Distinct neural correlates of visual long-term memory for spatial location and object identity: a positron emission tomography study in humans.

The purpose of the present study was to investigate by using positron emission tomography (PET) whether the cortical pathways that are involved in visual perception of spatial location and object identity are also differentially implicated in retrieval of these types of information from episodic long-term memory. Subjects studied a set of displays consisting of three unique representational line drawings arranged in different spatial configurations. Later, while undergoing PET scanning, subjects' memory for spatial location and identity of the objects in the displays was tested and compared to a perceptual baseline task involving the same displays. In comparison to the baseline task, each of the memory tasks activated both the dorsal and the ventral pathways in the right hemisphere but not to an equal extent. There was also activation of the right prefrontal cortex. When PET scans of the memory tasks were compared to each other, areas of activation were very circumscribed and restricted to the right hemisphere: For retrieval of object identity, the area was in the inferior temporal cortex in the region of the fusiform gyrus (area 37), whereas for retrieval of spatial location, it was in the inferior parietal lobule in the region of the supramarginal gyrus (area 40). Thus, our study shows that distinct neural pathways are activated during retrieval of information about spatial location and object identity from long-term memory.

Time-Dependent Effects of Acute Exercise-Induced Arousal on Long-Term Memory for Emotional and Neutral Stimuli

Psychological research has strongly documented the memory-enhancing effects of emotional arousal, while the effects of acute aerobic exercise on memory are not well understood. Manipulation of arousal has been shown to enhance long-term memory for emotional stimuli in a time-dependent fashion. This presents an opportunity to investigate the role of acute exercise in memory modulation. The purpose of this study was to determine the time-dependent relationship between acute exercise-induced arousal and long-term emotional memory. Participants viewed pleasant, neutral, and unpleasant images before or after completing a high-intensity session of cycling exercise. Salivary alpha-amylase, a biomarker of central norepinephrine, was measured as an indicator of arousal. No effects of exercise on recognition memory were revealed, however; a single session of high-intensity cycling increased salivary alpha-amylase. Our results also indicate that the influence of exercise on emotional responsiveness should be considered in further exploration of the memory-enhancing potential of acute exercise.

Memory of childbirth in the second year: the long-term effect of a negative birth experience and its modulation by the perceived intranatal relationship with caregivers

OBJECTIVE: To assess the memory of various subdimensions of the birth experience in the second year postpartum, and to identify women in the first weeks postpartum at risk of developing a long-term negative memory. DESIGN, METHOD, OUTCOME MEASURES: New mothers' birth experience (BE) was assessed 48-96 hours postpartum (T1) by means of the SIL-Ger and the BBCI (perception of intranatal relationships); early postnatal adjustment (week 3 pp: T1(bis)) was also assessed. Then, four subgroups of women were defined by means of a cluster-analysis, integrating the T1/T1(bis) variables. To evaluate the memory of the BE, the SIL-Ger was again applied in the second year after childbirth (T2). First, the ratings of the SIL-Ger dimensions of T1 were compared to those at T2 in the whole sample. Then, the four subgroups were compared with respect to their ratings of the birth experience at T2 (correlations, ANOVAs and t-tests). RESULTS: In general, fulfillment, emotional adaptation, physical discomfort, and anxiety improve spontaneously over the first year postpartum, whereas in negative emotional experience, control, and time-going-slowly no shift over time is observed. However, women with a negative overall birth experience and a low level of perceived intranatal relationship at T1 run a high risk of retaining a negative memory in all of the seven subdimensions of the birth experience. CONCLUSIONS: Women at risk of developing a negative long-term memory of the BE can be identified at the time of early postpartum, when the overall birth experience and the perceived intranatal relationship are taken into account.

A model of late long-term potentiation simulates aspects of memory maintenance.

