PKG-mediated MAPK signaling is necessary for long-term operant memory in Aplysia

Signaling pathways necessary for memory formation, such as the mitogen-activated protein kinase (MAPK) pathway, appear highly conserved across species and paradigms. Learning that food is inedible (LFI) represents a robust form of associative, operant learning that induces short- (STM) and long-term memory (LTM) in Aplysia. We investigated the role of MAPK signaling in LFI memory in vivo. Inhibition of MAPK activation in animals prior to training blocked STM and LTM. Discontinuing MAPK signaling immediately after training inhibited LTM with no impact on STM. Therefore, MAPK signaling appears necessary early in memory formation for STM and LTM, with prolonged MAPK activity required for LTM. We found that LFI training significantly increased phospho-MAPK levels in the buccal ganglia. Increased MAPK activation was apparent immediately after training with greater than basal levels persisting for 2 h. We examined the mechanisms underlying training-induced MAPK activation and found that PKG activity was necessary for the prolonged phase of MAPK activation, but not for the early MAPK phase required for STM. Furthermore, we found that neither the immediate nor the prolonged phase of MAPK activation was dependent upon nitric oxide (NO) signaling, although expression of memory was dependent on NO as previously reported. These studies emphasize the role of MAPK and PKG in negatively reinforced operant memory and demonstrate a role for PKG-dependent MAPK signaling in invertebrate associative memory.     

The amygdala is involved in the modulation of long-term memory, but not in working or short-term memory

Rats with cannulae implanted in the junction between the central and the basolateral nuclei of the amygdala were trained in one-trial step-down inhibitory avoidance and tested at 3 s for working memory (WM) or 1.5 or 24 h later for short-term memory (STM) and long-term memory (LTM), respectively. Several drugs were infused 6 min prior to training in the animals in which WM was measured or 0 min posttraining in those in which STM and LTM were measured: the glutamate receptor antagonists CNQX (0.5 microg) and AP5 (5.0 microg), the indirect GABA A receptor antagonist picrotoxin (0.08 microg), the cholinergic muscarinic receptor blocker scopolamine (2. 0 microg), norepinephrine (0.3 microg), the protein kinase C inhibitor staurosporin (1.0 microg), or the calcium/calmodulin dependent protein kinase II inhibitor Kn-62 (3.5 ng). None of the drugs had any effect on either WM or STM. All had, as previously shown, strong effects on LTM: picrotoxin and norepinephrine enhanced it, and CNQX, AP5, scopolamine, Kn-62, and staurosporin inhibited it. The results do not support the idea that memory of this task is formed in the amygdala; they indicate that the amygdala is not involved in WM or STM processing and support the idea that the amygdala modulates LTM storage processes carried out elsewhere.     

Alpha3-integrins are required for hippocampal long-term potentiation and working memory

Integrins comprise a large family of heterodimeric, transmembrane cell adhesion receptors that mediate diverse neuronal functions in the developing and adult CNS. Recent pharmacological and genetic studies have suggested that beta1-integrins are critical in synaptic plasticity and memory formation. To further define the role of integrins in these processes, we generated a postnatal forebrain and excitatory neuron-specific knockout of alpha3-integrin, one of several binding partners for beta1 subunit. At hippocampal Schaffer collateral-CA1 synapses, deletion of alpha3-integrin resulted in impaired long-term potentiation (LTP). Basal synaptic transmission and paired-pulse facilitation were normal in the absence of alpha3-integrin. Behavioral studies demonstrated that the mutant mice were selectively defective in a hippocampus-dependent, nonmatch-to-place working memory task, but were normal in other hippocampus-dependent spatial tasks. The impairment in LTP and working memory is similar to that observed in beta1-integrin conditional knockout mice, suggesting that alpha3-integrin is the functional binding partner for beta1 for these processes in the forebrain.     

