Differential Role of Hippocampal cAMP-Dependent Protein Kinase in Short- and Long-Term Memory

One-trial step-down inhibitory (passive) avoidance training is followed by two peaks of cAMP-dependent protein kinase (PKA) activity in rat CA1: one immediately after training and the other 3 h later. The second peak relies on the first: Immediate posttraining infusion into CA1 of the inhibitor of the regulatory subunit of PKA, Rp-cAMPS, at a dose that reduces PKA activity during less than 90 min, cancelled both peaks. Long-term memory (LTM) of this task measured at 24 h depends on the two peaks: Rp-cAMPS given into CA1 0 or 175 min posttraining, but not between those times, blocked LTM. However, the effect of immediate posttraining Rp-cAMPS on LTM could not be reversed by the activator of the regulatory subunit of PKA, Sp-cAMPS, given at 180 min, which suggests that, for LTM, the first peak may be more important than the second. When given at 0, 22, 45, or 90, but not at 175 min from training, Rp-cAMPS blocked short-term memory (STM) measured at 90 or 180 min. This effect of immediate posttraining Rp-cAMPS infusion on STM but not that on LTM was readily reversed by Sp-cAMPS infused 22 min later. On its own, Sp-cAMPS had effects exactly opposite to those of the inhibitor. It enhanced LTM when given at 0 or 175 min from training, and it enhanced STM when given at 0, 22, 45, or 90 min from training. These findings show that STM and LTM formation require separate PKA-dependent processes in CA1. STM relies on the continued activity of the enzyme during the first 90 min. LTM relies on the two peaks of PKA activity that occur immediately and 180 min posttraining.     

Dissociation of rugose‐dependent short‐term memory component from memory consolidation in Drosophila

Extensive investigations show several molecular and neuroanatomical mechanisms underlying short‐lived and long‐lasting memory in Drosophila. At the molecular level, the genetic pathway of memory formation, which was obtained through mutant research, seems to occur sequentially. So far, studies of Drosophila mutants appear to support the idea that mutants defective in short‐term memory (STM) are always associated with long‐term memory (LTM) impairment. At the neuroanatomical level, distinct memory traces are partially independently distributed. However, whether memory phase dissociation also exists at the molecular level remains unclear. Here, we report on molecular separation of STM and consolidated memory through genetic dissection of rugose mutants. Mutants in the rugose gene, which encodes an evolutionarily conserved A‐kinase anchor protein, show immediate memory defects as assayed through aversive olfactory conditioning. Intriguingly, two well‐defined consolidated memory components, anesthesia‐resistant memory and protein synthesis‐dependent LTM, are both normal in spite of the defective immediate memory after 10‐session massed and spaced training. Moreover, rugose genetically interacts with cyclic AMP‐protein kinase A signaling during STM formation. Considering our previous study that AKAP Yu specifically participates in LTM formation, these results suggest that there exists a molecular level of memory phase dissociation with distinct AKAPs in Drosophila.     

Short- and Long-term Memory are Differentialy Modulated by Hippocampal Nerve Growth Factor and Fibroblast Growth Factor

Rats were implanted with cannulae in the CA1 area of the dorsal hippocampus and trained in one-trial step-down inhibitory avoidance. Two retention tests were carried out in each animal, one at 1.5 h to measure short-term memory (STM) and another at 24 h to measure long-term memory (LTM). The purpose of the present study was to evaluate the modulation on hippocampal nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) on short- and long-term memory. Immediately after training, animals received 5 l of NGF (0.05, 0.5 or 5.0 ng), bFGF (1.25, 12.5 or 125 ng) or saline per side. At the higher dose, NGF blocked STM. In contrast, NGF at dose of 0.5 and 5.0 ng improved LTM. The bFGF infusion at a dose of 125 ng enhanced LTM. However, bFGF did not alter STM. These findings indicate that hippocampal NGF and bFGF modulate STM and LTM in a different manner.     

Parametric and genetic analysis of Drosophila appetitive long‐term memory and sugar motivation

Distinct forms of memory can be highlighted using different training protocols. In Drosophila olfactory aversive learning, one conditioning session triggers memory formation independently of protein synthesis, while five spaced conditioning sessions lead to the formation of long‐term memory (LTM), a long‐lasting memory dependent on de novo protein synthesis. In contrast, one session of odour–sugar association appeared sufficient for the fly to form LTM. We designed and tuned an apparatus that facilitates repeated discriminative conditioning by alternate presentations of two odours, one being associated with sugar, as well as a new paradigm to test sugar responsiveness (SR). Our results show that both SR and short‐term memory (STM) scores increase with starvation length before conditioning. The protein dependency of appetitive LTM is independent of the repetition and the spacing of training sessions, on the starvation duration and on the strength of the unconditioned stimulus. In contrast to a recent report, our test measures an abnormal SR of radish mutant flies, which might initiate their STM and LTM phenotypes. In addition, our work shows that crammer and tequila mutants, which are deficient for aversive LTM, present both an SR and an appetitive STM defect. Using the MB247‐P[switch] system, we further show that tequila is required in the adult mushroom bodies for normal sugar motivation.     

