Showing papers in "Learning & Memory in 2005"

Planting misinformation in the human mind: A 30-year investigation of the malleability of memory

Abstract: The misinformation effect refers to the impairment in memory for the past that arises after exposure to misleading information. The phenomenon has been investigated for at least 30 years, as investigators have addressed a number of issues. These include the conditions under which people are especially susceptible to the negative impact of misinformation, and conversely when are they resistant. Warnings about the potential for misinformation sometimes work to inhibit its damaging effects, but only under limited circumstances. The misinformation effect has been observed in a variety of human and nonhuman species. And some groups of individuals are more susceptible than others. At a more theoretical level, investigators have explored the fate of the original memory traces after exposure to misinformation appears to have made them inaccessible. This review of the field ends with a brief discussion of the newer work involving misinformation that has explored the processes by which people come to believe falsely that they experienced rich complex events that never, in fact, occurred.

Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage

Abstract: Deletions, translocations, or point mutations in the CREB-binding protein (CBP) gene have been associated with Rubinstein-Taybi Syndrome; a human developmental disorder characterized by retarded growth and reduced mental function. To examine the role of CBP in memory, transgenic mice were generated in which the CaMKIIα promoter drives expression of an inhibitory truncated CBP protein in forebrain neurons. Examination of hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory storage, revealed significantly reduced late-phase LTP induced by dopamine-regulated potentiation in hippocampal slices from CBP transgenic mice. However, four-train induced late-phase LTP is normal. Behaviorally, CBP transgenic mice exhibited memory deficits in spatial learning in the Morris water maze and deficits in long-term memory for contextual fear conditioning, two hippocampus-dependent tasks. Together, these results demonstrate that CBP is involved in specific forms of hippocampal synaptic plasticity and hippocampus-dependent long-term memory formation.

Encoding, consolidation, and retrieval of contextual memory: Differential involvement of dorsal CA3 and CA1 hippocampal subregions

Abstract: Studies on human and animals shed light on the unique hippocampus contributions to relational memory. However, the particular role of each hippocampal subregion in memory processing is still not clear. Hippocampal computational models and theories have emphasized a unique function in memory for each hippocampal subregion, with the CA3 area acting as an autoassociative memory network and the CA1 area as a critical output structure. In order to understand the respective roles of the CA3- and CA1-hippocampal areas in the formation of contextual memory, we studied the effects of the reversible inactivation by lidocaine of the CA3 or CA1 areas of the dorsal hippocampus on acquisition, consolidation, and retrieval of a contextual fear conditioning. Whereas infusions of lidocaine never impaired elementary tone conditioning, their effects on contextual conditioning provided interesting clues about the role of these two hippocampal regions. They demonstrated first that the CA3 area is necessary for the rapid elaboration of a unified representation of the context. Secondly, they suggested that the CA1 area is rather involved in the consolidation process of contextual memory. Third, they showed that CA1 or CA3 inactivation during retention test has no effect on contextual fear retrieval when a recognition memory procedure is used. In conclusion, our findings point as evidence that CA1 and CA3 subregions of the dorsal hippocampus play important and different roles in the acquisition and consolidation of contextual fear memory, whereas they are not required for context recognition.

Insulin receptor signaling in long-term memory consolidation following spatial learning.

Abstract: Evidence has shown that the insulin and insulin receptor (IR) play a role in cognitive function. However, the detailed mechanisms underlying insulin's action on learning and memory are not yet understood. Here we investigated changes in long-term memory-associated expression of the IR and downstream molecules in the rat hippocampus. After long-term memory consolidation following a water maze learning experience, gene expression of IR showed an up-regulation in the CA1, but a down-regulation in the CA3 region. These were correlated with a significant reduction in hippocampal IR protein levels. Learning-specific increases in levels of downstream molecules such as IRS-1 and Akt were detected in the synaptic membrane accompanied by decreases in Akt phosphorylation. Translocation of Shc protein to the synaptic membrane and activation of Erk1/2 were also observed after long-term memory formation. Despite the clear memory-correlated alterations in IR signaling pathways, insulin deficits in experimental diabetes mellitus (DM) rats induced by intraperitoneal injections of streptozotocin resulted in only minor memory impairments. This may be due to higher glucose levels in the DM brain, and to compensatory mechanisms from other signaling pathways such as the insulin-like growth factor-1 receptor (IGF-1R) system. Our results suggest that insulin/IR signaling plays a modulatory role in learning and memory processing, which may be compensated for by alternative pathways in the brain when an insulin deficit occurs.

The neural correlates of implicit and explicit sequence learning: Interacting networks revealed by the process dissociation procedure.