Forgotten but not gone: savings for pictures and words in long-term memory

Five experiments examined the relearning of words, simple line-drawing pictures, and complex photographic pictures after retention intervals of 1 to 10 weeks. For those items that were neither recalled nor recognized, the identical item was relearned better than an unrelated control item, as measured by a recall test following relearning. This relearning advantage in recall held for all three classes of material and extended to the cross-modality case (i.e., picture-word and word-picture) and the same-referent case (i.e., two pictures of the same object). However, recognition tests of relearning failed to detect this same relearning advantage for apparently forgotten items. Taken together, these findings conflict with the existing account of savings. Most fundamental, the classic argument that relearning serves a trace-strengthening function is undetermined by the observed recall-recognition contrast. An alternative explanation of savings is suggested wherein relearning assists retrieval of information, thereby affecting recall in particular.     

Distinctive shapes benefit short-term memory for color associations, but not for color

In four experiments, we examined the effect of pairing colors with either homogeneous or heterogeneous shapes on a short-term memory task. In Experiment 1, we found no differences in color memory for displays in which colors were each associated with different shapes, paired with individual homogeneous shapes, or paired with heterogeneous shapes. In contrast, in Experiment 2, we found that when participants were asked to remember the specific pairings of colors, memory was improved for heterogeneous-shape displays. The benefit for heterogeneous shapes appears to be memorial, rather than one that occurs at the time of encoding (Experiment 3) or retrieval (Experiment 4). The present study suggests that distinctive shapes can be used to help bind color associations in visual short-term memory.     

Object appearance and picture-specific viewpoint are not integrated in long-term memory

Previous work has demonstrated that visual long-term memory (VLTM) stores detailed information about object appearance. The current experiments investigate whether object appearance information in VLTM is integrated within representations that contain picture-specific viewpoint information. In three experiments using both incidental and intentional encoding instructions, participants were unable to perform above chance on recognition tests that required recognizing the conjunction of object appearance and viewpoint information (Experiments 1a, 1b, 2, and 3). However, performance was better when object appearance information (Experiments 1a, 1b, and 2) or picture-specific viewpoint information (Experiment 3) alone was sufficient to succeed on the memory test. These results replicate previous work demonstrating good memory for object appearance and viewpoint. However the current results suggest that object appearance and viewpoint are not episodically integrated in VLTM.     

Congenital amusia: A short-term memory deficit for non-verbal,but not verbal sounds

Congenital amusia refers to a lifelong disorder of music processing and is linked to pitch-processing deficits. The present study investigated congenital amusics’ short-term memory for tones, musical timbres and words. Sequences of five events (tones, timbres or words) were presented in pairs and participants had to indicate whether the sequences were the same or different. The performance of congenital amusics confirmed a memory deficit for tone sequences, but showed normal performance for word sequences. For timbre sequences, amusics’ memory performance was impaired in comparison to matched controls. Overall timbre performance was found to be correlated with melodic contour processing (as assessed by the Montreal Battery of Evaluation of Amusia). The present findings show that amusics’ deficits extend to non-verbal sound material other than pitch, in this case timbre, while not affecting memory for verbal material. This is in line with previous suggestions about the domain-specificity of congenital amusia.     

Congenital amusia: A short-term memory deficit for non-verbal,but not verbal sounds

Congenital amusia refers to a lifelong disorder of music processing and is linked to pitch-processing deficits. The present study investigated congenital amusics’ short-term memory for tones, musical timbres and words. Sequences of five events (tones, timbres or words) were presented in pairs and participants had to indicate whether the sequences were the same or different. The performance of congenital amusics confirmed a memory deficit for tone sequences, but showed normal performance for word sequences. For timbre sequences, amusics’ memory performance was impaired in comparison to matched controls. Overall timbre performance was found to be correlated with melodic contour processing (as assessed by the Montreal Battery of Evaluation of Amusia). The present findings show that amusics’ deficits extend to non-verbal sound material other than pitch, in this case timbre, while not affecting memory for verbal material. This is in line with previous suggestions about the domain-specificity of congenital amusia.     

Adult age differences in short-term memory and subsequent long-term memory for actions.

