Showing papers in "Learning & Memory in 2003"
TL;DR: Several potential mechanisms with which neuronal activity could control the synapse-specificity of neurotrophin regulation are discussed, with particular emphasis on BDNF.
Abstract: It is widely accepted that neuronal activity plays a pivotal role in synaptic plasticity. Neurotrophins have emerged recently as potent factors for synaptic modulation. The relationship between the activity and neurotrophic regulation of synapse development and plasticity, however, remains unclear. A prevailing hypothesis is that activity-dependent synaptic modulation is mediated by neurotrophins. An important but unresolved issue is how diffusible molecules such as neurotrophins achieve local and synapse-specific modulation. In this review, I discuss several potential mechanisms with which neuronal activity could control the synapse-specificity of neurotrophin regulation, with particular emphasis on BDNF. Data accumulated in recent years suggest that neuronal activity regulates the transcription of BDNF gene, the transport of BDNF mRNA and protein into dendrites, and the secretion of BDNF protein. There is also evidence for activity-dependent regulation of the trafficking of the BDNF receptor, TrkB, including its cell surface expression and ligand-induced endocytosis. Further study of these mechanisms will help us better understand how neurotrophins could mediate activity-dependent plasticity in a local and synapse-specific manner.
906 citations
TL;DR: Cold pressor stress, which significantly elevated salivary cortisol levels, enhanced memory for emotionally arousing slides compared with the controls, but did not affect memory for relatively neutral slides, which further support the view that post-learning stress hormone-related activity interacts with arousal at initial encoding to modulate memory consolidation.
Abstract: Abundant evidence indicates that endogenous stress hormones such as epinephrine and corticosterone modulate memory consolidation in animals. We recently provided the first demonstration that an endogenous stress hormone (epinephrine) can enhance human memory consolidation. However, these findings also suggested that post-learning stress hormone activation does not uniformly enhance memory for all recently acquired information; rather, that it interacts with the degree of arousal at initial encoding of material in modulating memory for the material. Here we tested this hypothesis by administering cold pressor stress (CPS) or a control procedure to subjects after they viewed slides of varying emotional content, and assessing memory for the slides 1 wk later. CPS, which significantly elevated salivary cortisol levels, enhanced memory for emotionally arousing slides compared with the controls, but did not affect memory for relatively neutral slides. These findings further support the view that post-learning stress hormone-related activity interacts with arousal at initial encoding to modulate memory consolidation.
657 citations
TL;DR: The evidence used to identify the neural substrates of classical eyeblink conditioning and potential mechanisms of memory formation in critical regions of the hippocampus and cerebellum are described.
Abstract: Classical conditioning of the eyeblink reflex to a neutral stimulus that predicts an aversive stimulus is a basic form of associative learning. Acquisition and retention of this learned response require the cerebellum and associated sensory and motor pathways and engage several other brain regions including the hippocampus, neocortex, neostriatum, septum, and amygdala. The cerebellum and its associated circuitry form the essential neural system for delay eyeblink conditioning. Trace eyeblink conditioning, a learning paradigm in which the conditioned and unconditioned stimuli are noncontiguous, requires both the cerebellum and the hippocampus and exhibits striking parallels to declarative memory formation in humans. Identification of the neural structures critical to the development and maintenance of the conditioned eyeblink response is an essential precursor to the investigation of the mechanisms responsible for the formation of these associative memories. In this review, we describe the evidence used to identify the neural substrates of classical eyeblink conditioning and potential mechanisms of memory formation in critical regions of the hippocampus and cerebellum. Addressing a central goal of behavioral neuroscience, exploitation of this simple yet robust model of learning and memory has yielded one of the most comprehensive descriptions to date of the physical basis of a learned behavior in mammals.
579 citations
TL;DR: The role of synaptic activity seems to be a determinant in the induction of intrinsic plasticity in cortical, hippocampal, and cerebellar neurons, but the learning rules and the underlying mechanisms remain to be defined.
Abstract: Spatio-temporal configurations of distributed activity in the brain is thought to contribute to the coding of neuronal information and synaptic contacts between nerve cells could play a central role in the formation of privileged pathways of activity. Synaptic plasticity is not the exclusive mode of regulation of information processing in the brain, and persistent regulations of ionic conductances in some specialized neuronal areas such as the dendrites, the cell body, and the axon could also modulate, in the long-term, the propagation of neuronal information. Persistent changes in intrinsic excitability have been reported in several brain areas in which activity is elevated during a classical conditioning. The role of synaptic activity seems to be a determinant in the induction, but the learning rules and the underlying mechanisms remain to be defined. We discuss here the role of synaptic activity in the induction of intrinsic plasticity in cortical, hippocampal, and cerebellar neurons. Activation of glutamate receptors initiates a long-term modification in neuronal excitability that may represent a parallel, synergistic substrate for learning and memory. Similar to synaptic plasticity, long-lasting intrinsic plasticity appears to be bidirectional and to express a certain level of input or cell specificity. These nonsynaptic forms of plasticity affect the signal propagation in the axon, the dendrites, and the soma. They not only share common learning rules and induction pathways with the better-known synaptic plasticity such as NMDA receptor dependent LTP and LTD, but also contribute in synergy with these synaptic changes to the formation of a coherent engram.