Abstract: In two H2(15)O PET scan experiments, we investigated the cerebral correlates of explicit and implicit knowledge in a serial reaction time (SRT) task. To do so, we used a novel application of the Process Dissociation Procedure, a behavioral paradigm that makes it possible to separately assess conscious and unconscious contributions to performance during a subsequent sequence generation task. To manipulate the extent to which the repeating sequential pattern was learned explicitly, we varied the pace of the choice reaction time task-a variable that is known to have differential effects on the extent to which sensitivity to sequence structure involves implicit or explicit knowledge. Results showed that activity in the striatum subtends the implicit component of performance during recollection of a learned sequence, whereas the anterior cingulate/mesial prefrontal cortex (ACC/MPFC) supports the explicit component. Most importantly, we found that the ACC/MPFC exerts control on the activity of the striatum during retrieval of the sequence after explicit learning, whereas the activity of these regions is uncoupled when learning had been essentially implicit. These data suggest that implicit learning processes can be successfully controlled by conscious knowledge when learning is essentially explicit. They also supply further evidence for a partial dissociation between the neural substrates supporting conscious and nonconscious components of performance during recollection of a learned sequence.

Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction.

Abstract: There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of the DH blunted the expression of conditional freezing to an auditory conditional stimulus (CS), but did not affect the acquisition of extinction to that CS. In contrast, DH lesions impaired the context-specific expression of extinction, eliminating the renewal of fear normally observed to a CS presented outside of the extinction context. Post-extinction DH lesions also eliminated the context dependence of fear extinction. These results are consistent with those using pharmacological inactivation of the DH and suggest that the DH is required for using contextual stimuli to regulate the expression of fear to a Pavlovian CS after extinction.

Recollection in an episodic-like memory task in the rat.

Abstract: Episodic memory in humans is the conscious recollection of a past event. Animal models of episodic-like memory assess the memory for "what"happened, "where" it happened, and either "when" it happened, or in "which" context it happened, although recollection on such tasks is often difficult to measure. Here we present the first evidence of successful recollection of a past event in a rat in a task which is easily performed, requires little training, and is easily adaptable for other commonly used laboratory species.

Neural activity during encoding predicts false memories created by misinformation.

Abstract: False memories are often demonstrated using the misinformation paradigm, in which a person's recollection of a witnessed event is altered after exposure to misinformation about the event. The neural basis of this phenomenon, however, remains unknown. We used fMRI to investigate encoding processes during the viewing of an event and misinformation to see whether neural activity during either encoding phase could predict what would be remembered. fMRI data were collected as participants studied eight vignettes (Original Event phase). Shortly afterward, participants studied the same vignettes during scanning, but with changes to several details, serving as the misinformation (Misinformation phase). Two days later, their memories for the Original Event were assessed. Activity that subsequently led to true and false memories was examined during both encoding phases. Two interaction patterns between encoding phase (Original Event and Misinformation) and type of memory (true and false) were observed in MTL and PFC regions. In the left hippocampus tail and perirhinal cortex, a predictive item-encoding pattern was observed. During the Original Event phase, activity was greater for true than false memories, whereas during the Misinformation phase, activity was greater for false than true memories. In other regions, a pattern suggestive of source encoding was observed, in which activity for false memories was greater during the Original Event phase than the Misinformation phase. Together, these results suggest that encoding processes play a critical role in determining true and false memory outcome in misinformation paradigms.

Lasting increases in basolateral amygdala activity after emotional arousal: Implications for facilitated consolidation of emotional memories

Abstract: Manipulations that reduce or enhance the activity of basolateral amygdala (BLA) neurons in the minutes to hours after training have been shown to respectively impair or facilitate retention on the inhibitory avoidance task. Although this suggests that BLA activity is altered after emotional arousal, such changes have not been directly demonstrated. To test this, we devised a feline analog of the inhibitory avoidance task and recorded BLA unit activity before and after a single inescapable footshock. Single-unit recordings revealed that the firing rate of many BLA neurons gradually increased after the footshock, peaking 30-50 min post-shock and then subsiding to baseline levels 2 h later. During this period of increased activity, the discharges of simultaneously recorded BLA cells were more synchronized than before the shock. Although it was known that pairing innocuous (conditioned stimulus, CS) and noxious stimuli modifies the responsiveness of BLA neurons to the CS, our results constitute the first demonstration that emotional arousal produces lasting increases in the spontaneous firing rates of BLA neurons. We propose that these changes in BLA activity may promote Hebbian interactions between coincident but spatially distributed activity patterns in BLA targets, facilitating the consolidation of emotional memories.

Involvement of the rat anterior cingulate cortex in control of instrumental responses guided by reward expectancy.