Short-term memory for actions was investigated for young adult and elderly adult subjects with the Brown-Peterson procedure at retention intervals of 0 and 15 s. The short-term memory trials were followed by the long-term recall of the prior to-be-remembered actions. The 15-s retention interval was filled either with no activity or with 1 of 3 different interfering activities. Verbal interference had little effect on short-term memory at either age level. Actions performed in the interval either by the subjects or by the experimenter produced significantly lower recall scores at each age level, with the decrement being more pronounced for the elderly than for the young subjects. The long-term memory results indicated that successful short-term recall enhanced later long-term recall, regardless of age level.     

Competitive short-term and long-term memory processes in spatial habituation

Exposure to a spatial location leads to habituation of exploration such that, in a novelty preference test, rodents subsequently prefer exploring a novel location to the familiar location. According to Wagner's (1981) theory of memory, short-term and long-term habituation are caused by separate and sometimes opponent processes. In the present study, this dual-process account of memory was tested. Mice received a series of exposure training trials to a location before receiving a novelty preference test. The novelty preference was greater when tested after a short, rather than a long, interval. In contrast, the novelty preference was weaker when exposure training trials were separated by a short, rather than a long interval. Furthermore, it was found that long-term habituation was determined by the independent effects of the amount of exposure training and the number of exposure training trials when factors such as the intertrial interval and the cumulative intertrial interval were controlled. A final experiment demonstrated that a long-term reduction of exploration could be caused by a negative priming effect due to associations formed during exploration. These results provide evidence against a single-process account of habituation and suggest that spatial habituation is determined by both short-term, recency-based memory and long-term, incrementally strengthened memory.     

Hippocampal CA1 kindling but not long-term potentiation disrupts spatial memory performance

Long-term synaptic enhancement in the hippocampus has been suggested to cause deficits in spatial performance. Synaptic enhancement has been reported after hippocampal kindling that induced repeated electrographic seizures or afterdischarges (ADs) and after long-term potentiation (LTP) defined as synaptic enhancement without ADs. We studied whether repeated stimulations that gave LTP or ADs resulted in spatial performance deficits on the radial arm maze (RAM) and investigated the minimal number of ADs required for such deficits. Three experimental groups were run as follows: (1) 5 hippocampal ADs in 1 d (5-AD group), (2) 10 hippocampal ADs in 2 d (10-AD group), and (3) 12 -frequency primed-burst stimulations (PBSs) in 2 d in order to induce LTP without ADs (LTP group). Each experimental group was run together with a control group during the same time period. Rats were first trained in a spatial task on a radial arm maze with four of the eight arms baited, then given control or experimental treatment, and maze performance was tested in the first week (1-4 d) and fourth week (22-25 d) after treatment. Basal dendritic population excitatory postsynaptic potentials (pEPSPs) and medial perforant path (MPP)-evoked dentate gyrus population spike and polysynaptic CA1 excitation were recorded before and after experimental and control treatment. Spatial memory errors, in particular reference memory errors, were significantly higher in the 10-AD kindled group than any other group on the first and fourth week after treatment. Spatial memory errors were not significantly different in the 5-AD and LTP groups as compared with any control groups at any time. Basal dendritic pEPSP in CA1 was enhanced for about 1 wk after 12 PBSs, 10 ADs, or 5 ADs, while the dentate gyrus population spike and CA1 polysynaptic excitation evoked by MPP was increased for up to 4 wk after 10 ADs, but not 12 PBSs. Thus, distributed alteration of multiple synaptic transmission in the entorhinal-hippocampal circuit, but not LTP at the basal dendritic synapses in CA1, may disrupt spatial performance after 10 hippocampal ADs.     

The effects of word co-occurrence on short-term memory: associative links in long-term memory affect short-term memory performance

In immediate serial recall tasks, high-frequency words are recalled better than low-frequency words. This has been attributed to high-frequency words' being better represented and providing more effective support to a redintegration process at retrieval (C. Hulme et al., 1997). In studies of free recall, there is evidence that frequency of word co-occurrence, rather than word frequency per se, may explain the recall advantage enjoyed by high-frequency words (J. Deese, 1960). The authors present evidence that preexposing pairs of low-frequency words, so as to create associative links between them, has substantial beneficial effects on immediate serial recall performance. These benefits, which are not attributable to simple familiarization with the words per se, do not occur for high-frequency words. These findings indicate that associative links between items in long-term memory have important effects on short-term memory performance and suggest that the effects of word frequency in short-term memory tasks are related to differences in interitem associations in long-term memory.     