Early Activation of Extracellular Signal-Regulated Kinase Signaling Pathway in the Hippocampus is Required for Short-Term Memory Formation of a Fear-Motivated Learning

1. According to its duration there are, at least, two major forms of memory in mammals: short term memory (STM) which develops in a few seconds and lasts several hours and long-term memory (LTM) lasting days, weeks and even a lifetime. In contrast to LTM, very little is known about the neural, cellular and molecular requirements for mammalian STM formation.2. Here we show that early activation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus is required for the establishment of STM for a one-trial inhibitory avoidance task in the rat. Immediate posttraining infusion of U0126 (a selective inhibitor of ERK kinase) into the CA1 region of the dorsal hippocampus blocked STM formation.3. Reversible inactivation of the entorhinal cortex through muscimol infusion produced deficits in STM and a selective and rapid decrease in hippocampal ERK2 activation.4. Together with our previous findings showing a rapid decrease in ERK2 activation and impaired STM after blocking BDNF function, the present results strongly suggest that ERK2 signaling in the hippocampus is a critical step in STM processing.Lionel Muller Igaz and Milena Winograd contributed equally to this work     

Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus

Persistence is the most characteristic attribute of long-term memory (LTM). To understand LTM, we must understand how memory traces persist over time despite the short-lived nature and rapid turnover of their molecular substrates. It is widely accepted that LTM formation is dependent upon hippocampal de novo protein synthesis and Brain-Derived Neurotrophic Factor (BDNF) signaling during or early after acquisition. Here we show that 12 hr after acquisition of a one-trial associative learning task, there is a novel protein synthesis and BDNF-dependent phase in the rat hippocampus that is critical for the persistence of LTM storage. Our findings indicate that a delayed stabilization phase is specifically required for maintenance, but not formation, of the memory trace. We propose that memory formation and memory persistence share some of the same molecular mechanisms and that recurrent rounds of consolidation-like events take place in the hippocampus for maintenance of the memory trace.     

Functional and evolutionary trade-offs co-occur between two consolidated memory phases in Drosophila melanogaster

Memory is a complex and dynamic process that is composed of different phases. Its evolution under natural selection probably depends on a balance between fitness benefits and costs. In Drosophila, two separate forms of consolidated memory phases can be generated experimentally: anaesthesia-resistant memory (ARM) and long-term memory (LTM). In recent years, several studies have focused on the differences between these long-lasting memory types and have found that, at the functional level, ARM and LTM are antagonistic. How this functional relationship will affect their evolutionary dynamics remains unknown. We selected for flies with either improved ARM or improved LTM over several generations, and found that flies selected specifically for improvement of one consolidated memory phase show reduced performance in the other memory phase. We also found that improved LTM was linked to decreased longevity in male flies but not in females. Conversely, males with improved ARM had increased longevity. We found no correlation between either improved ARM or LTM and other phenotypic traits. This is, to our knowledge, the first evidence of a symmetrical evolutionary trade-off between two memory phases for the same learning task. Such trade-offs may have an important impact on the evolution of cognitive capacities. On a neural level, these results support the hypothesis that mechanisms underlying these forms of consolidated memory are, to some degree, antagonistic.     

The Effects of Valence and Arousal on Associative Working Memory and Long-Term Memory

Background

Emotion can either facilitate or impair memory, depending on what, when and how memory is tested and whether the paradigm at hand is administered as a working memory (WM) or a long-term memory (LTM) task. Whereas emotionally arousing single stimuli are more likely to be remembered, memory for the relationship between two or more component parts (i.e., relational memory) appears to be worse in the presence of emotional stimuli, at least in some relational memory tasks. The current study investigated the effects of both valence (neutral vs. positive vs. negative) and arousal (low vs. high) in an inter-item WM binding and LTM task.

Methodology/Principal Findings

A five-pair delayed-match-to-sample (WM) task was administered. In each trial, study pairs consisted of one neutral picture and a second picture of which the emotional qualities (valence and arousal levels) were manipulated. These pairs had to be remembered across a delay interval of 10 seconds. This was followed by a probe phase in which five pairs were tested. After completion of this task, an unexpected single item LTM task as well as an LTM task for the pairs was assessed. As expected, emotional arousal impaired WM processing. This was reflected in lower accuracy for pairs consisting of high-arousal pictures compared to pairs with low-arousal pictures. A similar effect was found for the associative LTM task. However, the arousal effect was modulated by affective valence for the WM but not the LTM task; pairs with low-arousal negative pictures were not processed as well in the WM task. No significant differences were found for the single-item LTM task.

