Reactivation-dependent amnesia for appetitive memories is determined by the contingency of stimulus presentation

Previously acquired aversive and appetitive memories are not stable and permanent. The reactivation of such memories by re-exposure to training stimuli renders them vulnerable to disruption by amnestic agents such as the noncompetitive N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo{a,d}cyclohepten-5,10-imine maleate (MK-801). However, relatively little is known about the parameters that influence the reactivation process. Here, we show that the method of stimulus presentation during memory reactivation is of great importance. Male Lister Hooded rats were trained to acquire a lever press response that delivered a sucrose reward paired with a light conditioned stimulus (CS). The CS-sucrose association was then reactivated through re-exposure to the CS, either contingently upon the lever press response, or noncontingently in the absence of instrumental responding. Systemic administration of MK-801 (0.1 mg/kg) at the time of memory reactivation resulted in amnesia, and hence a reduction in subsequent sucrose seeking induced by, and dependent upon, presentation of the CS, only when the memory was reactivated contingently. Therefore, stimuli may have to be presented in the same manner at memory reactivation as during learning in order to render a previously acquired memory vulnerable to disruption. These results have important implications for the potential translational use of glutamatergic treatments in conjunction with targeted memory reactivation.     

Opposite actions of dopamine on aversive and appetitive memories in the crab

The understanding of how the reinforcement is represented in the central nervous system during memory formation is a current issue in neurobiology. Several studies in insects provide evidence of the instructive role of biogenic amines during the learning and memory process. In insects it was widely accepted that dopamine (DA) mediates aversive reinforcements. However, the idea of DA being exclusively involved in aversive memory has been challenged in recent studies. Here, we study the involvement of DA during aversive and appetitive memories in the crab Chasmagnathus. We found that DA-receptor antagonists impair aversive memory consolidation, in agreement with previous reports in insects, while administration of DA facilitates memory formation after a weak training protocol. In contrast, DA treatment during appetitive training was found to impair formation of long-term appetitive memory. In addition, as a first step in elucidating the neuroanatomical correlates of DA action on memory, we mapped dopaminergic neurons in the central nervous system of the crab. Results of the current study, together with those obtained in a previous work about the role of octopamine (OA), suggest that both amines (DA and OA) play a dual action in memory processes. On the one hand, DA and OA mediate the aversive and the appetitive signals, respectively, throughout training, while on the other hand, they interfere with the formation of memory of the opposite sign (DA in appetitive and OA in aversive). Our results support a new understanding about the way appetitive and aversive stimuli are processed during memory formation to ensure adaptive behavior.     

G(o) activation is required for both appetitive and aversive memory acquisition in Drosophila

Heterotrimeric G(o) is an abundant brain protein required for negatively reinforced short-term associative olfactory memory in Drosophila. G(o) is the only known substrate of the S1 subunit of pertussis toxin (PTX) in fly, and acute expression of PTX within the mushroom body neurons (MB) induces a reversible deficit in associative olfactory memory. We demonstrate here that the induction of PTX within the α/β and γ lobe MB neurons leads to impaired memory acquisition without affecting memory stability. The induction of PTX within these MB neurons also leads to a significant defect in an optimized positively reinforced short-term memory paradigm; however, this PTX-induced learning deficit is noticeably less severe than found with the negatively reinforced paradigm. Both negatively and positively reinforced memory phenotypes are rescued by the constitutive expression of G(o)α transgenes bearing the Cys(351)Ile mutation. Since this mutation renders the G(o) molecule insensitive to PTX, the results isolate the effect of PTX on both forms of olfactory associative learning to the inhibition of the G(o) activation.     

De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala

Memory consolidation is the process by which newly learned information is stabilized into long-term memory (LTM). Considerable evidence indicates that retrieval of a consolidated memory returns it to a labile state that requires it to be restabilized. Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of the amygdala (LA). We have previously shown that de novo protein synthesis in the LA is required for reconsolidation of auditory fear memories. One key question is whether protein synthesis during reconsolidation depends on already existing mRNAs or on synthesis of new mRNAs in the amygdala. In the present study, we examined the effect of mRNA synthesis inhibition during consolidation and reconsolidation of auditory fear memories. We first show that intra-LA infusion of two different mRNA inhibitors dose-dependently impairs long-term memory but leaves short-term memory (STM) intact. Next, we show that intra-LA infusion of the same inhibitors dose-dependently blocks post-reactivation long-term memory (PR-LTM), whereas post-reactivation short-term memory (PR-STM) is left intact. Furthermore, the same treatment in the absence of memory reactivation has no effect. Together, these results show that both consolidation and reconsolidation of auditory fear memories require de novo mRNA synthesis and are equally sensitive to disruption of de novo mRNA synthesis in the LA.     

