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Memory extinction requires gene expression in rat hippocampus
Abstract
Rats with cannulae in the dorsal CA1 region of the hippocampus were trained in one-trial step-down inhibitory avoidance, and submitted to four consecutive daily test sessions without the footshock. This produced extinction of the conditioned response in control animals. The bilateral infusion into the CA1 region of the dorsal hippocampus of two different inhibitors of gene transcription, DRB (80 microg/side) or alpha-amanitin (25 pg/side), or of the protein synthesis inhibitor, anisomycin (80 microg/side) blocked extinction of the CR. The treatments were effective when given 15 min before, but not 1 or 3h after the first test session. Retrieval itself was not affected by the drugs. The treatments did not affect general activity in an open field or anxiety levels measured in an elevated plus maze. The data indicate that gene transcription and protein synthesis are necessary at the time of the first test session in order to generate extinction. These requirements are to be expected from learning that involves new synaptic associations.
... Extensive evidence indicates that the hippocampus participates in the consolidation of long-term memory of learning that involves spatial/contextual elements (Balderas et al., 2008;Eichenbaum, 2004;Izquierdo et al., 2008;Jarrard, 1993;Martínez, Quirarte, Díaz-Cintra, Quiroz, & Prado-Alcalá, 2002;Squire, 1992). Further, the findings that intrahippocampal inhibition of transcription of mRNA (Alberini, 2008;Cammarota, Bevilaqua, Kerr, Medina, & Izquierdo, 2003;Donahue et al., 2002;Vianna, Igaz, Coitinho, Medina, & Izquierdo, 2003) and of its translation into proteins (Cammarota, Bevilaqua, Medina, & Izquierdo, 2004;Igaz, Vianna, Medina, & Izquierdo, 2002;Vianna et al., 2003) disrupt memory consolidation appears to provide convincing evidence supporting the view that consolidation requires protein synthesis within the hippocampus (McGaugh, 2000). ...
... Extensive evidence indicates that the hippocampus participates in the consolidation of long-term memory of learning that involves spatial/contextual elements (Balderas et al., 2008;Eichenbaum, 2004;Izquierdo et al., 2008;Jarrard, 1993;Martínez, Quirarte, Díaz-Cintra, Quiroz, & Prado-Alcalá, 2002;Squire, 1992). Further, the findings that intrahippocampal inhibition of transcription of mRNA (Alberini, 2008;Cammarota, Bevilaqua, Kerr, Medina, & Izquierdo, 2003;Donahue et al., 2002;Vianna, Igaz, Coitinho, Medina, & Izquierdo, 2003) and of its translation into proteins (Cammarota, Bevilaqua, Medina, & Izquierdo, 2004;Igaz, Vianna, Medina, & Izquierdo, 2002;Vianna et al., 2003) disrupt memory consolidation appears to provide convincing evidence supporting the view that consolidation requires protein synthesis within the hippocampus (McGaugh, 2000). ...
... DRB, ANI and their vehicle solutions (DMSO and saline solution, respectively) were infused 15 min before training. The doses of DRB and ANI used are within the ranges of the effective amnestic doses described earlier in a variety of learning tasks (Cammarota et al., 2003;Duvarci, Nader, & LeDoux, 2008;Igaz et al., 2002;Meiri & Rosenblum, 1998;Nader, Schafe, & Le Doux, 2000;Parsons, Gafford, Baruch, Riedner, & Helmstetter, 2006;Qi & Gold, 2009;Quevedo et al., 1999;Rodríguez-Durán & Escobar, 2014;Vianna et al., 2003). The different concentrations of DRB and ANI were prepared within one h before being used, and microinjections were performed in a room located away from the experimental room where the conditioning box was located. ...