Abstract: The rat anterior cingulate cortex (ACC) is an integral part of the prefrontal cortex (Paxinos and Watson 1997) lying on its medial surface caudal to the genu of the corpus callosum with interconnections to numerous regions including the caudate nucleus (McGeorge and Faull 1989), nucleus accumbens (ACB) (Berendse et al. 1992; Brog et al. 1993), ventral tegmental area (VTA), mediodorsal nucleus of the thalamus (Uylings and van Eden 1990), and amygdala (Divac and Diemer 1980). The ACC has been implicated in learning to discriminate multiple visual stimuli on the basis of the association of these stimuli with reward. Accordingly, lesions of the ACC impaired performance of rats preferentially in complex tasks including eight-pair concurrent visual discrimination (Bussey et al. 1997b), a two-stimulus temporally discriminated approach task (Cardinal et al. 2003), and autoshaping (Bussey et al. 1997a; Parkinson et al. 2000; Cardinal et al. 2002, 2003). In contrast, lesions of the ACC did not interfere with performance in simpler tasks such as one-pair concurrent visual discrimination (Bussey et al. 1997b), and even improved performance in some tasks (Bussey et al. 1996). From these and other studies it has been concluded that the ACC plays an important role in mediating instrumental behaviors that depend on stimulus-reinforcer contingencies and require discrimination of relatively similar stimuli. In particular, the ACC could represent a `disambiguating' structure enhancing stimulus discrimination, if stimuli share common elements, i.e., are in the same sensory modality and are similar (Cardinal et al. 2003). In addition, the ACC has been implicated in effort-based decision-making. Rats with ACC lesions tested in a cost-benefit T-maze task no longer preferred the effortful high-reward action; rather they preferred the less effortful low-reward action (Walton et al. 2003). Thus, ACC functions might be essential for decisions regarding whether it is worth making effortful actions given the value of the expected outcome (Rushworth et al. 2004). On the other hand, lesions of the ACC did not impair the high preference of rats for large, delayed rewards over immediate, low rewards in a delayed reinforcement choice task (Cardinal et al. 2001). These findings raise the possibility that the ACC is not necessary in all decisions involving cost-benefit analysis. Major variables influencing effort-based decisions are only partially known, and their impact is not fully understood. For instance, it is likely that response costs may include not only force requirements or caloric expenditure, but probably also skill or temporal requirements (Salamone et al. 2003). Thus, it remains to be further specified which kind of effort-based decisions depend on the ACC. The aim of the present study was to characterize the role of the ACC (including the Cg1 and Cg2 fields of the ACC) in stimulus-reward learning and effort-based decision-making in more detail. In Experiment 1, rats were trained in a T-maze cost-benefit task (Walton et al. 2003) in which they could either choose to climb a barrier (25 cm) to obtain a high reward (four pellets) in one arm of the maze or a low reward (two pellets) in the other arm with no barrier present. In Experiment 2, the same rats were tested in a modified lever-press task (Salamone et al. 1991) in which they had the choice between pressing a lever to receive preferred food pellets on a progressive ratio (PR) schedule, or free feeding on a less preferred food, i.e., lab chow. If the ACC plays a general role in effort-based decisions, rats with ACC lesions should be impaired in both kinds of cost-benefit tasks. In Experiment 3, another group of rats was examined in a reaction time (RT) task demanding conditioned lever release in which the upcoming reward magnitude (five vs. one food pellet) was signalled in advance by discriminative stimuli. Usually, intact rats rapidly discriminate reward magnitude-predictive stimuli and respond faster for expected high reward within a few days (e.g., Bohn et al. 2003a; Giertler et al. 2003). In this task, visual stimuli which predict reward magnitudes differ only in their brightness, i.e., they are in the same modality and not easy to discriminate. If the ACC is involved to facilitate discrimination of similar conditioned stimuli, rats with ACC lesions should be impaired in this discrimination task.

Sleep enhances explicit recollection in recognition memory.

Abstract: Recognition memory is considered to be supported by two different memory processes, i.e., the explicit recollection of information about a previous event and an implicit process of recognition based on an acontextual sense of familiarity. Both types of memory supposedly rely on distinct memory systems. Sleep is known to enhance the consolidation of memories, with the different sleep stages affecting different types of memory. In the present study, we used the process-dissociation procedure to compare the effects of sleep on estimates of explicit (recollection) and implicit (familiarity) memory formation on a word-list discrimination task. Subjects studied two lists of words before a 3-h retention interval of sleep or wakefulness, and recognition was tested afterward. The retention intervals were positioned either in the early night when sleep is dominated by slow-wave sleep (SWS), or in the late night, when sleep is dominated by REM sleep. Sleep enhanced explicit recognition memory, as compared with wakefulness (P < 0.05), whereas familiarity was not affected by sleep. Moreover, explicit recognition was particularly enhanced after sleep in the early-night retention interval, and especially when the words were presented with the same contextual features as during learning, i.e., in the same font (P < 0.05). The data indicate that in a task that allows separating the contribution of explicit and implicit memory, sleep particularly supports explicit memory formation. The mechanism of this effect appears to be linked to SWS.

Endogenous BDNF is required for long-term memory formation in the rat parietal cortex.