Late long-term potentiation (L-LTP) denotes long-lasting strengthening of synapses between neurons. L-LTP appears essential for the formation of long-term memory, with memories at least partly encoded by patterns of strengthened synapses. How memories are preserved for months or years, despite molecular turnover, is not well understood. Ongoing recurrent neuronal activity, during memory recall or during sleep, has been hypothesized to preferentially potentiate strong synapses, preserving memories. This hypothesis has not been evaluated in the context of a mathematical model representing ongoing activity and biochemical pathways important for L-LTP. In this study, ongoing activity was incorporated into two such models - a reduced model that represents some of the essential biochemical processes, and a more detailed published model. The reduced model represents synaptic tagging and gene induction simply and intuitively, and the detailed model adds activation of essential kinases by Ca(2+). Ongoing activity was modeled as continual brief elevations of Ca(2+). In each model, two stable states of synaptic strength/weight resulted. Positive feedback between synaptic weight and the amplitude of ongoing Ca(2+) transients underlies this bistability. A tetanic or theta-burst stimulus switches a model synapse from a low basal weight to a high weight that is stabilized by ongoing activity. Bistability was robust to parameter variations in both models. Simulations illustrated that prolonged periods of decreased activity reset synaptic strengths to low values, suggesting a plausible forgetting mechanism. However, episodic activity with shorter inactive intervals maintained strong synapses. Both models support experimental predictions. Tests of these predictions are expected to further understanding of how neuronal activity is coupled to maintenance of synaptic strength. Further investigations that examine the dynamics of activity and synaptic maintenance can be expected to help in understanding how memories are preserved for up to a lifetime in animals including humans.

Memory and long-term potentiation (LTP) dissociated: Normal spatial memory despite CA1 LTP elimination with Kv1.4 antisense

Long-term potentiation (LTP) in the hippocampal slice preparation has been proposed as an in vitro model for long-term memory. However, correlation of LTP with memory in living animals has been difficult to demonstrate. Furthermore, in the last few years evidence has accumulated that dissociate the two. Because potassium channels might determine the weight of synapses in networks, we studied the role of Kv1.4, a presynaptic A-type voltage-dependent K+ channel, in both memory and LTP. Reverse transcription–PCR and Western blot analysis with specific antibodies showed that antisense oligodeoxyribonucleotide to Kv1.4 microinjected intraventricularly into rat brains obstructed hippocampal Kv1.4 mRNA, “knocking down” the protein in the hippocampus. This antisense knockdown had no effect on rat spatial maze learning, memory, or exploratory behavior, but eliminated both early- and late-phase LTP and reduced paired-pulse facilitation (a presynaptic effect) in CA1 pyramidal neurons without affecting dentate gyrus LTP. This presynaptic Kv1.4 knockdown together with previous postsynaptic Kv1.1 knockdown demonstrates that CA1 LTP is neither necessary nor sufficient for rat spatial memory.

In search of a theory of list memory: an inquiry into the efects of long-term information on short-term recall

Over recent years, evidence has been accumulating in favour of the importance of long-term information as a variable which can affect the success of short-term recall. Lexicality, word frequency, imagery and meaning have all been shown to augment short term recall performance. Two competing theories as to the causes of this long-term memory influence are outlined and tested in this thesis. The first approach is the order-encoding account, which ascribes the effect to the usage of resources at encoding, hypothesising that word lists which require less effort to process will benefit from increased levels of order encoding, in turn enhancing recall success. The alternative view, trace redintegration theory, suggests that order is automatically encoded phonologically, and that long-term information can only influence the interpretation of the resultant memory trace. The free recall experiments reported here attempted to determine the importance of order encoding as a facilitatory framework and to determine the locus of the effects of long-term information in free recall. Experiments 1 and 2 examined the effects of word frequency and semantic categorisation over a filled delay, and experiments 3 and 4 did the same for immediate recall. Free recall was improved by both long-term factors tested. Order information was not used over a short filled delay, but was evident in immediate recall. Furthermore, it was found that both long-term factors increased the amount of order information retained. Experiment 5 induced an order encoding effect over a filled delay, leaving a picture of short-term processes which are closely associated with long-term processes, and which fit conceptions of short-term memory being part of language processes rather better than either the encoding or the retrieval-based models. Experiments 6 and 7 aimed to determine to what extent phonological processes were responsible for the pattern of results observed. Articulatory suppression affected the encoding of order information where speech rate had no direct influence, suggesting that it is ease of lexical access which is the most important factor in the influence of long-term memory on immediate recall tasks. The evidence presented in this thesis does not offer complete support for either the retrieval-based account or the order encoding account of long-term influence. Instead, the evidence sits best with models that are based upon language-processing. The path urged for future research is to find ways in which this diffuse model can be better specified, and which can take account of the versatility of the human brain.