Findings of several experiments indicate that many treatments that typically interfere with memory consolidation are ineffective in preventing or attenuating memory induced by intense training. As extensive evidence suggests that the consolidation of newly acquired memories requires gene expression and de novo protein synthesis the present study investigated whether intense training prevents consolidation impairment induced by blockers of mRNA and protein synthesis. Rats were given a single inhibitory training trial using a moderate (1.0 mA) or a relatively intense (2.0 mA) foot-shock. Bilateral hippocampal infusions of the mRNA synthesis blocker DRB (10, 40 or 80 ng/0.5 µl/hemisphere) or the protein synthesis inhibitor anisomycin (ANI), an inhibitor de novo protein synthesis (15.62, 31.25, or 62.50 µg/0.5 µl/hemisphere) were administered 15 min prior to training. Retention was measured at 30 min or 48 hours following training. DRB and ANI impaired memory of moderate training in a dose-dependent manner without affecting short-term memory. In contrast, memory consolidation was not impaired in the groups trained with 2.0 mA. The findings showed that: 1) inhibitors of transcription and translation in the hippocampus impair the consolidation of memory of inhibitory avoidance learning induced by moderate levels of aversive stimulation and 2) blocking of mRNA and protein synthesis does not prevent the consolidation of memory induced by relatively high levels of aversive stimulation. These findings do not support the hypothesis that gene expression and de novo protein synthesis are necessary steps for long-term memory formation as memory was not impaired if intense foot-shock was used in training.
... However, if the CS is not accompanied by the US, the animals detect the new CS-no US association at the same time [3, 22, 23]. In a one-trial step-down avoidance task, this takes place as soon as the animals step down from the safe platform (CS) and receive no footshock when they place their paws on the grid (no US) [24]. The initiation of extinction, in which a CS-no US connection supersedes or superimposes upon the original CS-US connection should somehow involve the synapses used for the original learning. ...
... Associative learning is believed to result from synaptic changes [1, 5, 52, 58, 62]. Not surprisingly, much recent research on the mechanisms of memory extinction has focused on the hippo- campus [3,2425262728 , which is held responsible for the consolidation of many forms of learning, particularly those of a declarative and episodic type [11, 15]. In particular, it was recently demonstrated that the context-specificity of extinction (i.e., animals extinguish better in the apparatus in which they had originally been trained) is inhibited by the administration of the GABA A agonist, muscimol, into the dorsal hippocampus [25]. ...
... Similarly, retrieval of one-trial step-down inhibitory avoidance learning is hindered by the intrahippocampal infusion of CNQX but not of AP5 [48] . However, the extinction of these tasks is strongly affected by the intra- amygdala [30] and the intrahippocampal infusion of AP5 [24], respectively, when the drugs are administered on the first retrieval session. Further, in fear-potentiated startle, extinction is facilitated by the intra-amygdala infusion of Dcycloserine , a partial agonist at the glycine recognition site of the NMDA receptor complex, which would be expected to increase the function of that receptor [33]. . ...
Retrieval procedures, if carried out without reinforcement, initiate memory extinction. The extinction of one-trial avoidance learning requires glutamate NMDA receptors, calcium-calmodulin dependent protein kinase II, cAMP-dependent protein kinase and mitogen-activated protein kinases, and, importantly, protein synthesis and gene expression in the hippocampus. The extinction of fear-potentiated startle requires NMDA receptors and mitogen-activated protein kinases in the basolateral amygdala. The extinction of conditioned taste aversion requires protein synthesis in the insular cortex. Thus, extinction is an active process that involves a variety of molecular events and –at least for the one task in which it was studied— both gene expression and protein synthesis. Insofar as in each of the tasks mentioned, the treat-ments were studied in a different brain region, therefore, it is still not known whether extinction in general uses those brain areas in parallel, or whether the extinction of each task is metabolically different. A role of endogenous cannabi-noids in extinction has been postulated; some evidence indicate that they act on the amygdala, but indirect findings sug-gest that they may also exert their action in the hippocampus. When carried out using methods that enhance perception that the reinforcement is absent, extinction can be quite profound, and the animals require "de novo" gene expression and protein synthesis in the hippocampus in order to reinstall the original learning. This might be of value in the design of "exposure" therapies for the treatment of phobias and of post-traumatic stress disorders.
... The effects of central administration of PSIs on memory have also been studied. Inhibition of hippocampal transcription of mRNA [44][45][46][47] and of its translation into proteins [45,46,48] impair memory consolidation of IA; nonetheless, these effects are impeded when animals are subjected to intense IA training [31]. Likewise, the amnestic effect of anisomycin infusion into the striatum is prevented by intense IA training [30]. ...
