours-to-weeks is different from memory performance after several months. Recall answers, which we considered as the highest confidence answers, proved to be reliable measures of memory only for shorter durations, while HCR answers were highly reliable throughout the measured time span. Despite manipulation of movie and test materials, meant to disrupt narrative construction during encoding and/or retrieval, memory performance was unaffected. One possible explanation is that subjects were still able to successfully reconstruct the narrative from the scrambled segments. We further demonstrate that information content significantly influences memorability over time (though some time is needed for this effect to become evident). Finally, we use the unique resolution of our memory questionnaire to suggest that memory capacity for real-life information might be higher than previously estimated. In clinical neurology and in cellular neurobiology, memory after 3 h is already long-term memory, and memory after 9 mo could be considered remote memory. Studies of human longterm memory and remote memory are abundant in the literature (for review, se