516 citations
TL;DR: Sleep deprivation from 0-5 h after training for this task impaired memory consolidation for contextual fear conditioning whereas sleep deprivation from 5-10H after training had no effect, suggesting that sleep deprivation may act by modifying these molecular mechanisms of memory storage.
Abstract: Many behavioral and electrophysiological studies in animals and humans have suggested that sleep and circadian rhythms influence memory consolidation. In rodents, hippocampus-dependent memory may be particularly sensitive to sleep deprivation after training, as spatial memory in the Morris water maze is impaired by rapid eye movement sleep deprivation following training. Spatial learning in the Morris water maze, however, requires multiple training trials and performance, as measured by time to reach the hidden platform is influenced by not only spatial learning but also procedural learning. To determine if sleep is important for the consolidation of a single-trial, hippocampus-dependent task, we sleep deprived animals for 0–5 and 5–10 h after training for contextual and cued fear conditioning. We found that sleep deprivation from 0–5 h after training for this task impaired memory consolidation for contextual fear conditioning whereas sleep deprivation from 5–10 h after training had no effect. Sleep deprivation at either time point had no effect on cued fear conditioning, a hippocampus-independent task. Previous studies have determined that memory consolidation for fear conditioning is impaired when protein kinase A and protein synthesis inhibitors are administered at the same time as when sleep deprivation is effective, suggesting that sleep deprivation may act by modifying these molecular mechanisms of memory storage.
436 citations
TL;DR: It is demonstrated that following initial training, small practice-dependent improvements are possible before, but not following the large practice-independent gains that develop across a night of sleep, suggesting the existence of two discrete motor-learning processes.
Abstract: Growing evidence suggests that sleep plays an important role in the process of procedural learning. Most recently, sleep has been implicated in the continued development of motor-skill learning following initial acquisition. However, the temporal evolution of motor learning before and after sleep, the effects of different training regimens, and the long-term development of motor learning across multiple nights of sleep remain unknown. Here, we report data for subjects trained and retested on a sequential finger-tapping task across multiple days. The findings demonstrate firstly that following initial training, small practice-dependent improvements are possible before, but not following the large practice-independent gains that develop across a night of sleep. Secondly, doubling the quantity of initial training does not alter the amount of subsequent sleep-dependent learning that develops overnight. Thirdly, the amount of sleep-dependent learning does not correlate with the amount of practice-dependent learning achieved during training, suggesting the existence of two discrete motor-learning processes. Finally, whereas the majority of sleep-dependent motor-skill learning develops during the first night of sleep following training, additional nights of sleep still offer continued improvements.
434 citations
TL;DR: These findings suggest that OFC and ABL serve partially overlapping roles in the use of incentive information that supports normal discrimination performance.
Abstract: Recent work indicates that both orbitofrontal cortex (OFC) and the basolateral complex of the amygdala (ABL) are involved in processes by which cues are associated with predicted outcomes. To examine the respective roles of these structures in discrimination learning, rats with bilateral sham or neurotoxic lesions of either OFC or ABL were trained on a series of four 2-odor discrimination problems in a thirst-motivated go, no-go task. After acquisition of the series of odor problems, the rats were trained on serial reversals of the final odor problem. Performance on each problem was assessed by monitoring accuracy of choice behavior, and also by measuring latency to respond for fluid outcomes after odor sampling. During discrimination learning, rats in both lesioned groups had similar deficits, failing to show normal changes in response latency during learning, while at the same time exhibiting normal choice behavior relative to controls. Choice behavior was affected only during the reversal phase of training, in which OFC and ABL lesions produced distinctive deficits. Rats with ABL lesions were impaired on the first reversal (S1-/S2+), but were unimpaired at acquiring a reversal back to the original odor-outcome contigencies (S1+/S2-), whereas rats with OFC lesions were impaired on both types of reversals. These findings suggest that OFC and ABL serve partially overlapping roles in the use of incentive information that supports normal discrimination performance.
301 citations
TL;DR: The results indicate that the mechanisms underlying cannabinoid action in the LA partly resemble those observed in the nucleus accumbens and differ from those described for the hippocampus, and modulate both excitatory and inhibitory synaptic transmission via CB1.