... The effects of central administration of PSIs on memory have also been studied. Inhibition of hippocampal transcription of mRNA [44][45][46][47] and of its translation into proteins [45,46,48] impair memory consolidation of IA; nonetheless, these effects are impeded when animals are subjected to intense IA training [31]. Likewise, the amnestic effect of anisomycin infusion into the striatum is prevented by intense IA training [30]. ...
The long-standing hypothesis that memory consolidation is dependent upon de novo protein synthesis is based primarily on the amnestic effects of systemic administration of protein synthesis inhibitors (PSIs), and recent chemogenetic approaches give further support to this hypothesis. Early experiments on mice showed that PSIs produced interference with memory consolidation that was dependent on the doses of PSIs, on the interval between drug injection and training, and, importantly, on the degree and duration of protein synthesis inhibition in the brain. Surprisingly, there is a conspicuous lack of information regarding the relationship between the duration of protein synthesis inhibition produced by PSIs and memory consolidation in the rat, one of the species most widely used to study memory processes. We found that, in the male rat, a single injection of cycloheximide (CXM), a commonly used PSI, produced a significant imbalance in protein homeostasis: an early inhibition of protein synthesis that lasted for at least one hour, followed by hyperproduction of proteins that lasted three days. We evaluated memory consolidation of inhibitory avoidance trained with either low or high intensity of foot-shock at the peaks of protein synthesis inhibition and protein hyperproduction. We found that, independent of the moment of training, the low-foot-shock groups showed amnesia, while the high-foot-shock groups displayed optimal memory performance. These results indicate that memory consolidation of relatively weak training is impaired by the inhibition or hyperproduction of protein synthesis, and that intense training overcomes this dysregulation of protein homeostasis allowing for memory formation probably through non-genomic mechanisms.
... The involvement of the vmPFC (50-54) and the CA1 region of the hippocampus (17,54,55) together with the baso-LA and other brain structures (7,8,18,55,56) in the extinction learning has been extensively described. The manipulation with protein synthesis inhibitors and signaling pathways indicates that these brain structures are crucial for the consolidation of extinction (57). ...
... The involvement of the vmPFC (50-54) and the CA1 region of the hippocampus (17,54,55) together with the baso-LA and other brain structures (7,8,18,55,56) in the extinction learning has been extensively described. The manipulation with protein synthesis inhibitors and signaling pathways indicates that these brain structures are crucial for the consolidation of extinction (57). ...
Significance
The presence of a familiar nonfearful conspecific during the extinction training session inhibits the retrieval but not the consolidation of the extinction of contextual fear conditioning. This effect relies on ventromedial prefrontal cortex rather than hippocampal gene expression and on ribosomal- and mTOR-dependent protein synthesis. These results provide knowledge about the cellular mechanisms and brain structures involved on the effect of social support in changing behavior and fear extinction memory.
... The step-down test apparatus was made according to previous reports [33,34] . Briefly, rats were placed in 25 cm伊 22 cm伊30 cm acrylic training apparatus in which the floor is a series of parallel bronze bars spaced 0.8 cm apart. ...
... The increased accumulation of these products is strongly reflected by AlCl 3 inflicted oxidative damage. TBA-RS is the secondary byproduct of LPO and has shown to catalyze the process of oxidative insult to membrane, so here LPO was found to be significantly increased with AlCl 3 exposure (4.2 mg/kg per day i.p. for 28 d) 33.68% with respect to normal saline. The observations are in accordance to previous studies which have shown that the mechanism of action of COX-2 inhibitor is believed to include inhibition of prostaglandin synthesis via selective inhibition of COX-2. ...
Objective: To assess potential of quercetin and etodolac to treat oxidative stress in neuronal
death and inflammation in Alzheimer’s disease of AlCl3 induced rat models. All results of this
AlCl3 model are compared with those obtained in controls.
Methods: Wistar rats, housed in a controlled environment were treated with aluminum chloride
(4.2 mg/kg of body weight, i.p.) for 28 d rather than oral to ensure neurotoxic concentration in
hippocampus and hypothalamic region, part highly active in memory control and cognition, while
control group was injected with saline. Estimation of thiobarbituric acid reactive substance,
superoxide dismutase, reduced glutathione and acetylcholine levels gave estimation of neuronal
damage. Low (20 mg/kg and 25 mg/kg) and high (40 mg/kg and 50 mg/kg) doses of quercetin and
etodolac were administered to the test groups respectively. Histopathology study was conducted
to perform relative study.