Conclusions/Significance

The present study provides additional evidence that processes during initial perception/encoding and post-encoding processes, the time interval between study and test and the interaction between valence and arousal might modulate the effects of “emotion” on associative memory.     

A molluscan model system in the search for the engram.

A 3-neuron central pattern generator, whose sufficiency and necessity has been directly demonstrated, mediates aerial respiratory behaviour in the pond snail, Lymnaea stagnalis. This behaviour can be operantly conditioned, and this associative learning is consolidated into long-lasting memory. Depending on the operant conditioning training procedure used the learning can be consolidated into intermediate term (ITM) or long-term memory (LTM). ITM persists for only 2-3 h, whilst LTM persists for days to weeks. LTM is dependent on both altered gene activity and new protein synthesis while ITM is only dependent on new protein synthesis. We have now directly established that one of the 3-CPG neurons, RPeD1, is a site of LTM formation and storage. We did this by ablating the soma of RPeD1 and leaving behind a functional primary neurite capable of mediating the necessary synaptic interactions to drive aerial respiratory behaviour by the 3-neuron CPG. However, following soma ablation the neuronal circuit is only capable of mediating learning and ITM. LTM can no longer be demonstrated. However, if RPeD1's soma is ablated after LTM consolidation memory is still present. Thus the soma is not needed for the retention of LTM. Using a similar strategy it may be possible to block forgetting.     

Über die Wirkung einiger Inhibitoren der Protein-Biosynthese auf Aktivität und Lernverhalten beim Goldfisch (Carassius auratus auratus L.)

Concerning the problems of learning and memory there is a distinction of a short term memory (STM) and a long term memory (LTM). It is supposed that the STM is an electrical phenomenon, whereas the LTM depends on material changes. The assumed materials are RNA, proteins, lipids, amines etc. and the primary carrier of the information is DNA. But there is a discrepancy: learning-specifity is based on environmental changes, but not the structure of DNA. For the investigation of this, we trained goldfish in a shock-free task to take food from coloured cups under the influence of inhibitors of the proteinbiosynthesis. There was no inhibition on memory-processes in our experiments     

Brain metabolic activity associated with long-term memory consolidation

The use of day-old chickens trained on a single-trial passive avoidance task provides a useful paradigm for investigations into cellular mechanisms underlying memory formation. Pharmacological intervention studies indicate that there are three temporally identifiable stages of memory processing leading to the consolidation of information for this task. These stages, designated as short-term (STM; up to 15 min), intermediate-term (ITM; 15-55 min), and long-term (LTM; more than 55 min) memory, have been found to be sequentially dependent (Ng and Gibbs, 1989). In addition, ITM appears to consist of two physiologically distinguishable phases, A and B. Evidence in this laboratory suggests that the crossover between these ITM phases (at 30 min after training) represents a critical time-point for the triggering of LTM.     

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.     

Dissociable roles for histone acetyltransferases p300 and PCAF in hippocampus and perirhinal cortex‐mediated object memory

The importance of histone acetylation for certain types of memory is now well established. However, the specific contributions of the various histone acetyltransferases to distinct memory functions remain to be determined; therefore, we employed selective histone acetyltransferase protein inhibitors and short‐interference RNAs to evaluate the roles of CREB‐binding protein (CBP), E1A‐binding protein (p300) and p300/CBP‐associated factor (PCAF) in hippocampus and perirhinal cortex (PRh)‐mediated object memory. Rats were tested for short‐ (STM) and long‐term memory (LTM) in the object‐in‐place task, which relies on the hippocampus and PRh for spatial memory and object identity processing, respectively. Selective inhibition of these histone acetyltransferases by small‐interfering RNA and pharmacological inhibitors targeting the HAT domain produced dissociable effects. In the hippocampus, CBP or p300 inhibition impaired long‐term but not short‐term object memory, while inhibition of PCAF impaired memory at both delays. In PRh, HAT inhibition did not impair STM, and only CBP and PCAF inhibition disrupted LTM; p300 inhibition had no effects. Messenger RNA analyses revealed findings consistent with the pattern of behavioral effects, as all three enzymes were upregulated in the hippocampus (dentate gyrus) following learning, whereas only CBP and PCAF were upregulated in PRh. These results demonstrate, for the first time, the necessity of histone acetyltransferase activity for PRh‐mediated object memory and indicate that the specific mnemonic roles of distinctive histone acetyltransferases can be dissociated according to specific brain regions and memory timeframe.     