Abstract: The endogenous cannabinoid system has been shown recently to play a crucial role in the extinction of aversive memories. As the amygdala is presumably involved in this process, we investigated the effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN-2) on synaptic transmission in the lateral amygdala (LA) of wild-type and cannabinoid receptor type 1 (CB1)-deficient mice. Extracellular field potential recordings and patch-clamp experiments were performed in an in vitro slice preparation. We found that WIN-2 reduces basal synaptic transmission and pharmacologically isolated AMPA receptor- and GABA(A) receptor-mediated postsynaptic currents in wild-type, but not in CB1-deficient mice. These results indicate that, in the LA, cannabinoids modulate both excitatory and inhibitory synaptic transmission via CB1. WIN-2-induced changes of paired-pulse ratio and of spontaneous and miniature postsynaptic currents suggest a presynaptic site of action. Inhibition of G(i/o) proteins and blockade of voltage-dependent and G protein-gated inwardly rectifying K(+) channels inhibited WIN-2 action on basal synaptic transmission. In contrast, modulation of the adenylyl cyclase-protein kinase A pathway, and blockade of presynaptic N- and P/Q- or of postsynaptic L- and R/T-type voltage-gated Ca(2+) channels did not affect WIN-2 effects. Our results indicate that the mechanisms underlying cannabinoid action in the LA partly resemble those observed in the nucleus accumbens and differ from those described for the hippocampus.
226 citations
TL;DR: Differential effects of aging on adaptation to gradual versus sudden visual feedback distortions, and may help to explain the conflicting results obtained in previous visuomotor adaptation studies, are suggested.
Abstract: Visuomotor adaptation to a gradual or sudden screen cursor rotation was investigated in healthy young and elderly subjects Both age groups were equally divided into two subgroups; one subgroup was exposed to 1125° step increments of visual feedback rotation, every 45 trials (up to a total of 90°), whereas a second subgroup was subjected to 90° rotation from the onset of exposure Participants performed discrete, horizontal hand movements to virtual targets in four randomized directions Targets appeared on a computer screen in front of them, and a board prevented vision of the hand at all times Differential effects of aging on visuomotor adaptation were found, depending on the time course of the visual distortion In both age groups, early exposure to the sudden visual feedback distortion resulted in typical spiral-like trajectories, which became straighter by late exposure However, the final adaptation level was reduced in the aged group, although the aftereffects were similar When subjects were exposed to the gradual distortion, no statistically significant differences in measures of adaptation with advancing age were found In this case, both age groups appeared to adapt equally However, after removal of the distortion, elderly subjects showed reduced aftereffects as compared with the young group These findings suggest differential effects of aging on adaptation to gradual versus sudden visual feedback distortions, and may help to explain the conflicting results obtained in previous visuomotor adaptation studies
199 citations
TL;DR: It was concluded that the 5-HT2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.
Abstract: This study reviews the role of the serotonin 5-HT2A receptor in learning as measured by the acquisition of the rabbit's classically conditioning nictitating membrane response, a component of the eyeblink response. Agonists at the 5-HT2A receptor including LSD (d-lysergic acid diethylamide) enhanced associative learning at doses that produce cognitive effects in humans. Some antagonists such as BOL (d-bromolysergic acid diethylamide), LY53,857, and ketanserin acted as neutral antagonists in that they had no effect on learning, whereas others (MDL11,939, ritanserin, and mianserin) acted as inverse agonists in that they retarded learning through an action at the 5-HT2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT2A receptors in schizophrenia. It was concluded that the 5-HT2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.
192 citations
TL;DR: Compared to young and middle-aged dogs, old and senior dogs were impaired on both the initial learning of the size task and the reversal of original reward contingencies, which may reflect different rates of aging in subregions of the frontal cortex.
Abstract: Several studies converge on the idea that executive processes age earlier than other cognitive processes. As part of a larger effort to investigate age-related changes in executive processes in the dog, inhibitory control was measured in young, middle-aged, old, and senior dogs using size discrimination learning and reversal procedures. Compared to young and middle-aged dogs, old and senior dogs were impaired on both the initial learning of the size task and the reversal of original reward contingencies. Impaired performance in the two aged groups was characterized as a delay in learning the correct stimulus-reward contingencies and, among the senior dogs in particular, an increase in perseverative responding. These separate patterns of reversal impairments in the old and senior dogs may reflect different rates of aging in subregions of the frontal cortex.
TL;DR: A differential conditioning paradigm in which odorants are paired with positive or negative gustatory reinforcers is developed and it is shown that breaks improve performance, in accord with basic principles of associative learning.
Abstract: Insect and mammalian olfactory systems are strikingly similar. Therefore, Drosophila can be used as a simple model for olfaction and olfactory learning. The brain of adult Drosophila, however, is still complex. We therefore chose to work on the larva with its yet simpler but adult-like olfactory system and provide evidence for olfactory learning in individually assayed Drosophila larvae. We developed a differential conditioning paradigm in which odorants are paired with positive ("+" fructose) or negative ("-" quinine or sodium chloride) gustatory reinforcers. Test performance of individuals from two treatment conditions is compared-one received odorant A with the positive reinforcer and odorant B with a negative reinforcer (A+/B-); animals from the other treatment condition were trained reciprocally (A-/B+). During test, differences in choice between A and B of individuals having undergone either A+/B- or A-/B+ training therefore indicate associative learning. We provide such evidence for both combinations of reinforcers; this was replicable across repetitions, laboratories, and experimenters. We further show that breaks improve performance, in accord with basic principles of associative learning. The present individual assay will facilitate electrophysiological studies, which necessarily use individuals. As such approaches are established for the larval neuromuscular synapse, but not in adults, an individual larval learning paradigm will serve to link behavioral levels of analysis to synaptic physiology.