Results: Co-administration of quercetin and etodolac either alone or in combination prevented
the changes in biochemical markers of Alzheimer’s disease, but significant results (P
... Durante la adquisición están presentes los estímulos que deben ser asociados, en la consolidación se estabiliza la información adquirida, mediante la evocación se recupera la información y durante la extinción se observa un decremento en la respuesta previamente condicionada debido a que ya no se presenta la consecuencia comúnmente aversiva. Medina et al., 2007, (o) Fischer et al., 2004 Szapiro et al., 2003, (q) Liang, Hu y Chang, 1996 Barros et al., 2000, (s) Barros et al., 2001, (t) De Quervain, Roozendaal y McGaugh, 1998, (k) Lamprecht y LeDoux, 2004, (l) Prado-Alcalá et al., 1985, (m) Pravosudov, 2010 Medina et al., 2007, (o) Fischer et al., 2004 Szapiro et al., 2003, (q) Liang, Hu y Chang, 1996 Barros et al., 2000, (s) Barros et al., 2001, (t) De Quervain, Roozendaal y McGaugh, 1998 Tronson et al., 2012, (v) Vianna et al., 2003, (w) Falls, Miserendino y Davis, 1992 Kim et al., 2007, (y) Prado-Alcalá et al., 1994 largo plazo. Se ha observado que los niños que tienen dificultades en la memoria de trabajo experimentan problemas para seguir instrucciones con pasos múltiples (Engle, Carullo y Collins, 1991) o completar problemas aritméticos de restas y divisiones a la hora de mantener el registro del orden de las operaciones y manipular las cantidades intermedias (Geary, Hoard, Byrd-Craven y DeSoto, 2004). ...
... La expresión génica y la síntesis de proteínas también son requeridos para la extinción de la memoria (Vianna, Igaz, Coitinho, Medina e Izquierdo, 2003). Los hallazgos apuntan a que la ventana temporal en la que acontecen estos cambios nucleares durante la extinción es menor que en la consolidación, lo anterior posiblemente significaría que durante la extinción hay un tiempo acotado para modificar esta información porque los cambios en las neuronas ocurren por poco tiempo. ...
La memoria es un proceso esencial en los animales que les permite adaptarse al medio en el que
viven. Ésta consta de varias etapas en las que la información que ha sido adquirida previamente es
almacenada, recuperada y susceptible a la extinción. Las etapas de la memoria comparten elementos
celulares pero también requieren de otros específicos para el procesamiento de información; estos
elementos serán descritos a lo largo del capítulo. Cuando el sujeto se expone a un evento donde hay
información relevante para almacenar, esta información es transmitida a distintas estructuras encefálicas;
donde sistemas de neurotransmisión como el glutamatérgico, el GABAérgico, el colinérgico y el
adrenérgico se activan en redes neuronales discretas para poder almacenar los trazos mnemónicos. La
activación de los receptores y canales por parte de estos sistemas permite la entrada de iones como el
Na+, K+, Ca2+ y Cl- así como la activación de proteínas G. La actividad de los canales iónicos y los
receptores inicia entonces una cadena de señalización que desemboca en la transcripción y la síntesis de
nuevas proteínas. Las señales del citoplasma y las nuevas proteínas sintetizadas modificarán la
arquitectura neuronal y las propiedades de la red, haciéndola eficiente para que la memoria pueda ser
almacenada. Para acceder a la memoria se requiere de sólo algunos elementos que se caracterizan por
ser de rápida activación como los sistemas de neurotransmisión y enzimas. Cuando recordamos
experiencias, estos trazos de memoria entran en un estado lábil donde pueden integrar nueva
información. Lo anterior ocurre durante la extinción, donde los estímulos que habían estado asociados
previamente cambian sus relaciones causales. La extinción es entonces un nuevo aprendizaje que
requiere de la mayoría de los elementos celulares que participan durante la formación de la memoria.