ROLE OF SYNAPSIN IN LONG-TERM SYNAPTIC FACILITATION IN APLYSIA

Enhanced expression of the presynaptic protein synapsin has been correlated with certain forms of long-term plasticity and learning and memory. However, the regulation and requirement for enhanced synapsin expression in long-term memory remains unknown. In the present study the technical advantages of the marine mollusc Aplysia were exploited in order to address this issue. In Aplysia, learning-induced enhancement in synaptic strength is modulated by serotonin (5-HT) and treatment with 5-HT in vitro of the sensorimotor synapse induces long-term facilitation (LTF) of synaptic transmission, which lasts for days, as well as the formation of new connections between the sensory and motor neuron. Results from immunofluorescence analysis indicated that 5-HT treatment upregulates synapsin protein levels within sensory neuron varicosities, the presumed site of neurotransmitter release. To investigate the mechanisms underlying increased synapsin expression, the promoter region of the Aplysia synapsin gene was cloned and a cAMP response element (CRE) was identified, raising the possibility that the transcriptional activator cAMP response element-binding protein-1 (CREB1) mediates the 5-HT-induced regulation of synapsin. Results from Chromatin Immunoprecipitation (ChIP) assays indicated that 5-HT treatment enhanced association of CREB1 surrounding the CRE site in the synapsin promoter and led to increased acetylation of histones H3 and H4 and decreased association of histone deacetylase 5 surrounding the CRE site in the synapsin promoter, a sign of transcriptional activation. In addition, sensory neurons injected with an enhanced green fluorescent protein (EGFP) reporter vector driven by the synapsin promoter exhibited a significant increase in EGFP expression following treatment with 5-HT. These results suggest that synapsin expression is regulated by 5-HT in part through transcriptional activation of the synapsin gene and through CREB1 association with the synapsin promoter. Furthermore, RNA interference that blocks 5-HT-induced elevation of synapsin expression also blocked long-term synaptic facilitation. These results indicate that 5-HT-induced regulation of synapsin is necessary for LTF and that synapsin is part of the cascade of synaptic events involved in the consolidation of memory.

Long-term synaptic facilitation of tail sensorimotor connections in {\it Aplysia\/}