TL;DR: It is shown that Fyn is a key molecule linking the BDNF receptor TrkB with NMDA receptors, which play an important role in spatial memory formation in a radial arm maze, and the importance of interaction between BDNF/TrkB signaling andNMDA receptors for spatial memory in the hippocampus is suggested.
Abstract: The N-methyl-D-aspartate (NMDA) receptors are involved in long-term potentiation (LTP), and are phosphorylated by several tyrosine kinases including a Src-family tyrosine kinase Fyn. Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which also enhances hippocampal synaptic transmission and efficacy by increasing NMDA receptor activity. Here, we show that Fyn is a key molecule linking the BDNF receptor TrkB with NMDA receptors, which play an important role in spatial memory formation in a radial arm maze. Spatial learning induced phosphorylation of TrkB, Fyn, and NR2B, but not NR2A, in the hippocampus. Fyn was coimmunoprecipitated with TrkB and NR2B, and this association was increased in well-trained rats compared with control animals. Continuous intracerebroventricular infusion of PP2, a tyrosine kinase inhibitor, in rats delayed memory acquisition in the radial arm maze, but PP2-treated animals reached the same level of learning as the controls. The phosphorylation of Fyn and NR2B, but not TrkB, was diminished by PP2 treatment. Our findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory in the hippocampus.
TL;DR: The results showed that auditory and visual working memory performance improves with age, suggesting functional maturation of underlying cognitive processes and brain areas.
Abstract: The neural processes subserving working memory, and brain structures underlying this system, continue to develop during childhood. We investigated the effects of age and gender on audiospatial and visuospatial working memory in a nonclinical sample of school-aged children using n-back tasks. The results showed that auditory and visual working memory performance improves with age, suggesting functional maturation of underlying cognitive processes and brain areas. The gender differences found in the performance of working memory tasks suggest a larger degree of immaturity in boys than girls at the age period of 6–10 yr. The differences observed between the mastering of auditory and visual working memory tasks may indicate that visual working memory reaches functional maturity earlier than the corresponding auditory system.
TL;DR: It is shown that predator stress selectively impaired recently acquired spatial working memory without affecting long-term (hippocampal-independent) spatial reference memory, and increased corticosterone levels correlated with impaired spatialWorking memory only under predator exposure, that is, fear-provoking conditions.
Abstract: We have shown previously that psychological stress (predator exposure) impairs spatial memory in rats. We have extended that finding here to show that predator stress selectively impaired recently acquired (hippocampal-dependent) spatial working memory without affecting long-term (hippocampal-independent) spatial reference memory. We also investigated why predator exposure impairs memory. Was spatial memory impaired because of the fear-provoking aspects of predator exposure or only because the cat was a novel and arousing stimulus? If the latter possibility was correct, then any novel and arousing stimulus, independent of its emotional valence (i.e., aversive or appetitive), would impair memory. We found that spatial working memory was not impaired when the male rats were exposed to a sexually receptive female rat, a stimulus that was novel and arousing to them, but not aversive. We also found that there was an equivalent increase in serum corticosterone levels in male rats exposed to either a cat or a female rat, but only the cat-exposed rats exhibited a significant correlation between corticosterone levels and impaired memory. Overall, this series of experiments demonstrates that (1) predator stress selectively impaired working (hippocampal-dependent), but not reference (hippocampal-independent), memory; (2) a fear-provoking stimulus, and not merely novelty and increased arousal, impaired spatial memory; and (3) increased corticosterone levels correlated withimpaired spatial working memory only under predator exposure, that is, fear-provoking conditions.
TL;DR: Overall, the data indicate that the progressive increase in spiking observed during TBS represents a form of physiologic temporal integration that is dependent on ERK MAPK activity, and may function in the regulation of neuronal excitability in hippocampal area CA1.
