Molecular pharmacological dissection of short- and long-term memory

1. It has been discussed for over 100 years whether short-term memory (STM) is separate from, or just an early phase of, long-term memory (LTM). The only way to solve this dilemma is to find out at least one treatment that blocks STM while keeping LTM intact for the same task in the same animal.2. The effect of a large number of treatments infused into the hippocampus, amygdala, and entorhinal, posterior parietal or prefrontal cortex on STM and LTM of a one-trial step-down inhibitory avoidance task was studied. The animals were tested at 1.5 h for STM, and again at 24 h for LTM. The treatments were given after training.3. Eleven different treatments blocked STM without affecting LTM. Eighteen treatments affected the two memory types differentially, either blocking or enhancing LTM alone. Thus, STM is separate from, and parallel to the first hours of processing of, LTM of that task.4. The mechanisms of STM are different from those of LTM. The former do not include gene expression or protein synthesis; the latter include a double peak of cAMP-dependent protein kinase activity, accompanied by the phosphorylation of CREB, and both gene expression and protein synthesis.5. Possible cellular and molecular events that do not require mRNA or protein synthesis should account for STM. These might include a hyperactivation of glutamate AMPA receptors, ribosome changes, or the exocytosis of glycoproteins that participate in cell addition.     

Parallel processing of appetitive short- and long-term memories in Drosophila

It is broadly accepted that long-term memory (LTM) is formed sequentially after learning and short-term memory (STM) formation, but the nature of the relationship between early and late memory traces remains heavily debated [1-5]. To shed light on this issue, we used an olfactory appetitive conditioning in Drosophila, wherein starved flies learned to associate an odor with the presence of sugar [6]. We took advantage of the fact that both STM and LTM are generated after a unique conditioning cycle [7, 8] to demonstrate that appetitive LTM is able to form independently of STM. More specifically, we show that (1) STM retrieval involves output from γ neurons of the mushroom body (MB), i.e., the olfactory memory center [9, 10], whereas LTM retrieval involves output from αβ MB neurons; (2) STM information is not transferred from γ neurons to αβ neurons for LTM formation; and (3) the adenylyl cyclase RUT, which is thought to operate as a coincidence detector between the olfactory stimulus and the sugar stimulus [11-14], is required independently in γ neurons to form appetitive STM and in αβ neurons to form LTM. Taken together, these results demonstrate that appetitive short- and long-term memories are formed and processed in parallel.     

An analytical short- and long-term memory model of presynaptic plasticity

A mathematical model, called the Learning Gate Model (LGM), that describes phenomena responsible for biological synaptic plasticity, is presented. The functionality of the model are mainly based on the work of Kandel and colleagues on the most elementary forms of learning observed in the Aplysia Californica marine mollusc. In particular, emphasis is placed on the double temporal dynamics of synaptic plasticity and the temporal specificity of classical conditioning. By properly modeling the effect of the binding of Ca⁺⁺ ions to the serotonin-sensitive adenylate cyclase enzyme, it is shown how a positively accelerated learning curve can be obtained for sensitization and classical conditioning. Phenomena of spontaneous recovery and second-order conditioning are reproduced through simulations. Mathematical analyses of the temporal trace of conditioned stimulus and of the Short-Term Memory steady state are also given.     

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 carcinogenesis, 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.     

Temporal characteristics of the initial stage of the verbal information processing in healthy subjects and in schizophrenia

The study aimed to investigate the early coding of visually presented words and pseudowords using event-related potentials (ERP). We conducted comparative analysis of the characteristics of P100 and N170 in healthy controls and in patients with the first episode of schizophrenia during passive perception of verbal stimuli as well as under conditions of relevant words and pseudowords. The latency of early ERP components P100 and N170 appeared to be shorter in comparison with healthy subjects in the temporal, parietal and occipital areas. The latency of P100 in patients was significantly shorter in the temporal, parietal and occipital areas, whereas the latency of N170 was shorter in the parietal and occipital areas than in controls. The latency of N170 in healthy subjects was significantly longer to words than to pseudowords and in patients - vice versa. The latencies of N170 in all TPO areas were equal in healthy subjects during word processing, and this equality was upset during non-word processing. In patients with schizophrenia the equality was upset, but, opposite to healthy patients, the upset of equality was more expressed during words processing. Thus, the early stage of verbal information processing in schizophrenic patients is insufficient in time. The time deficit of the automatic processes may lead to defective processing of overall information.     