Abstract: Information storage in the brain is a temporally graded process involving different memory phases as well as different structures in the mammalian brain. Cortical plasticity seems to be essential to store stable long-term memories, although little information is available at the moment regarding molecular and cellular events supporting memory consolidation in the neocortex. Brain-derived neurotrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in hippocampal and cortical neurons. We have recently demonstrated that endogenous BDNF in the hippocampus is involved in memory formation. Here we examined the role of BDNF in the parietal cortex (PCx) in short-term (STM) and long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the PCx impaired both STM and LTM retention scores and decreased the phosphorylation state of cAMP response element-binding protein (CREB). In contrast, intracortical administration of recombinant human BDNF facilitated LTM and increased CREB activation. Moreover, inhibitory avoidance training is associated with a rapid and transient increase in phospho-CREB/total CREB ratio in the PCx. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of inhibitory avoidance learning, possibly involving CREB activation-dependent mechanisms. The present data support the idea that early sensory areas constitute important components of the networks subserving memory formation and that information processing in neocortex plays an important role in memory formation.

Systemic Blockade of D2-Like Dopamine Receptors Facilitates Extinction of Conditioned Fear in Mice.

Abstract: Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear conditioning mice with three pairings of a white noise conditional stimulus (CS) with moderate footshock, we injected the D2 antagonist, sulpiride, the D2 agonist, quinpirole, or vehicle, just before repeated CS presentations to generate extinction. We assayed fear by measuring behavioral freezing during extinction presentations and then drug-free during CS presentations 1 d later. We found that sulpiride injections before extinction training facilitated extinction memory 24 h later, while quinpirole partially blocked extinction memory compared with vehicle-injected controls. Notably, sulpiride treatment yielded significant extinction after spaced CS presentations, which yield no extinction at all in vehicle-treated mice. These findings suggest that dopamine D2-mediated signaling contributes physiological inhibition of extinction, and that D2 antagonists may be useful adjuncts to behavior therapy of human anxiety disorders.

Working memory deficits in retinoid X receptor γ-deficient mice

Abstract: Retinoid signaling has been recently shown to be required for mnemonic functions in rodents. To dissect the behavioral and molecular mechanisms involved in this requirement, we have analyzed the spatial and recognition working memory in mice carrying null mutations of retinoid receptors RARβ and RXRγ. Double mutants appeared deficient in spatial working memory as tested in spontaneous alternation in the Y-maze and delayed nonmatch to place (DNMTP) test in the T-maze. These mutant mice did acquire, however, spatial place reference or right/left discrimination tasks in the T-maze set-up, indicating that basic sensorimotor functions, spatial orientation, and motivational factors are unlikely to account for deficits in working memory-sensitive tasks. Double-mutant mice were also deficient in novel object recognition at intermediate, but not short delays. RXRγ appeared to be the functionally predominant receptor in modulation of the working memory, as RXRγ, but not RARβ single null mutant mice exhibited deficits similar to those observed in the double mutants. The mechanism of this modulation is potentially related to functions of RXRγ in frontal and perirhinal cortex, structures in which we detected RXRγ expression and which are functionally implicated in working memory processes.

Social recognition memory requires two stages of protein synthesis in mice

Abstract: Olfactory recognition memory was tested in adult male mice using a social discrimination task. The testing was conducted to begin to characterize the role of protein synthesis and the specific brain regions associated with activity in this task. Long-term olfactory recognition memory was blocked when the protein synthesis inhibitor anisomycin was injected 20 min before, immediately after, or 6 h after sampling. No effect was observed when anisomycin was administered 3 h or 18 h after sampling. Immunohistochemical analysis of Fos expression revealed that sampling-like exposure to a juvenile increased the activity of a subset of cells in the accessory olfactory bulb and the brain areas that are associated with it. Additionally, increased Fos expression was measured in the main olfactory bulb and the piriform cortex, whereas no signs of activation were seen in the cortical nucleus of the amygdala, all components of the main olfactory system. No increases in Fos immunoreactivity were observed after 4 h. Our data suggest that long-lasting olfactory recognition memory requires two stages of protein synthesis. The first stage takes place within 1-2 h and the second stage between 6-7 h after sampling. The first but not the second stage is paralleled by an increase in the number of Fos-immunoreactive cells in brain areas associated with both the main and accessory olfactory systems. It therefore appears that the role of the second stage of protein synthesis in recognition memory depends on the integrity of the first stage of protein synthesis.

Protein synthesis underlies post-retrieval memory consolidation to a restricted degree only when updated information is obtained.

Abstract: Consolidation theory proposes that through the synthesis of new proteins recently acquired memories are strengthened over time into a stable long-term memory trace. However, evidence has accumulated suggesting that retrieved memory is susceptible to disruption, seeming to consolidate again (reconsolidate) to be retained in long-term storage. Here we show that intracortical blockade of protein synthesis in the gustatory cortex after retrieval of taste-recognition memory disrupts previously consolidated memory to a restricted degree only if the experience is updated. Our results suggest that retrieved memory can be modified as part of a mechanism for incorporating updated information into previously consolidated memory.

Insular cortex is involved in consolidation of object recognition memory.