Abstract: Recent studies demonstrate a requirement for the Extracellular signal Regulated Kinase (ERK) mitogen-activated protein kinase (MAPK) cascade in both the induction of long-lasting forms of hippocampal synaptic plasticity and in hippocampus-dependent associative and spatial learning. In the present studies, we investigated mechanisms by which ERK might contribute to synaptic plasticity at Schaffer collateral synapses in hippocampal slices. We found that long-term potentiation (LTP) induced with a pair of 100-Hz tetani does not require ERK activation in mice whereas it does in rats. However, in mice, inhibition of ERK activation blocked LTP induced by two LTP induction paradigms that mimicked the endogenous θ rhythm. In an additional series of studies, we found that mice specifically deficient in the ERK1 isoform of MAPK showed no impairments in tests of hippocampal physiology. To investigate ERK-dependent mechanisms operating during LTP-inducing stimulation paradigms, we monitored spike production in the cell body layer of the hippocampus during the period of θ-like LTP-inducing stimulation. θ-burst stimulation (TBS) produced a significant amount of postsynaptic spiking, and the likelihood of spike production increased progressively over the course of the three trains of TBS independent of any apparent increase in Excitatory Post-Synaptic Potential (EPSP) magnitude. Inhibition of ERK activation dampened this TBS-associated increase in spiking. These data indicate that, for specific patterns of stimulation, ERK may function in the regulation of neuronal excitability in hippocampal area CA1. Overall, our data indicate that the progressive increase in spiking observed during TBS represents a form of physiologic temporal integration that is dependent on ERK MAPK activity.
TL;DR: It is suggested that environmental enrichment initiated at middle age can reduce age-related impairments in spatial memory in males and females, although the underlying neurobiological mechanisms of this effect remain unknown.
Abstract: The present study compared the effects of environmental enrichment on spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin levels in middle-aged male and female mice. Prior to testing, a subset of 18-month-old male and female C57BL/6 mice was housed with two to three toys and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both sexes and the remaining middle-aged mice were group (social) housed, but not exposed to enriching objects. After the enrichment period, all mice were tested in a 1-day version of the Morris water maze, in which both spatial and nonspatial memory were assessed. Immediately after testing, the hippocampus and frontoparietal cortex were dissected, and GAD activity and synaptophysin levels were measured. Environmental enrichment reduced the age-related impairment in spatial acquisition and retention; relative to adult social controls, middle-aged enriched mice were unimpaired, whereas middle-aged social controls were impaired. This reduction was similar in middle-aged males and females. Enrichment did not affect cued memory in either sex. Although hippocampal GAD activity was increased by enrichment in males, all other neurochemical measurements were unaffected by enrichment or aging in either sex. These data suggest that environmental enrichment initiated at middle age can reduce age-related impairments in spatial memory in males and females, although the underlying neurobiological mechanisms of this effect remain unknown.
TL;DR: The results indicate that the brain uses circuits that are dedicated to specific time spans, and that each circuit processes stimuli across nontemporal stimulus features, which indicates that temporal learning does not rely on changes in early, subcortical processing, because the nontem temporal features are encoded by different channels at early stages.
Abstract: Although temporal processing is used in a wide range of sensory and motor tasks, there is little evidence as to whether a single centralized clock or a distributed system underlies timing in the range of tens to hundreds of milliseconds We investigated this question by studying whether learning on an auditory interval discrimination task generalizes across stimulus types, intervals, and frequencies The degree to which improvements in timing carry over to different stimulus features constrains the neural mechanisms underlying timing Human subjects trained on a 100- or 200-msec interval discrimination task showed an improvement in temporal resolution This learning generalized to a perceptually distinct duration stimulus, as well as to the trained interval presented with tones at untrained spectral frequencies The improvement in performance did not generalize to untrained intervals To determine if spectral generalization was dependent on the importance of frequency information in the task, subjects were simultaneously trained on two different intervals identified by frequency As a whole, our results indicate that the brain uses circuits that are dedicated to specific time spans, and that each circuit processes stimuli across nontemporal stimulus features The patterns of generalization additionally indicate that temporal learning does not rely on changes in early, subcortical processing, because the nontemporal features are encoded by different channels at early stages
TL;DR: A new model for classical conditioning of odor preference learning in rat pups proposes that the interaction of noradrenergic and serotonergic input with odor occurs in the mitral cells of the olfactory bulb through activation of cyclic adenosine monophosphate (cAMP).
Abstract: In the present study we assess a new model for classical conditioning of odor preference learning in rat pups. In preference learning beta(1)-adrenoceptors activated by the locus coeruleus mediate the unconditioned stimulus, whereas olfactory nerve input mediates the conditioned stimulus, odor. Serotonin (5-HT) depletion prevents odor learning, with 5-HT(2A/2C) agonists correcting the deficit. Our new model proposes that the interaction of noradrenergic and serotonergic input with odor occurs in the mitral cells of the olfactory bulb through activation of cyclic adenosine monophosphate (cAMP). Here, using selective antibodies and immunofluorescence examined with confocal microscopy, we demonstrate that beta(1)-adrenoceptors and 5-HT(2A) receptors colocalize primarily on mitral cells. Using a cAMP assay and cAMP immunocytochemistry, we find that beta-adrenoceptor activation by isoproterenol, at learning-effective and higher doses, significantly increases bulbar cAMP, as does stroking. As predicted by our model, the cAMP increases are localized to mitral cells. 5-HT depletion of the olfactory bulb does not affect basal levels of cAMP but prevents isoproterenol-induced cAMP elevation. These results support the model. We suggest the mitral-cell cAMP cascade converges with a Ca(2+) pathway activated by odor to recruit CREB phosphorylation and memory-associated changes in the olfactory bulb. The dose-related increase in cAMP with isoproterenol implies a critical cAMP window because the highest dose of isoproterenol does not produce learning.