Cell adhesion molecules and the transition from short- to long-term memory

Training chicks on a one-trial passive avoidance task results in a cascade of molecular and cellular processes in two forebrain regions, culminating within 60–90 min in post-translational glycosylation of synaptic membrane proteins and expression of immediate early genes c-fos and c-jun. We have now found a second window of vulnerability of memory to the protein synthesis inhibitor anisomycin, 4 h downstream of training. By 5.5 h post-training this window closes, to be replaced by a window of sensitivity to blockade of glycoprotein synthesis, presumably representing post-translational modification of the newly synthesised proteins. Amongst the pre- and post-synaptic membrane glycoproteins involved at both first and second time windows are the cell adhesion molecules, L1 (at both times) and NCAM (at the later). Molecular dissection of the external membrane domains of L1 distinguishes between a requirement for the IgG domain at the early time, the fibronectin-like domain at the later. The second time window only occurs if the animal is trained on a stimulus strong enough to be remembered for a long period. Weak memories do not persist beyond 6–8 h and the second wave of glycoprotein synthesis does not occur. Thus the second wave may represent the molecular processes required for the alterations in synaptic configuration, by way of the adhesion molecules amongst others, required for the morphological changes in neuronal connectivity hypothesised to encode memory.     

Effects of microcystins over short- and long-term memory and oxidative stress generation in hippocampus of rats

Microcystins produced by cyanobacteria are potent inhibitors of some protein phosphatases, but recent evidence also indicates its potential to generate oxidative stress. In the present study, the effects of microcystin raw extracts (Mic; 0.01 and 20microg/L) and purified okadaic acid (OA; 0.01 and 10microg/L) on short- and long-term memory alteration and antioxidant and oxidative damage were investigated in hippocampus of rats. The results showed an amnesic effect with 0.01 and 20microg/L Mic on retrieval and only with 0.01microg/L Mic on spatial learning. Parallel to these effects oxidative damage was observed as evidenced by augmented levels of lipid peroxides and DNA damage and the absence of antioxidant responses in terms of total oxyradical scavenging capacity. Phase II reactions catalyzed by glutathione-S-transferase were not modified after microcystins exposure. Overall this study showed physiological events (retrieval and spatial learning) that can be related to the classical toxic effects of microcystins (i.e., phosphatase inhibition). In addition, evidence of alternative toxicity mechanisms via oxidative stress generation was also obtained. The fact that organic anion transporter polypeptides (OATP) involved in microcystins uptake are expressed not only in liver but also in brain points to the environmental relevance of the observed effects.     

Microstructural abnormalities of the corpus callosum and fasciculus uncinatus and auditory information processing in patients with juvenile paroxysmal schizophrenia

One approach to the problem of determining the mechanisms coupling the structure and functions of the brain is studies in clinical populations aimed at assessing the presence or absence of congruence of anatomical/ morphological and functional abnormalities. Magnetic resonance imaging (MRI), including structural MRI and diffusion tensor imaging with tractography, as well as the recording of auditory event-related potentials (ERPs) in the standard two-tone oddball paradigm and the sensory gating paradigm, was conducted in 26 male patients with paroxysmal juvenile schizophrenia and 26 mentally healthy men with no family history of mental illness. MRI abnormalities have been found in the genu of the corpus callosum and fasciculus uncinatus of the left hemisphere of the patients. Reduction of the fractional anisotropy in the genu of the corpus callosum was correlated with P300 reduction in the right temporal region.     

慢性精神分裂症患者前瞻性记忆障碍的康复训练

目的探讨慢性精神分裂症患者前瞻性记忆障碍实施康复训练的效果。方法选取我院2014年1月~2016年3月收治的60例慢性精神分裂症前瞻性记忆障碍患者,采用随机数字表法将患者分为对照组和观察组,对照组患者实施常规康复训练,观察组患者实施综合康复训练,观察两组患者实施康复训练6周和12周后记忆障碍的恢复情况。结果经过康复训练,观察组患者在康复训练6周和12周后记忆功能均较康复训练前的瞬时、短时、长时记忆有明显好转(P0.05),对照组患者在康复训练6周和12周后记忆功能与康复训练前比较无明显差异性(P0.05),两组患者康复训练后同时期记忆功能比较差异有统计学意义(P0.05)。两组患者入院时和出院时的焦虑情况比较,观察组患者明显优于对照组,差异有统计学意义(P0.05);出院时SCL-90症状自评量表评分,观察组各项指标均低于住院时(P0.05),而对照组各项指标与住院时比较无明显改变(P0.05),两组指标比较,观察组明显低于对照组,差异具有统计学意义(P0.05)。结论在慢性精神分裂症患者前瞻性记忆障碍的治疗中采取康复训练,能使患者的记忆功能显著提高,缓解了患者的临床症状,促进了患者康复。     

eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory

The late phase of long-term potentiation (LTP) and memory (LTM) requires new gene expression, but the molecular mechanisms that underlie these processes are not fully understood. Phosphorylation of eIF2alpha inhibits general translation but selectively stimulates translation of ATF4, a repressor of CREB-mediated late-LTP (L-LTP) and LTM. We used a pharmacogenetic bidirectional approach to examine the role of eIF2alpha phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2alpha(+/S51A) mice, in which eIF2alpha phosphorylation is reduced, the threshold for eliciting L-LTP in hippocampal slices is lowered, and memory is enhanced. In contrast, only early-LTP is evoked by repeated tetanic stimulation and LTM is impaired, when eIF2alpha phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2alpha. These findings highlight the importance of a single phosphorylation site in eIF2alpha as a key regulator of L-LTP and LTM formation.     