BDNF-induced synaptic delivery of AMPAR subunits is differentially dependent on NMDA receptors and requires ERK

Previous studies using an in vitro model of eyeblink classical conditioning in turtles suggest that increased numbers of synaptic AMPARs supports the acquisition and expression of conditioned responses (CRs). Brain-derived neurotrophic factor (BDNF) and its associated receptor tyrosine kinase, TrkB, is also required for acquisition of CRs. Bath application of BDNF alone induces synaptic delivery of GluR1- and GluR4-containing AMPARs that is blocked by coapplication of the receptor tyrosine kinase inhibitor K252a. The molecular mechanisms involved in BDNF-induced AMPAR trafficking remain largely unknown. The aim of this study was to determine whether BDNF-induced synaptic AMPAR incorporation utilizes similar cellular mechanisms as AMPAR trafficking that occurs during in vitro classical conditioning. Using pharmacological blockade and confocal imaging, the results show that synaptic delivery of GluR1 subunits during conditioning or BDNF application does not require activity of NMDARs but is mediated by extracellular signal-regulated kinase (ERK). In contrast, synaptic delivery of GluR4-containing AMPARs during both conditioning and BDNF application is NMDAR- as well as ERK-dependent. These findings indicate that BDNF application mimics AMPAR trafficking observed during conditioning by activation of some of the same intracellular signaling pathways and suggest that BDNF is a key signal transduction element in postsynaptic events that mediate conditioning.     

Configural learning without reinforcement: Integrated memories for correlates of what,where, and when

In 2 experiments we examined the ability of rats to form configural memories of what auditory stimulus (X or Y) was presented where (Context A or B) and when (morning or afternoon). In both experiments, rats received morning presentations of X in Context A and Y in Context B and afternoon presentations of X in B and Y in A. Subsequently, at midday the rats were exposed to trials where X was paired with footshock whereas Y was not. We then assessed the degree of contextual fear in A and B in the morning and the afternoon. In the morning, rats showed more fear in A than in B, and in the afternoon they showed more fear in B than in A. These results indicate that rats can form configural memories that represent what (X or Y) was presented, where (A or B), and when (morning or afternoon).     

Configural learning without reinforcement: integrated memories for correlates of what, where, and when

In 2 experiments we examined the ability of rats to form configural memories of what auditory stimulus (X or Y) was presented where (Context A or B) and when (morning or afternoon). In both experiments, rats received morning presentations of X in Context A and Y in Context B and afternoon presentations of X in B and Y in A. Subsequently, at midday the rats were exposed to trials where X was paired with footshock whereas Y was not. We then assessed the degree of contextual fear in A and B in the morning and the afternoon. In the morning, rats showed more fear in A than in B, and in the afternoon they showed more fear in B than in A. These results indicate that rats can form configural memories that represent what (X or Y) was presented, where (A or B), and when (morning or afternoon).     

Muscarinic suppression in stratum radiatum of CA1 shows dependence on presynaptic M1 receptors and is not dependent on effects at GABA(B) receptors

Cholinergic modulation of synaptic transmission is vital to memory processes and may be responsible for setting network dynamics in the hippocampus appropriate for encoding of information. found evidence suggesting M1 receptors cause presynaptic inhibition of glutamatergic transmission, while research supports a role of the M2 receptor. We examined muscarinic inhibition of fEPSPs in stratum radiatum of mice lacking m1 subtype receptors (KO) compared to wild type (WT) controls. WT mice exhibit greater suppression of transmission by muscarine as compared to KO in a dose dependent fashion. Oxotremorine shows no significant difference in suppression between WT and KO, while MCN-A-343, an M1 agonist, exhibits a significant difference between KO and WT, with KO showing no suppression. One hundred micromolar SGS-742, a selective GABA(B) antagonist, fails to affect either normal transmission or muscarinic suppression in either WT or KO suggesting that differences in suppression between the groups is not attributable to differences in GABA(B) receptor activation due to muscarinic activation of GABAergic interneurons. These findings support a role for presynaptic m1 mAChRs in modulation of synaptic transmission in CA1, but indicate that other muscarinic receptor subtypes, such as M2, are also involved in suppression of synaptic potentials.     