TL;DR: The multiplicity of serotonergic mechanisms recruited into action during learning in Aplysia can now be addressed from a molecular point of view.
Abstract: The neurotransmitter serotonin (5-HT) plays an important role in memory encoding in Aplysia. Early evidence showed that during sensitization, 5-HT activates a cyclic AMP-protein kinase A (cAMP-PKA)-dependent pathway within specific sensory neurons (SNs), which increases their excitability and facilitates synaptic transmission onto their follower motor neurons (MNs). However, recent data suggest that serotonergic modulation during sensitization is more complex and diverse. The neuronal circuits mediating defensive reflexes contain a number of interneurons that respond to 5-HT in ways opposite to those of the SNs, showing a decrease in excitability and/or synaptic depression. Moreover, in addition to acting through a cAMP-PKA pathway within SNs, 5-HT is also capable of activating a variety of other protein kinases such as protein kinase C, extracellular signal-regulated kinases, and tyrosine kinases. This diversity of 5-HT responses during sensitization suggests the presence of multiple 5-HT receptor subtypes within the Aplysia central nervous system. Four 5-HT receptors have been cloned and characterized to date. Although several others probably remain to be characterized in molecular terms, especially the Gs-coupled 5-HT receptor capable of activating cAMP-PKA pathways, the multiplicity of serotonergic mechanisms recruited into action during learning in Aplysia can now be addressed from a molecular point of view.
TL;DR: Results indicate that pharmacological manipulation of 5-HT1-7 receptors or5-HT reuptake sites might modulate memory consolidation, which is consistent with the emerging notion that 5- HT plays a key role in memory formation.
Abstract: Recent studies using both invertebrates and mammals have revealed that endogenous serotonin (5-hydroxytryptamine [5-HT]) modulates plasticity processes, including learning and memory. However, little is currently known about the mechanisms, loci, or time window of the actions of 5-HT. The aim of this review is to discuss some recent results on the effects of systemic administration of selective agonists and antagonists of 5-HT on associative learning in a Pavlovian/instrumental autoshaping (P/I-A) task in rats. The results indicate that pharmacological manipulation of 5-HT1-7 receptors or 5-HT reuptake sites might modulate memory consolidation, which is consistent with the emerging notion that 5-HT plays a key role in memory formation.
TL;DR: It is suggested that the visual input of a recently learned face can rapidly trigger retrieval of associated person-specific information through reactivation of distributed cortical networks linked via hippocampal connections.
Abstract: Rapidly identifying known individuals is an essential skill in human society. To elucidate the neural basis of this skill, we monitored brain activity while experimental participants demonstrated their ability to recognize people on the basis of viewing their faces. Each participant first memorized the faces of 20 individuals who were not known to the participants in advance. Each face was presented along with a voice simulating the individual speaking their name and a biographical fact. Following this learning procedure, the associated verbal information could be recalled accurately in response to each face. These learned faces were subsequently viewed together with new faces in a memory task. Subjects made a yes-no recognition decision in response to each face while also covertly retrieving the person-specific information associated with each learned face. Brain activity that accompanied this retrieval of person-specific information was contrasted to that when new faces were processed. Functional magnetic resonance imaging in 10 participants showed that several brain regions were activated during blocks of learned faces, including left hippocampus, left middle temporal gyrus, left insula, and bilateral cerebellum. Recordings of event-related brain potentials in 10 other participants tracked the time course of face processing and showed that learned faces engaged neural activity responsible for person recognition 300-600 msec after face onset. Collectively, these results suggest that the visual input of a recently learned face can rapidly trigger retrieval of associated person-specific information through reactivation of distributed cortical networks linked via hippocampal connections.
TL;DR: The data imply that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms and further indicate that these opposed effects are related to the task-inherent reinforcement contingencies.
Abstract: The brain's histaminergic system has been implicated in hippocampal synaptic plasticity, learning, and memory, as well as brain reward and reinforcement. Our past pharmacological and lesion studies indicated that the brain's histamine system exerts inhibitory effects on the brain's reinforcement respective reward system reciprocal to mesolimbic dopamine systems, thereby modulating learning and memory performance. Given the close functional relationship between brain reinforcement and memory processes, the total disruption of brain histamine synthesis via genetic disruption of its synthesizing enzyme, histidine decarboxylase (HDC), in the mouse might have differential effects on learning dependent on the task-inherent reinforcement contingencies. Here, we investigated the effects of an HDC gene disruption in the mouse in a nonreinforced object exploration task and a negatively reinforced water-maze task as well as on neo- and ventro-striatal dopamine systems known to be involved in brain reward and reinforcement. Histidine decarboxylase knockout (HDC-KO) mice had higher dihydrophenylacetic acid concentrations and a higher dihydrophenylacetic acid/dopamine ratio in the neostriatum. In the ventral striatum, dihydrophenylacetic acid/dopamine and 3-methoxytyramine/dopamine ratios were higher in HDC-KO mice. Furthermore, the HDC-KO mice showed improved water-maze performance during both hidden and cued platform tasks, but deficient object discrimination based on temporal relationships. Our data imply that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms and further indicate that these opposed effects are related to the task-inherent reinforcement contingencies.