Long-term sensitization in Aplysia is a well studied model for the examination of the cellular and molecules mechanisms of long-term memory. Several lines of evidence suggest long-term sensitization is mediated at least partially by long-term synaptic facilitation between the sensory and motor neurons. The sensitization training and one of its analogues, serotonin (5-HT), can induce long-term facilitation. In this study, another analogue to long-term sensitization training has been developed. Stimulation of peripheral nerves of pleural-pedal ganglia preparation induced long-term facilitation at both 24 hr and 48 hr. This is the first report that long-term facilitation in Aplysia persists for more than 24 hr, which is consistent with the observation that long-term sensitization lasts for more than one day. Thus, the data support the hypothesis that long-term facilitation is an important mechanism for long-term sensitization.^ One of the major differences between short-term and long-term facilitation is that long-term facilitation requires protein synthesis. Therefore, the effects of anisomycin, a protein synthesis inhibitor, on long-term facilitation was examined. Long-term facilitation induced by nerve stimulation was inhibited by 2 $\mu$M anisomycin, which inhibits $\sim$90% of protein synthesis. Nevertheless, at higher concentration (20 $\mu$M), anisomycin induced long-term facilitation by itself, which raises an interesting question about the function of anisomycin other than protein synthesis inhibition.^ Since protein synthesis is critical for long-term facilitation, a major goal is to identify and functionally characterize the molecules whose mRNA levels are altered during the formation of long-term facilitation. Behavioral training or its analogues (nerve stimulation and 5-HT) increases the level of mRNA of calmodulin (CaM). Thus, the role of Ca$\sp{2+}$-CaM-dependent protein kinase II (CaMKII), a major substrate of CaM, in long-term facilitation induced by nerve stimulation was examined. KN-62, a specific CaMKII inhibitor, did not block either the induction or the maintenance of long-term facilitation induced by nerve stimulation. These data indicate that CaMKII may not be involved in long-term facilitation. Another protein whose mRNA level of a molecule was increased by the behavioral training and the treatment of 5-HT is Aplysia tolloid/BMP-1-like protein 1 (apTBL-1). Tolloid in Drosophila and BMP-1 in human tissues are believed to be secreted as a metalloprotease to activate TGF-$\beta.$ Thus, the long-term effects of recombinant human TGF-$\beta1$ on synaptic strength were examined. Treatment of ganglia with TGF-$\beta1$ produced long-term facilitation, but not short-term or intermediate-term facilitation ($\le$4 hr). In addition, TGF-$\beta1$ and 5-HT were not additive in producing long-term facilitation, which indicates an interaction between two cascades. Moreover, 5-HT-induced facilitation (at both 24 hr and 48 hr) and nerve stimulation-induced facilitation (at 24 hr) were inhibited by TGF-$\beta$ sRII, a TGF-$\beta$ inhibitor. These results suggest that TGF-$\beta$ is part of the cascade of events underlying long-term sensitization, and also indicate that a signaling molecule used in development may also have functions in adult neuronal plasticity. ^

Signals underlying the induction and expression of long-term, injury-related plasticity in sensory neurons of Aplysia

An important goal in the study of long-term memory is to understand the signals that induce and maintain the underlying neural alterations. In Aplysia, long-term sensitization of defensive reflexes has been examined in depth as a simple model of memory. Extensive studies of sensory neurons (SNs) in Aplysia have led to a cellular and molecular model of long-term memory that has greatly influenced memory research. According to this model, induction of long-term memory in Aplysia depends upon serotonin (5-HT) release and subsequent activation of the cAMP-PKA pathway in SNs. The evidence supporting this model mainly came from studies of long-term synaptic facilitation (LTF) using dissociated (and therefore axotomized) cells growing in culture. However, studies in more intact preparations have produced complex and discrepant results. Because these SNs function as nociceptors, and display similar alterations (long-term hyperexcitability [LTH], LTF, and growth) in models of memory and nerve injury, this study examined the roles of 5-HT and the cAMP-PKA pathway in the induction and expression of long-term, injury-related LTH and LTF in Aplysia SNs. ^ The results presented here suggest that 5-HT is not a primary signal for inducing LTH (and perhaps LTF) in Aplysia SNs. Prolonged treatment with 5-HT failed to induce LTH of Aplysia SNs in either ganglia or dissociated-cell preparations. Treatment with a 5-HT antagonist, methiothepin, during noxious nerve stimulation failed to reduce 24 hr LTH. Furthermore, while 5-HT can induce LTF of SN synapses, this LTF appears to be an indirect effect of 5-HT on other cells. When neural activity was suppressed by elevating divalent cations or by using tetrodotoxin (TTX), 5-HT failed to induce LTF. Unlike LTF, LTH of the SNs could not be produced, even when 5-HT treatment occurred in normal artificial sea water (ASW), suggesting that LTH and LTF are likely to depend on different signals for induction. However, methiothepin reduced the later expression of LTH induced by nerve stimulation, suggesting that 5-HT contributes to the maintenance of LTH in Aplysia SNs.n of somata from the ganglion (which axotomizes SNs) or crushing peripheral n. ^ In summary, this study found that 5-HT and the cAMP-PKA pathway are not involved in the induction of long-term, injury-related LTH of Aplysia SNs, but persistent release of 5-HT and persistent PKA activity contribute to the maintenance of LTH induced by injury. (Abstract shortened by UMI.)^