The hippocampal dentate gyrus is essential for generating contextual memories of fear and drug-induced reward

The hippocampus is believed to play a role in processing information relative to the context in which emotionally salient experiences occur but evidence on the specific contribution of the hippocampal dentate gyrus (DG) to these processes is limited. Here, we have used two classical behavioral paradigms to study the participation of the dorsal DG in context-conditioned reward and context-conditioned fear. Rats received intra-hippocampal vehicle or colchicine injections (4 microg/microl solution; 0.2 microl injections at 10 sites) that damaged the DG but spared other hippocampal subfields. In the first experiment, we used a place conditioning procedure pairing cocaine exposure (20 mg/kg, i.p.) with a specific context and vehicle treatment with another. While rats with sham lesions exhibited preference for the cocaine-paired context following conditioning, rats with lesions of the DG showed no evidence of cocaine-induced place preference. In the second experiment, rats with sham or colchicine lesions received a foot shock in a given context and conditioned freezing was measured upon reexposure to the shock-paired context (2, 24, 48 and 96 h after conditioning). Rats with sham lesions exhibited high levels of conditioned freezing when exposed to the conditioning context but rats with lesions of the DG showed impaired conditioning, behaving as controls that had experienced shock in a different context. These observations indicate that the integrity of the DG is essential for establishing a coherent representation of the context to which emotional experiences, either hedonic or aversive, are bound.     

Stress-induced facilitation of host response to bacterial challenge in F344 rats is dependent on extracellular heat shock protein 72 and independent of alpha beta T cells

Activation of the in vivo stress response can facilitate antibacterial host defenses. One possible mechanism for this effect is stress-induced release of heat shock protein 72 (Hsp72) into the extracellular environment. Hsp72 is a ubiquitous cellular protein that is up-regulated in response to cellular stress, and modulates various aspects of immune function including macrophage inflammatory/bactericidal responses and T-cell function when found in the extracellular environment. The current study tested the hypothesis that in vivo extracellular Hsp72 (eHsp72) at the site of inflammation contributes to stress-induced restricted development of bacteria, and facilitated recovery from bacteria-induced inflammation, and that this effect is independent of alpha beta (αβ) T cells. Male F344 rats were exposed to either inescapable electrical tail-shocks or no stress, and subcutaneously injected with Escherichia coli (ATCC 15746). The role of eHsp72 was investigated by Hsp72-immunoneutralization at the inflammatory site. The potential contribution of T cells was examined by testing male athymic (rnu/rnu) nude rats lacking mature αβ T cells and heterozygous thymic intact control (rnu/+) rats. The results were that stressor exposure increased plasma concentrations of eHsp72 and facilitated recovery from bacterial inflammation. Immunoneutralization of eHsp72 at the inflammatory site attenuated this effect. Stressor exposure impacted bacterial inflammation and eHsp72 equally in both athymic and intact control rats. These results support the hypothesis that eHsp72 at the site of inflammation, and not αβ T cells, contributes to the effect of stressor exposure on subcutaneous bacterial inflammation.     

The effect of introspection on judgment and decision making is dependent on the quality of conscious thinking

That introspection may impair certain judgments and result in fabrication has been attributed to a distracting shift from more adaptive intuitive processing to more analytic and conscious processing. This phenomenon was studied in an experiment where participants made multidimensional visual choices. It was found that the effect of this shift on decision-making performance was dependent on the quality of the explanations during introspection, while the performance in silent conditions was not. Therefore, it appears that the effect of introspection on judgments is not only influenced by the thinking mode per se, but also by the individual’s ability to approach the decision problem analytically.     

Effectiveness of treatment of childhood memories in cognitive therapy for personality disorders: a controlled study contrasting methods focusing on the present and methods focusing on childhood memories

This study tested the hypothesis that treatment of childhood memories is an effective way to change personality disorder related schemas and psychopathology in cognitive therapy for personality disorders. To test this hypothesis, a crossover design was used to compare the effectiveness of methods focusing on the present and methods focusing on childhood memories. After the exploration period, the therapist focused either first on the present during 24 sessions and than for 24 sessions on childhood memories, or followed the reverse order. Twenty-one patients with one or more Axis II disorders were included. Participants were randomly assigned to order of focus. Results indicate that CT methods focusing on childhood memories produce good outcomes, comparable to those of methods focusing on the present. There was no significant effect of order, but both patients and therapists preferred the past-present order. Total effects of the package were large and were maintained till one-year follow-up (d's 0.97-1.90). Experience of the therapist with CT for personality disorders was related to better outcome (d=0.73).     