TL;DR: Subprocesses of experimental extinction of conditioned taste aversion are dissected to suggest spontaneous overtaking of the behavioral control by the original association is regulated at least in part by beta-adrenergic input, probably operating via the cAMP cascade, long after the offset of the conditioned stimulus.
Abstract: The study of experimental extinction and of the spontaneous recovery of the extinguished memory could cast light on neurobiological mechanisms by which internal representations compete to control behavior. In this work, we use a combination of behavioral and molecular methods to dissect subprocesses of experimental extinction of conditioned taste aversion (CTA). Extinction of CTA becomes apparent only 90 min after the extinction trial. This latency is insensitive to muscarinic and β-adrenergic modulation and to protein synthesis inhibition in the insular cortex (IC). Immediately afterwards, however, the extinguishing trace becomes sensitive to β-adrenergic blockade and protein synthesis inhibition. The subsequent kinetics and magnitude of extinction depend on whether a spaced or massed extinction protocol is used. A massed protocol is highly effective in the short run, but results in apparent stagnation of extinction in the long-run, which conceals fast spontaneous recovery of the preextinguished trace. This recovery can be truncated by a β-adrenergic agonist or a cAMP analog in the insular cortex, suggesting that spontaneous overtaking of the behavioral control by the original association is regulated at least in part by β-adrenergic input, probably operating via the cAMP cascade, long after the offset of the conditioned stimulus. Hence, the performance of the subject in experimental extinction is the sum total of multiple, sometimes conflicting, time-dependent processes.
TL;DR: Honeybees were not able to differentiate reinforced from nonreinforced stimuli in Experiment 1, but in Experiment 2, differentiation between the single odorant A and the ternary compound developed more easily than between the binary compound BC and ABC.
Abstract: We investigated the capability of honeybees to discriminate between single odorants, binary olfactory mixtures, and ternary olfactory mixtures in olfactory conditioning of the proboscis extension reflex. In Experiment 1, three single odorants (A+, B+, and C+) and three binary mixtures of these odors (AB+, AC+, and BC+) were reinforced while the ternary compound, consisting of all three odors (ABC-), was nonreinforced. In Experiment 2, only one single odorant (A+) and one binary olfactory compound (BC+) were reinforced while the ternary compound (ABC-) consisting of the single odor and the binary compound was nonreinforced. We studied whether bees can solve these problems and whether the course of differentiation can be predicted by the unique cue theory, a modified unique cue theory, or Pearce's configural theory. Honeybees were not able to differentiate reinforced from nonreinforced stimuli in Experiment 1. However, summation to ABC observed at the beginning of training contradicts the predictions of Pearce's configural theory. In Experiment 2, differentiation between the single odorant A and the ternary compound developed more easily than between the binary compound BC and ABC. This pattern of differentiation is in line with a modified unique cue theory and Pearce's configural theory. Summation to ABC at the beginning of training, however, again was at odds with Pearce's configural theory. Thus, olfactory compound processing in honeybees can best be explained by a modified unique cue theory.
TL;DR: This study provides the first unequivocal evidence that arg 3.1/arc expression is induced by a learning task and strongly suggests a role of arg 2.3/arc mRNA in the early and late cellular mechanisms underlying the stabilization of the memory trace.
Abstract: The effector immediate-early gene (IEG) arg 3.1, also called arc, encodes a protein interacting with the neuronal cytoskeleton. The selective localization of arg 3.1/arc mRNA in activated dendritic segments suggests that the arg 3.1/arc protein may be synthesized at activated post-synaptic sites and that arg 3.1/arc could participate in structural and functional modifications underlying cognitive processes like memory formation. To analyze whether learning itself is sufficient to trigger expression of arg 3.1/arc, we developed a one-trial learning paradigm in which mice learned to enter a dark compartment to escape from an aversively illuminated area. Arg 3.1/arc mRNA expression was analyzed by in situ hybridization in three groups of mice as follows: a control group with no access to the dark compartment, a learning group having access to the dark compartment for one trial, and a retrieval group having access to the dark compartment for two trials on consecutive days. All animals from the learning and retrieval groups escaped the illuminated area, and those tested 24 h later (retrieval group) showed a strongly reduced latency to enter the dark compartment, demonstrating the validity of our learning paradigm to induce long-term memory. Our results show that acquisition of a simple task results in a brain area-specific biphasic increase in arg 3.1/arc mRNA expression 15 min and 4.5 h post-training. This increase was detected specifically in the learning group but neither in the control nor in the retrieval groups. The pattern of arg 3.1/arc mRNA expression corresponds temporally to the two mRNA- and protein-synthesis-dependent periods of long-term memory formation. Our study provides the first unequivocal evidence that arg 3.1/arc expression is induced by a learning task and strongly suggests a role of arg 3.1/arc mRNA in the early and late cellular mechanisms underlying the stabilization of the memory trace.