Pavlovian conditioning-specific increases of the Ca2+- and GTP-binding protein,calexcitin in identified Hermissenda visual cells

Hermissenda CNS, immunolabeled for the memory protein calexcitin showed significant immunostaining over background in the B-photoreceptor cells of the eye. The degree of staining correlated positively with the number of Pavlovian training events experienced by the animals and the degree of Pavlovian conditioning induced. The training regime consisted of exposing animals to light (conditioned stimulus, CS) paired with orbital rotation (unconditioned stimulus, US). In animals that exhibited the conditioned response, calexcitin immunolabeling was more intense than was found for naive (unconditioned) animals or animals given the CS and US in random sequence. Animals exposed to lead (maintained in 1.2 ppm lead acetate) at a dosage known to impair learning in children, showed reduced learning and less intense calexcitin staining whether the CS and US were paired or given randomly. However, the levels were still higher than that of naive animals. Immuno-electron microscopy indicated that the labeling was predominantly within calcium sequestering organelles such as the endoplasmic reticulum, and to lesser extent within mitochondria, and photopigments. The calexcitin density after a short-term memory (STM) regime was the same whether measured 5 minutes after conditioning (when STM was evidenced by foot contraction) or 90 minutes later when no recall was detected. The staining density was also similar to the levels found 5 minutes after long-term memory (LTM) conditioning. However, the LTM regime produced a greater calexcitin intensity at 90 minutes when the memory had been consolidated. This learning-specific increase in calexcitin is consistent with the previously implicated sequence of molecular events that are associated with progressively longer time domains of memory storage.     

Effects of beta-carboline alkaloids on the object recognition task in mice

beta-carboline alkaloids are found in several medicinal plants and display a variety of actions on the central nervous, muscular and cardiovascular systems. The aim of the present study was to evaluate the effects of systemic administration of beta-carboline alkaloids on object recognition in mice. Adult Swiss mice received an intra-peritoneal injection (i.p.) of alkaloids (1.0, 2.5 or 5.0 mg/kg) 30 min before training in an object recognition task. The fully aromatic beta-carbolines, harmine and harmol, induced an enhancement of short-term memory (STM) at all doses tested when compared to controls. Harmaline, a dihydro beta-carboline and inverse agonist of the MK-801 binding site on the N-methyl-d-aspartate (NMDA) receptor, also induced an enhancement of both short-term memory (STM) and long-term memory (LTM). These results demonstrate that systemic administration of beta-carboline alkaloids can improve object recognition memory in mice.     

BDNF Activates mTOR to Regulate GluR1 Expression Required for Memory Formation

Background

The mammalian target of Rapamycin (mTOR) kinase plays a key role in translational control of a subset of mRNAs through regulation of its initiation step. In neurons, mTOR is present at the synaptic region, where it modulates the activity-dependent expression of locally-translated proteins independently of mRNA synthesis. Indeed, mTOR is necessary for different forms of synaptic plasticity and long-term memory (LTM) formation. However, little is known about the time course of mTOR activation and the extracellular signals governing this process or the identity of the proteins whose translation is regulated by this kinase, during mnemonic processing.

Methodology/Principal Findings

Here we show that consolidation of inhibitory avoidance (IA) LTM entails mTOR activation in the dorsal hippocampus at the moment of and 3 h after training and is associated with a rapid and rapamycin-sensitive increase in AMPA receptor GluR1 subunit expression, which was also blocked by intra-hippocampal delivery of GluR1 antisense oligonucleotides (ASO). In addition, we found that pre- or post-training administration of function-blocking anti-BDNF antibodies into dorsal CA1 hampered IA LTM retention, abolished the learning-induced biphasic activation of mTOR and its readout, p70S6K and blocked GluR1 expression, indicating that BDNF is an upstream factor controlling mTOR signaling during fear-memory consolidation. Interestingly, BDNF ASO hindered LTM retention only when given into dorsal CA1 1 h after but not 2 h before training, suggesting that BDNF controls the biphasic requirement of mTOR during LTM consolidation through different mechanisms: an early one involving BDNF already available at the moment of training, and a late one, happening around 3 h post-training that needs de novo synthesis of this neurotrophin.

Conclusions/Significance

In conclusion, our findings demonstrate that: 1) mTOR-mediated mRNA translation is required for memory consolidation during at least two restricted time windows; 2) this kinase acts downstream BDNF in the hippocampus and; 3) it controls the increase of synaptic GluR1 necessary for memory consolidation.