Object correspondence across brief occlusion is established on the basis of both spatiotemporal and surface feature cues

The correspondence problem is a classic issue in vision and cognition. Frequent perceptual disruptions, such as saccades and brief occlusion, create gaps in perceptual input. How does the visual system establish correspondence between objects visible before and after the disruption? Current theories hold that object correspondence is established solely on the basis of an object’s spatiotemporal properties and that an object’s surface feature properties (such as color or shape) are not consulted in correspondence operations. In five experiments, we tested the relative contributions of spatiotemporal and surface feature properties to establishing object correspondence across brief occlusion. Correspondence operations were strongly influenced both by the consistency of an object’s spatiotemporal properties across occlusion and by the consistency of an object’s surface feature properties across occlusion. These data argue against the claim that spatiotemporal cues dominate the computation of object correspondence. Instead, the visual system consults multiple sources of relevant information to establish continuity across perceptual disruption.     

rTMS stimulation on left DLPFC increases the correct recognition of memories for emotional target and distractor words

According to a recent hypothesis, the prefrontal cortex has been proposed as the site of emotional memory integration, because it is sensitive to the recognition of emotional contents. In the present research, we explored the role of the dorsolateral prefrontal cortex (DLPFC) in memory recognition processes for positive versus negative emotional stimuli when old (target) and new (distractor, either semantically related or unrelated to the target) stimuli were presented. The role of the DLPFC was analysed using an rTMS (repeated transcranial magnetic stimulation) paradigm that induced increased cortical activation of the left DLPFC. The subjects were required to perform a task that consisted of two experimental phases (i.e., an encoding and a recognition phase) in which the targets and the distractors were presented and recognition performance was measured. rTMS stimulation was provided over the left DLPFC during the recognition phase. We found that the rTMS stimulation affected the memory recognition of positive emotional material. Moreover, related and unrelated distractors were discarded better when they were positively valenced, and a more significant effect (i.e., increased performance) was produced in response to related distractors. This result suggests that the activation of the left DLPFC favours the memory recognition of positive emotional information, and that such activation is able to induce a more appropriate selective process to distinguish target from distractor stimuli in the presence of more complex processes (related distractors). The valence model of emotional cue processing may explain this increased performance by demonstrating the distinct role of the left hemisphere in the retrieval of positive emotional information.     

Beyond drug effects and dependent variables: the use of the Poisson-Erlang model to assess the effects of D-amphetamine on information processing

Several studies have shown that d-amphetamine (DAMP) speeds mean reaction time (RT). However, the use of mean RT may obscure important aspects of the drug response. Therefore we applied the Poisson-Erlang (PE) stochastic model of choice reaction time proposed by Pieters (1985) to the RT distribution. This model proposes that the RT distribution is generated by two states: Processing (P) and Distraction (D). RT represents the sum of the time spent in each of these states. P is the time taken to complete a set of cognitive operations which are required to give a correct response. D represents the time taken by all other activities. RTs were collected using a task (SERS) in which stimulus and response complexity each had two levels, easy and hard. Subjects were tested pre- and postdrug. Drug conditions were: placebo, 10 mg d-amphetamine (DAMP), 4 mg of the dopamine agonist, pimozide, and a combination of DAMP and pimozide (COMBO). Parameters of the model were derived using methods described by Pieters. Four measures were analyzed: Processing Time (PT); Mean Time per distraction (XTD); Distraction Rate (DR); and Total Distraction Time per trial (TDT). Mean RT is also presented. Analyses of the effects of task conditions on the parameters of the model were made using the predrug sessions. Mean RT was increased by both stimulus and response complexities as was PT. TDT was increased by the task conditions. The PE measures did not change over days. DAMP speeded mean RT. However, this effect did not interact with the task factors. DAMP speeded processing and reduced distraction. Processing was speeded only in the hard response condition, distraction time was reduced only in the easy response condition. The results indicate that the PE model can be successfully applied to fast RT tasks. More importantly, the parameters of the model revealed important pharmacological effects that were not apparent in mean RT. DAMP speeds cognitive operations related to motor preparation and reduces the effects of distraction. Consistent with past studies there are no indications that DAMP interacted with stimulus processing. The distraction effect appears to be mediated by an increase in the rate of distraction and a decrease in the average time of these distractions.