Season of birth affects short- and long-term survival

Recent research findings have highlighted the importance of early life conditions as risk factors for adult diseases and therefore determinants of subsequent survival. Given that individuals born during different seasons in seasonal environments experience different early-developmental conditions, an analysis of the effects of the season of birth on survival is considered an effective approach in clarifying the influence of early life conditions on survival in later life. In the present study, we analyzed the long-term effects of early developmental conditions in a historical population in which both nutritional levels and the burden of infectious diseases showed a seasonal variation. Using a semi-computerized linkage process, we were able to match birth and death data for 4,646 individuals born between 1634 and 1870 in the village of Es Mercadal (Minorca Island, Spain). To determine ecological differences associated with the season of birth, we first evaluated the association between season of birth and early life survival. This analysis helped us to determine seasonal variations in early life conditions such as infectious burden and nutritional levels. The season of birth had a significant effect on long-term survival in the birth cohort 1800-1870: summer births had a lower risk of death after age 15. We explain these results in terms of lower susceptibility to degenerative diseases in adult years due to superior in utero nutrition for summer births. These findings support the fetal origin hypothesis which states that the early life environment plays a key role in shaping the subsequent phenotype and risk of adult disease.     

Randomised trial of personalised computer based information for patients with schizophrenia

ObjectivesTo compare use, effect, and cost of personalised computer education with community psychiatric nurse education for patients with schizophrenia.DesignRandomised trial of three interventions. Modelling of costs of alternatives.Participants112 patients with schizophrenia in contact with community services; 67 completed the intervention.InterventionsThree interventions of five educational sessions: (a) computer intervention combining information from patient''s medical record with general information about schizophrenia; (b) sessions with a community psychiatric nurse; (c) “combination” (first and last sessions with nurse and remainder with computer).ResultsRates of completion of intervention did not differ significantly (71% for combination intervention, 61% for computer only, 46% for nurse only). Computer sessions were shorter than sessions with nurse (14 minutes v 60 minutes). More patients given nurse based education thought the information relevant. Of 20 patients in combination group, 13 preferred the sessions with the nurse and seven preferred the computer. There were no significant differences between groups in psychological outcomes. Because of the need to transport patients to the computer for their sessions, there was no difference between interventions in costs, but computer sessions combined with other patient contacts would be substantially cheaper.ConclusionsThe computer based patient education offered no advantage over sessions with a community psychiatric nurse. Investigation of computer use combined with other health service contacts would be worth while.

What is already known on this topic

Education of patients with schizophrenia has limited but positive outcomesComputer based approaches have not been thoroughly evaluated

What this study adds

A computer based method of education for patients with schizophrenia, which personalised the information with details from each patient''s medical record, was acceptable and as effective as educational sessions given by a community psychiatric nurseHowever, because of the need to provide transport for patients to attend their sessions, the computer based intervention was as costly as the nurse based oneInvestigating the addition of computer based education to other routine patient contacts would be worthwhile     

Arginine vasopressin improves the memory deficits in Han Chinese patients with first-episode schizophrenia

The memory impairment is a core deficit in the first-episode schizophrenia patients. Arginine vasopressin (AVP) in the brain can improve learning and memory. We performed multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial to study the cognitive functioning in Han Chinese first-episode schizophrenic patients in a 12-week treatment regime with the intranasal administration of AVP (128 cases) or placebo (131 cases) in addition to the conventional treatment. The methods of positive and negative syndrome scale (PANSS), Wechsler memory scale-4th edition (WMS-IV) and event-related potential (ERP) were used to study the effects of AVP on the cognitive function. The results showed that (1) AVP concentration decreased in cerebrospinal fluid (CSF) of the right-handed Han Chinese first-episode schizophrenic patients comparing with that of the health volunteers (7.1 ± 1.5 pg/ml vs 13.3 ± 1.9 pg/ml, p < 0.01), and did not change in plasma; (2) AVP significantly improved PANSS scores including total scores, positive symptoms, negative symptoms and general psychopathology comparing with those of the placebo group; (3) AVP elevated WMS-IV scores including the long-term memory (accumulation), short-term memory (recognition, comprehension), immediate memory (number recitation) and memory quotient 4, 8 and 12 weeks after treatment; and (4) AVP did not influence the latency and wave amplitude of target stimulus of P₃₀₀ of right-handed Han Chinese first-episode schizophrenic patients. The data suggested that AVP might improve cognitive process, such as memorizing and extraction of the information although there were many changes of cognitive functions in the right-handed Han Chinese first-episode schizophrenic patients.