Latent memory for sensitization in Aplysia

In the analysis of memory it is commonly observed that, even after a memory is apparently forgotten, its latent presence can still be revealed in a subsequent learning task. Although well established on a behavioral level, the mechanisms underlying latent memory are not well understood. To begin to explore these mechanisms, we have used Aplysia, a model system that permits the simultaneous study of memory at the behavioral, cellular, and molecular levels. We first demonstrate that robust latent memory is induced by long-term sensitization training of the tail-elicited siphon withdrawal reflex. It is revealed by its ability to facilitate the subsequent induction of three mechanistically distinct temporal domains of sensitization memory: short-term, intermediate-term, and long-term memory. Under our training conditions, the latent memory persists for at least 2 d following the decay of original memory expression but appears to be gone by 4 d. Interestingly, we also find that latent memory is induced even in the absence of overt memory for the original training. These findings now permit the analysis of the cellular and molecular architecture of a common feature of learning and memory.     

Perceptual asymmetries are preserved in short-term memory tasks

Visual performance is heterogeneous at isoeccentric locations; it is better on the horizontal than on the vertical meridian and worse at the upper than at the lower region of the vertical meridian (Carrasco, Talgar, & Cameron, 2001; Talgar & Carrasco, 2002). It is unknown whether these performance inhomogeneities are also present in spatial frequency tasks and whether asymmetries present during encoding of visual information also emerge in visual short-term memory (VSTM) tasks. Here, we investigated the similarity of the perceptual and VSTM tasks in spatial frequency discrimination (Experiments 1 and 2) and perceived spatial frequency (Experiments 3 and 4). We found that (1) performance in both simultaneous (perceptual) and delayed (VSTM) spatial frequency discrimination tasks varies as a function of location; it is better along the horizontal than along the vertical meridian; and (2) perceived spatial frequency in both tasks is higher along the horizontal than along the vertical meridian. These results suggest that perceived spatial frequency may mediate performance differences in VSTM tasks across the visual field, implying that the quality with which we encode information affects VSTM.     

The role of long-term familiarity and attentional maintenance in short-term memory for timbre

We study short-term recognition of timbre using familiar recorded tones from acoustic instruments and unfamiliar transformed tones that do not readily evoke sound-source categories. Participants indicated whether the timbre of a probe sound matched with one of three previously presented sounds (item recognition). In Exp. 1, musicians better recognised familiar acoustic compared to unfamiliar synthetic sounds, and this advantage was particularly large in the medial serial position. There was a strong correlation between correct rejection rate and the mean perceptual dissimilarity of the probe to the tones from the sequence. Exp. 2 compared musicians' and non-musicians' performance with concurrent articulatory suppression, visual interference, and with a silent control condition. Both suppression tasks disrupted performance by a similar margin, regardless of musical training of participants or type of sounds. Our results suggest that familiarity with sound source categories and attention play important roles in short-term memory for timbre, which rules out accounts solely based on sensory persistence.     

Deficits in verbal long-term memory and learning in children with poor phonological short-term memory skills

Possible links between phonological short-term memory and both longer term memory and learning in 8-year-old children were investigated in this study. Performance on a range of tests of long-term memory and learning was compared for a group of 16 children with poor phonological short-term memory skills and a comparison group of children of the same age with matched nonverbal reasoning abilities but memory scores in the average range. The low-phonological-memory group were impaired on longer term memory and learning tasks that taxed memory for arbitrary verbal material such as names and nonwords. However, the two groups performed at comparable levels on tasks requiring the retention of visuo-spatial information and of meaningful material and at carrying out prospective memory tasks in which the children were asked to carry out actions at a future point in time. The results are consistent with the view that poor short-term memory function impairs the longer term retention and ease of learning of novel verbal material.