Abstract: Federico Bermudez-Rattoni, Shoki Okuda, Benno Roozendaal, and James L. McGaugh Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, California 92697-3800, USA; Departamento de Neurociencias, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico D.F., 04510, Mexico; CNS Disorder Research, Tsukuba Research Institute, Banyu Pharmaceutical Co., Tsukuba, Ibaraki, 300-2611, Japan

Glutamate receptor antagonist infusions into the basolateral and medial amygdala reveal differential contributions to olfactory vs. context fear conditioning and expression

Abstract: The basolateral amygdala's involvement in fear acquisition and expression to visual and auditory stimuli is well known. The involvement of the basolateral and other amygdala areas in fear acquisition and expression to stimuli of other modalities is less certain. We evaluated the contribution of the basolateral and medial amygdala to olfactory and to context fear and fear conditioning by infusing into these areas the NMDA receptor antagonist AP5, the AMPA/kainate receptor antagonist NBQX, or vehicle prior to either odor-shock pairings or fear-potentiated startle testing. Pre-training AP5 infusions into the basolateral amygdala disrupted fear conditioning to the odor but not the context conditioned stimulus (CS). Pre-test NBQX infusions disrupted fear-potentiated startle to the odor but not context CS. Neither compound blocked fear conditioning when infused into the medial amygdala prior to training, but pre-test NBQX infusions did block fear-potentiated startle. The results confirm and extend recent findings suggesting a role for the basolateral amygdala in olfactory fear and fear conditioning, reveal an unexpected dissociation of the basolateral amygdala's involvement in discrete cue versus context fear and fear conditioning, and implicate for the first time the medial amygdala in fear-potentiated startle.

Sensory responsiveness and the effects of equal subjective rewards on tactile learning and memory of honeybees

Abstract: In tactile learning, sucrose is the unconditioned stimulus and reward, which is usually applied to the antenna to elicit proboscis extension and which the bee can drink when it is subsequently applied to the extended proboscis. The conditioned stimulus is a tactile object that the bee can scan with its antennae. In this paper we describe the quantitative relationships between gustatory antennal stimulation, gustatory proboscis stimulation, and tactile learning and memory. Bees are 10-fold more responsive to sucrose solutions when they are applied to the antenna compared to proboscis stimulation. During tactile conditioning, the sucrose solution applied to the proboscis determines the level of acquisition, whereas antennal input is of minor importance. Bees differing in their gustatory responsiveness measured at the antenna differ strongly in their tactile acquisition and memory. We demonstrate how these differences in tactile acquisition and memory can be greatly reduced by calculating equal subjective rewards, based on individual gustatory responsiveness.

A simple neural network model of the hippocampus suggesting its pathfinding role in episodic memory retrieval.

Abstract: The goal of this work is to extend the theoretical understanding of the relationship between hippocampal spatial and memory functions to the level of neurophysiological mechanisms underlying spatial navigation and episodic memory retrieval. The proposed unifying theory describes both phenomena within a unique framework, as based on one and the same pathfinding function of the hippocampus. We propose a mechanism of reconstruction of the context of experience involving a search for a nearly shortest path in the space of remembered contexts. To analyze this concept in detail, we define a simple connectionist model consistent with available rodent and human neurophysiological data. Numerical study of the model begins with the spatial domain as a simple analogy for more complex phenomena. It is demonstrated how a nearly shortest path is quickly found in a familiar environment. We prove numerically that associative learning during sharp waves can account for the necessary properties of hippocampal place cells. Computational study of the model is extended to other cognitive paradigms, with the main focus on episodic memory retrieval. We show that the ability to find a correct path may be vital for successful retrieval. The model robustly exhibits the pathfinding capacity within a wide range of several factors, including its memory load (up to 30,000 abstract contexts), the number of episodes that become associated with potential target contexts, and the level of dynamical noise. We offer several testable critical predictions in both spatial and memory domains to validate the theory. Our results suggest that (1) the pathfinding function of the hippocampus, in addition to its associative and memory indexing functions, may be vital for retrieval of certain episodic memories, and (2) the hippocampal spatial navigation function could be a precursor of its memory function.

Dissociable contributions within the medial temporal lobe to encoding of object-location associations

Abstract: The crucial role of the medial temporal lobe (MTL) in episodic memory is well established. Although there is little doubt that its anatomical subregions-the hippocampus, peri-, entorhinal and parahippocampal cortex (PHC)-contribute differentially to mnemonic processes, their specific functions in episodic memory are under debate. Data from animal, human lesion, and neuroimaging studies suggest somewhat contradictory perspectives on this functional specialization: a general participation in declarative memory, an exclusive involvement in associative mnemonic processes, and a specific contribution to spatial memory are reported for the hippocampus, adjacent cortices, and the PHC. A functional lateralization in humans dependent on the verbalizability of the material is also discussed herein. To further elucidate the differential contributions of the various MTL subregions to encoding, we employed an object-location association memory paradigm. The memory for each of the studied associations was tested twice: by the object, and by the location serving as retrieval cue. The memory accuracy in response to both cue types was also assessed parametrically. Brain activity during encoding which leads to different degrees of subsequent memory accuracy under the two retrieval conditions was compared. We found the bilateral posterior PHC to participate in encoding of both the object associated with a location and the location associated with an object. In contrast, activity in an area in the left anterior PHC and the right anterior MTL was only correlated with the memory for the location associated with an object.