Long-term hyperexcitability of sensory and motor axons in Aplysia californica: Induction by axotomy, serotonin, and transient depolarization

Neuropathic pain is a debilitating neurological disorder that may appear after peripheral nerve trauma and is characterized by persistent, intractable pain. The well-studied phenomenon of long-term hyperexcitability (LTH), in which sensory somata become hyperexcitable following peripheral nerve injury may be important for both chronic pain and long-lasting memory formation, since similar cellular alterations take place after both injury and learning. Though axons have previously been considered simple conducting cables, spontaneous afferent signals develop from some neuromas that form at severed nerve tips, indicating intrinsic changes in sensory axonal excitability may contribute to this intractable pain. Here we show that nerve transection, exposure to serotonin, and transient depolarization induce long-lasting sensory axonal hyperexcitability that is localized to the treated nerve segment and requires local translation of new proteins. Long-lasting functional plasticity may be a general property of axons, since both injured and transiently depolarized motor axons display LTH as well. Axonal hyperexcitability may represent an adaptive mechanism to overcome conduction failure after peripheral injury, but also displays key features shared with cellular analogues of memory including: site-specific changes in neuronal function, dependence on transient, focal depolarization for induction, and requirement for synthesis of new proteins for expression of long-lasting effects. The finding of axonal hyperexcitability after nerve injury sheds new light on the clinical problem of chronic neuropathic pain, and provides more support for the hypothesis that mechanisms of long-term memory storage evolved from primitive adaptive responses to injury. ^

The cGMP -PKG pathway is critical for inducing long-term sensitization of identified nociceptive sensory neurons

In various species, peripheral injury produces long-lasting sensitization of central and peripheral neurons representing the affected area. In Aplysia, memory-like traces (lasting days or weeks) of noxious peripheral stimulation include enhancement of central synaptic transmission and enhanced excitability of the central soma and peripheral branches of nociceptive sensory neurons. An important role for the cAMP-PKA-CREB pathway in consolidating long-term memory and inducing transcription-dependent synaptic potentiation has also been indicated by studies in rodents and Drosophila. ^ Much less attention has been paid to the cGMP-PKG pathway for transcription-dependent plasticity. Nevertheless, the cGMP-PKG pathway has been implicated in activity-dependent neural alterations lasting hours, and may trigger some forms of persistent pain. Recent evidence indicates PKG can regulate gene expression in the brain and several properties make it an attractive candidate for inducing long-term memories. ^ This dissertation reports that brief, noxious stimulation of a behaving, semi-intact preparation from mollusc, Aplysia californica, produces transcription-dependent, long-term hyperexcitability (LTH) of nociceptive sensory neurons that requires a nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway and which lasts for at least 24 hours. Intracellular injection of cGMP is sufficient to induce LTH. Similarly, body wall injury induces LTH which can be blocked with specific inhibitors of the NO-cGMP-PKG pathway such as L-NMMA, ODQ, Rp-8-cGMPS, PKI-G and KT5823 by isolated perfusion of pleural ganglion sensory cells in or directly by intracellular injection. In contrast, specific inhibitors of the cAMP-PKA pathway (Rp-8-cAMPS, PKI-A and H-89) failed to block injury-induced LTH. Interestingly, co-injection of the cAMP-responsive element (CRE) blocked the induction of both cAMP and injury-induced LTH, but not cGMP-induced LTH. Furthermore, co-injection of cAMP and cGMP with the Ca2+ buffer BAPTA in reduced Ca2+ seawater blocked cAMP-, but not cGMP-induced LTH. These findings demonstrate that the NO-cGMP-PKG pathway and at least one other pathway (perhaps mediated by Ca2+), but not the cAMP-PKA pathway, are critical for inducing LTH during transient, noxious stimulation.^

Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress

Stress early in postnatal life may result in long-term memory deficits and selective loss of hippocampal neurons. The mechanisms involved are poorly understood, but they may involve molecules and processes in the immature limbic system that are activated by stressful challenges. We report that administration of corticotropin-releasing hormone (CRH), the key limbic stress modulator, to the brains of immature rats reproduced the consequences of early-life stress, reducing memory functions throughout life. These deficits were associated with progressive loss of hippocampal CA3 neurons and chronic up-regulation of hippocampal CRH expression. Importantly, they did not require the presence of stress levels of glucocorticoids. These findings indicate a critical role for CRH in the mechanisms underlying the long-term effects of early-life stress on hippocampal integrity and function.

Amygdala activity at encoding correlated with long-term, free recall of emotional information.

Positron emission tomography of cerebral glucose metabolism in adult human subjects was used to investigate amygdaloid complex (AC) activity associated with the storage of long-term memory for emotionally arousing events. Subjects viewed two videos (one in each of two separate positron emission tomography sessions, separated by 3-7 days) consisting either of 12 emotionally arousing film clips ("E" film session) or of 12 relatively emotionally neutral film clips ("N" film session), and rated their emotional reaction to each film clip immediately after viewing it. Three weeks after the second session, memory for the videos was assessed in a free recall test. As expected, the subjects' average emotional reaction to the E films was higher than that for the N films. In addition, the subjects recalled significantly more E films than N films. Glucose metabolic rate of the right AC while viewing the E films was highly correlated with the number of E films recalled. AC activity was not significantly correlated with the number of N films recalled. The findings support the view derived from both animal and human investigations that the AC is selectively involved with the formation of enhanced long-term memory associated with emotionally arousing events.

Toward an object-based semantic memory for long-term operation of mobile service robots

Throughout a lifetime of operation, a mobile service robot needs to acquire, store and update its knowledge of a working environment. This includes the ability to identify and track objects in different places, as well as using this information for interaction with humans. This paper introduces a long-term updating mechanism, inspired by the modal model of human memory, to enable a mobile robot to maintain its knowledge of a changing environment. The memory model is integrated with a hybrid map that represents the global topology and local geometry of the environment, as well as the respective 3D location of objects. We aim to enable the robot to use this knowledge to help humans by suggesting the most likely locations of specific objects in its map. An experiment using omni-directional vision demonstrates the ability to track the movements of several objects in a dynamic environment over an extended period of time.

Double-strand breaks and the concept of short- and long-term epigenetic memory

Double-strand breaks represent an extremely cytolethal form of DNA damage and thus pose a serious threat to the preservation of genetic and epigenetic information. Though it is well-known that double-strand breaks such as those generated by ionising radiation are among the principal causative factors behind mutations, chromosomal aberrations, genetic instability and carcino-genesis, significantly less is known about the epigenetic consequences of double-strand break formation and repair for carcinogenesis. Double-strand break repair is a highly coordinated process that requires the unravelling of the compacted chromatin structure to facilitate repair machinery access and then restoration of the original undamaged chromatin state. Recent experimental findings have pointed to a potential mechanism for double-strand break-induced epigenetic silencing. This review will discuss some of the key epigenetic regulatory processes involved in double-strand break (DSB) repair and how incomplete or incorrect restoration of chromatin structure can leave a DSB-induced epigenetic memory of damage with potentially pathological repercussions