TL;DR: It is demonstrated that TA-CA1 synapses undergo both early- and late-phase long-term potentiation (LTP) in rat hippocampal slices, indicating that the TA- CA1 synapse may rely on a refined modulation of inhibition to exhibit LTP.
Abstract: The hippocampus and the nearby medial temporal lobe structures are required for the formation, consolidation, and retrieval of episodic memories. Sensory information enters the hippocampus via two inputs from entorhinal cortex (EC): One input (perforant path) makes synapses on the dendrites of dentate granule cells as the first set of synapses in the trisynaptic circuit, the other (temporoammonic; TA) makes synapses on the distal dendrites of CA1 neurons. Here we demonstrate that TA–CA1 synapses undergo both early- and late-phase long-term potentiation (LTP) in rat hippocampal slices. LTP at TA–CA1 synapses requires both NMDA receptor and voltage-gated Ca2+ channel activity. Furthermore, TA–CA1 LTP is insensitive to the blockade of fast inhibitory transmission (GABAA-mediated) and, interestingly, is dependent on GABAB-dependent slow inhibitory transmission. These findings indicate that the TA–CA1 synapses may rely on a refined modulation of inhibition to exhibit LTP.
TL;DR: Bilateral amygdala damage resulted in severe impairment in both odor-name matching as well as in odor-odor recognition memory, suggesting that the human amygdala is essential for olfactory memory.
Abstract: The medial temporal lobe is known to play a role in the processing of olfaction and memory. The specific contribution of the human amygdala to memory for odors has not been addressed, however. The role of this region in memory for odors was assessed in patients with unilateral amygdala damage due to temporal lobectomy (n = 20; 11 left, 9 right), one patient with selective bilateral amygdala damage, and in 20 age-matched normal controls. Fifteen odors were presented, followed 1 h later by an odor-name matching test and an odor-odor recognition test. Signal detection analyses showed that both unilateral groups were impaired in their memory for matching odors with names, these patients were not significantly impaired on odor-odor recognition. Bilateral amygdala damage resulted in severe impairment in both odor-name matching as well as in odor-odor recognition memory. Importantly, none of the patients were impaired on an auditory verbal learning task, suggesting that these findings reflect a specific impairment in olfactory memory, and not merely a more general memory deficit. Taken together, the data provide neuropsychological evidence that the human amygdala is essential for olfactory memory.
TL;DR: When rats are tested on a task with demands dependent on the hippocampus, it appears that the hippocampus is not fully activated after diencephalic damage.
Abstract: A rodent model of diencephalic amnesia, pyrithiamine-induced thiamine deficiency (PTD), was used to investigate diencephalic-hippocampal interactions. Acetylcholine (ACh) release, a marker of memory-related activation, was measured in the hippocampus of PTD-treated and control rats prior to, during, and after spontaneous alternation test. During behavioral testing, all animals displayed increases in ACh release. However, both the percent increase of ACh release during spontaneous alternation testing and the alternation scores were higher in control rats relative to PTD-treated rats. Thus, when rats are tested on a task with demands dependent on the hippocampus, it appears that the hippocampus is not fully activated after diencephalic damage.
TL;DR: The present results suggest that multiple working memory processes are engaged during complex tests of visuospatial function and the neuroanatomical substrates controlling these processes are affected differentially by age in the beagle dog.
Abstract: The present study used two versions of a spatial list learning (SLL) paradigm to examine the effects of increased cognitive load on visuospatial working memory processes in young and old beagle dogs. In the first experiment, young, and a select group of old dogs were first presented with one item, then two, and then three, and were rewarded for responding to the novel position. The dogs were able to learn the task at short delays, but compared with young dogs, old dogs performed worse at delays of 10 sec, and could not reach longer delays. Analysis of errors indicated that memory was best for end items in the spatial list and that within sessions, the number of errors in later trials was greater than the number of errors in earlier trials. A second version of the task, a modified SLL (mSLL) was developed to control for the use of non-mnemonic strategies on the SLL task. In this version, the first two items were presented individually. Acquisition and maximal memory performance were better in the young relative to the old dogs. Similar to the original SLL design, memory for early list items was worse than memory for later list items in both young and old dogs. The within-session pattern of errors however, did not change from trial to trial on the mSLL. The present results suggest that multiple working memory processes are engaged during complex tests of visuospatial function and the neuroanatomical substrates controlling these processes are affected differentially by age in the beagle dog.