Modulation of memory consolidation by the basolateral amygdala or nucleus accumbens shell requires concurrent dopamine receptor activation in both brain regions.

Abstract: Previous findings indicate that the basolateral amygdala (BLA) and the nucleus accumbens (NAc) interact in influencing memory consolidation. The current study investigated whether this interaction requires concurrent dopamine (DA) receptor activation in both brain regions. Unilateral, right-side cannulae were implanted into the BLA and the ipsilateral NAc shell or core in male Sprague-Dawley rats ( approximately 300 g). One week later, the rats were trained on an inhibitory avoidance (IA) task and, 48 h later, they were tested for retention. Drugs were infused into the BLA and NAc shell or core immediately after training. Post-training intra-BLA infusions of DA enhanced retention, as assessed by latencies to enter the shock compartment on the retention test. Infusions of the general DA receptor antagonist cis-Flupenthixol (Flu) into the NAc shell (but not the core) blocked the memory enhancement induced by the BLA infusions of DA. In the reverse experiment, post-training intra-NAc shell infusions of DA enhanced retention and Flu infusions into the BLA blocked the enhancement. These findings indicate that BLA modulation of memory consolidation requires concurrent DA receptor activation in the NAc shell but not the core. Similarly, NAc shell modulation of memory consolidation requires concurrent DA receptor activation in the BLA. Together with previous findings, these results suggest that the dopaminergic innervation of the BLA and NAc shell is critically involved in the modulation of memory consolidation.

Trace fear conditioning is enhanced in mice lacking the δ subunit of the GABAA receptor

Abstract: In the central nervous system, fast inhibitory transmission is mediated primarily by γ-aminobutyric acid type A receptors (GABAARs) (Macdonald and Olsen 1994; Olsen and Homanics 2000). These ligand-gated receptors are pentamers composed of various subunit combinations (α, β, γ, e, π, ρ, and δ) that exhibit differential expression in the brain (Barnard et al. 1998; Sieghart and Sperk 2002). For example, the δ subunit is highly expressed in the dentate gyrus, but not CA3 or CA1 regions of the hippocampus (Persohn et al. 1992; Peng et al. 2002). The pharmacologic and kinetic properties of GABAARs are highly dependent on the specific configuration of these subunits (Quirk et al. 1994; Gunther et al. 1995; Smith and Olsen 1995; Khan et al. 1996; Benke et al. 1997). Recent studies have shown that genetic deletion of the δ subunit of the GABAAR produces a significant reduction in neurosteroid sensitivity (Mihalek et al. 1999; Vicini et al. 2002; Porcello et al. 2003; Spigelman et al. 2003) and accelerates the decay of spontaneous mIPSCs and evoked IPSPs in hippocampal granule cells and thalamic relay neurons (Mihalek et al. 1999; Porcello et al. 2003; Spigelman et al. 2003). These data suggest that δ-containing GABAARs contribute to synaptic and extrasynaptic inhibition and facilitate modulation by neuroactive steroids. Pharmacologic or genetic manipulations that reduce GABAergic inhibition often enhance synaptic plasticity and learning (Introini-Collison et al. 1994; Crestani et al. 1999, 2002; Staubli et al. 1999; Shumyatsky et al. 2002). For example, recent experiments on GABAAR mutants (α5 and γ2) found enhanced trace but normal delay conditioning (Crestani et al. 1999, 2002). Trace conditioning is a form of hippocampus-dependent learning in which the conditional stimulus (CS) and unconditional stimulus (US) are separated in time (Solomon et al. 1986; Moyer Jr. et al. 1990; McEchron et al. 1998; Huerta et al. 2000; Quinn et al. 2002). This is distinct from hippocampus-independent delay conditioning in which the CS and US are presented contiguously. Previous work has demonstrated that trace conditioning engages the CA1 region of the hippocampus (Moyer Jr. et al. 1996, 2000; McEchron and Disterhoft 1999; McEchron et al. 2001, 2003; Leuner et al. 2003) and requires NMDAR-dependent plasticity in this region (Huerta et al. 2000). Relatively little is known about the contribution of the dentate gyrus to trace conditioning, although recent studies suggest this region also plays an important role. For example, exposure to a trace-conditioned cue produces significant increases in immediate early gene expression in the dentate gyrus (Weitemier and Ryabinin 2004). Trace conditioning also increases neurogenesis in the dentate gyrus (Gould et al. 1999) and is impaired by a reduction in the number of newly generated neurons in this region (Shors et al. 2001). The current experiments used δ knockout (KO) mice to examine the effects of reduced inhibition and neurosteroid sensitivity in the dentate gyrus on the acquisition of trace fear conditioning. We also looked for nonspecific effects of δ subunit deletion by examining performance on open-field and RotaRod tests.

Activation of the transcription factor NF-κB by retrieval is required for long-term memory reconsolidation

Abstract: Several studies support that stored memories undergo a new period of consolidation after retrieval. It is not known whether this process, termed reconsolidation, requires the same transcriptional mechanisms involved in consolidation. Increasing evidence supports the participation of the transcription factor NF-kappaB in memory. This was initially demonstrated in the crab Chasmagnathus model of associative contextual memory, in which re-exposure to the training context induces a well characterized reconsolidation process. Here we studied the role of NF-kappaB in reconsolidation. NF-kappaB was specifically activated in trained animals re-exposed to the training context but not to a different context. NF-kappaB was not activated when animals were re-exposed to the context after a weak training protocol insufficient to induce long-term memory. A specific inhibitor of the NF-kappaB pathway, sulfasalazine, impaired reconsolidation when administered 20 min before re-exposure to the training context but was not effective when a different context was used. These findings indicate for the first time that NF-kappaB is activated specifically by retrieval and that this activation is required for memory reconsolidation, supporting the view that this molecular mechanism is required in both consolidation and reconsolidation.

A different recruitment of the lateral and basolateral amygdala promotes contextual or elemental conditioned association in Pavlovian fear conditioning.

Abstract: Convergent data suggest dissociated roles for the lateral (LA) and basolateral (BLA) amygdaloid nuclei in fear conditioning, depending on whether a discrete conditioned stimulus (CS)-unconditional stimulus (US) or context-US association is considered. Here, we show that pretraining inactivation of the BLA selectively impaired conditioning to context. In contrast, inactivation of the LA disrupted conditioning to the discrete tone CS, but also either impaired or enhanced contextual conditioning, depending on whether the context was in the foreground or in the background. Hence, these findings refine the current model of the amygdala function in emotional learning by showing that the BLA and the LA not only differentially contribute to elemental and context-US association, but also promote, through their interaction, the most relevant of these two associations.

Purkinje cell activity in the cerebellar anterior lobe after rabbit eyeblink conditioning.

Abstract: The cerebellar anterior lobe may play a critical role in the execution and proper timing of learned responses. The current study was designed to monitor Purkinje cell activity in the rabbit cerebellar anterior lobe after eyeblink conditioning, and to assess whether Purkinje cells in recording locations may project to the interpositus nucleus. Rabbits were trained in an interstimulus interval discrimination procedure in which one tone signaled a 250-msec conditioned stimulus-unconditioned stimulus (CS-US) interval and a second tone signaled a 750-msec CS-US interval. All rabbits showed conditioned responses to each CS with mean onset and peak latencies that coincided with the CS-US interval. Many anterior lobe Purkinje cells showed significant learning-related activity after eyeblink conditioning to one or both of the CSs. More Purkinje cells responded with inhibition than with excitation to CS presentation. In addition, when the firing patterns of all conditioning-related Purkinje cells were pooled, it appeared that the population showed a pattern of excitation followed by inhibition during the CS-US interval. Using cholera toxin-conjugated horseradish peroxidase, Purkinje cells in recording areas were found to project to the interpositus nucleus. These data support previous studies that have suggested a role for the anterior cerebellar cortex in eyeblink conditioning as well as models of cerebellar-mediated CR timing that postulate that Purkinje cell activity inhibits conditioned response (CR) generation during the early portion of a trial by inhibiting the deep cerebellar nuclei and permits CR generation during the later portion of a trial through disinhibition of the cerebellar nuclei.

Kindling-induced changes in plasticity of the rat amygdala and hippocampus.

Abstract: Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar rats were kindled through daily administration of brief electrical stimulations to the left basolateral nucleus of the amygdala. Field potential recordings were performed in slices obtained from kindled rats 48 h after the last induced seizure, and in slices from sham-implanted and nonimplanted controls. Kindling resulted in a significant impairment of long-term potentiation (LTP) in both the LA and the CA1, the magnitude of which was dependent on the number of prior stage V seizures. Saturation of CA1-LTP, assessed through repeated spaced delivery of high-frequency stimulation, occurred at lower levels in kindled compared to sham-implanted animals, consistent with the hypothesis of reduced capacity of further synaptic strengthening. Furthermore, theta pulse stimulation elicited long-term depression in the amygdala in nonimplanted and sham-implanted controls, whereas the same stimulation protocol stimulation caused LTP in kindled rats. In conclusion, kindling differentially affects the magnitude, saturation, and polarity of LTP in the CA1 and LA, respectively, most likely indicating an activity-dependent mechanism in the context of synaptic metaplasticity.

Reinforcement of rat hippocampal LTP by holeboard training.

Abstract: Hippocampal long-term potentiation (LTP) can be dissociated in early-LTP lasting 4-5 h and late-LTP with a duration of more than 8 h, the latter of which requires protein synthesis and heterosynaptic activity during its induction. Previous studies in vivo have shown that early-LTP in the dentate gyrus can protein synthesis-dependently be transformed (reinforced) into late-LTP by the association of arousing novel environmental stimuli. Here we show that consolidation of spatial memory also reinforces early-LTP in the dentate gyrus. Both memory consolidation and LTP-reinforcement depend on protein synthesis. Four groups of animals were trained by five, seven, eight or 10 trials, respectively, to recognize a fixed pattern of baited holes. The last trial was performed 15 min after tetanus. Errors of long-term reference memory during the last trial were significantly decreased only in the eight- and 10-trial experimental groups compared to pseudo-trained animals. In correlation to this learning effect we found a reinforcement of early-LTP only in these experimental groups compared to controls. The data suggest that the synthesis of new proteins required for spatial reference-memory formation also contributes to LTP maintenance in the hippocampal dentate gyrus.

A latent consolidation phase in auditory identification learning: time in the awake state is sufficient.

Abstract: Large gains in performance, evolving hours after practice has terminated, were reported in a number of visual and some motor learning tasks, as well as recently in an auditory nonverbal discrimination task. It was proposed that these gains reflect a latent phase of experience-triggered memory consolidation in human skill learning. It is not clear, however, whether and when delayed gains in performance evolve following training in an auditory verbal identification task. Here we show that normal-hearing young adults trained to identify consonant-vowel stimuli in increasing levels of background noise showed significant, robust, delayed gains in performance that became effective not earlier than 4 h post-training, with most participants improving at more than 6 h post-training. These gains were retained for over 6 mo. Moreover, although it has been recently argued that time including sleep, rather than time per se, is necessary for the evolution of delayed gains in human perceptual learning, our results show that 12 h post-training in the waking state were as effective as 12 h, including no less than 6 h night's sleep. Altogether, the results indicate, for the first time, the existence of a latent, hours-long, consolidation phase in a human auditory verbal learning task, which occurs even during the awake state.

AMPA/kainate, NMDA, and dopamine D1 receptor function in the nucleus accumbens core: a context-limited role in the encoding and consolidation of instrumental memory.

Abstract: In order to survive in changing environments, animals must be able to acquire, consolidate, and retrieve pertinent information regarding a given stimulus situation. The ability to learn associations between various stimuli and events, including motor actions, is the basis of instrumental learning (Rescorla 1991; Dickinson and Balleine 1994). Appetitive instrumental learning occurs when an animal associates its behavior with a favorable outcome such as food, sex, or the avoidance of pain. For instance, in a common experimental model of instrumental learning, a hungry rat learns to press a lever to obtain a food reward. The nucleus accumbens (NAc) and its associated circuitry have been linked to the acquisition of adaptive motor responses and the control of behaviors related to natural reinforcers (Setlow 1997; Parkinson et al. 2000; Corbit et al. 2001). Because of the rich glutamatergic and dopaminergic innervation of the NAc from regions associated with motivational, cognitive, and sensory processes, many studies have focused on the role of these neurotransmitter systems with respect to instrumental and incentive learning (Berridge and Robinson 1998; Cardinal et al. 2002; Beninger and Gerdjikov 2004; Kelley 2004). For example, blockade of glutamate (N-methyl-d-aspartate, NMDA) or dopamine D1 receptors within the NAc core potently impairs instrumental learning, and coinfusion of low, individually ineffective doses of AP-5 and SCH23390 also prevents learning, suggesting that convergence of both systems on post-synaptic neurons is required (Smith-Roe and Kelley 2000). The coincident detection of glutamate and dopamine signals has been shown to be required for long-term potentiation (Wickens et al. 1996; Arbuthnott et al. 2000; Floresco et al. 2001; Kerr and Wickens 2001) by regulating the transcription and translation of plasticity-related immediate-early genes through various second messenger systems (Sharp et al. 1995; Sutton and Beninger 1999; Berke and Hyman 2000; Horvitz 2002; Reynolds and Wickens 2002; Steward and Worley 2002; Kelley 2004). Indeed, post-training inhibition of cAMP-dependent protein kinase (PKA) (Baldwin et al. 2002a) or inhibition of de novo protein synthesis within the NAc core (Hernandez et al. 2002) prevents the consolidation, or long-term stabilization, of memory for response-outcome contingencies. In the aforementioned studies, pre-trial blockade of NMDA and D1 receptors appeared to prevent the encoding (or acquisition) of information; however, it is possible that disruption of the consolidation phase of learning or retrieval could have contributed to the observed impairments. Thus, it remains unclear as to whether glutamate and dopamine are required only to initiate plasticity or whether these neurotransmitters also modulate consolidation. As such, post-trial infusions are often used to temporally dissociate encoding from consolidation (Breen and McGaugh 1961). Therefore, the present study compared the effects of pre- and post-trial infusions of antagonists specific for NMDA or D1 receptors in the NAc core of male Sprague-Dawley rats in the same task. In addition, we investigated the effects of an antagonist specific for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/KA) receptors, since their role in instrumental learning has not yet been described. Lastly, we used a time-stamp behavioral analysis program that records the temporal relationship of task-related events and behaviors during training in order to gain insight into which behaviors are critical for instrumental learning.