Por otra parte, existen diversos padecimientos como el síndrome de Down, el Alzheimer, y el estrés
post-traumático que alteran las distintas etapas de la memoria. Estas patologías se deben en parte a
cambios en vías de señalización; éstos serán descritos brevemente en este capítulo. Finalmente se
abordarán tecnologías recientes como el proyecto Conectoma Humano, la Optogenética y CLARITY
que prometen generar nuevos conocimientos para el entendimiento de las bases moleculares de la
memoria.
... Este nuevo aprendizaje requiere expresión genética y síntesis de nuevas proteínas. La extinción puede completarse hasta tal punto que no ocurran nunca recuperaciones espontáneas de la respuesta condicionada, que para volver a producirse esta última requiera nueva expresión genética y síntesis de proteínas y que su recuerdo no pueda mejorarse por sustancias que ordinariamente lo facilitan [52]. ...
... Olvido ¿Qué es el olvido, un proceso pasivo de pérdida de la memoria o un proceso activo que inhibe su expresión? Para Vianna et al [52], una pérdida real de la memoria podría deberse a la falta de uso de las sinapsis involucradas o a la pérdida física de esas sinapsis o las neuronas que las sustentan. Sin embargo, suele ocurrir que las memorias aparentemente perdidas vuelven a ser accesibles cuando cambia el contexto externo o interno del sujeto. ...
Aim. This review describes the concepts, temporal dynamics and main features of learning and memory systems from a comprehensive molecular, neuroanatomical, neurophysiological, cognitive and behavioural approach. Development. Starting with molecular mechanisms of synaptic plasticity we describe the memory stages, implicit and explicit memory systems, working memory, remembering and forgetting. Each process is illustrated with examples of recent experimental and clinical research. Conclusions. Learning and memory are closely related brain processes which give rise to adaptive changes in behaviour. Implicit memory is a kind of unconscious and rigid memory for habits, which is based on brain regions processing perceptions and motor and emotional information, like the neocortex, the neostriatum, the cerebellum or the amygdala. Explicit or declarative memory is a conscious and flexible memory, hippocampus-dependent. Working memory is actually a system of executive cognition, based on interactions between the prefrontal cortex and other brain regions. The retrieval of complex memories consist of an active process of reconstruction of the past which incorporates new experiences of the subject who is remembering. The reactivation of memories can initiate genuine processes of reconsolidation and extinction. Forgetting could depend on alterations in the neural networks storing the information or, otherwise, on active processes which hinder consolidation or block the expression of the memories. (REV NEUROL 2005; 40: 289-97) Key words. Amnesia. Executive cognition. Explicit memory. Extinction. Fear conditioning. Forgetting. Implicit memory. Learning. Memory consolidation. Reconsolidation. Remembering. Working memory.
... The fact that extinction memory requires protein synthesis during a defined time window during and/or after induction led to the assumption that it is a new memory that consolidates as the original one. Some experimental data suggest that extinction consolidation requires transcription as well (Lin et al., 2003b;Vianna et al., 2003;Mamiya et al., 2009). However, the temporary nature of the behavioral expression of extinction points to mechanistic differences with the original memory consolidation. ...
... The role of the hippocampus in fear memory extinction is not as well understood as the role of other neural structures such as amygdala and prefrontal cortex (Maren and Quirk, 2004). For example, contradictory results were reported using hippocampal injections of protein synthesis inhibitors (Vianna et al., 2003;Fischer et al., 2004). Here, the inhibition of molecular processes that regulate gene expression in the hippocampus either improved or impaired extinction, supporting the fact that gene expression in this neural structure is also involved in extinction. ...
In fear conditioning, aversive stimuli are readily associated with contextual features. A brief reexposure to the training context causes fear memory reconsolidation, whereas a prolonged reexposure induces memory extinction. The regulation of hippocampal gene expression plays a key role in contextual memory consolidation and reconsolidation. However, the mechanisms that determine whether memory will reconsolidate or extinguish are not known. Here, we demonstrate opposing roles for two evolutionarily related transcription factors in the mouse hippocampus. We found that nuclear factor-κB (NF-κB) is required for fear memory reconsolidation. Conversely, calcineurin phosphatase inhibited NF-κB and induced nuclear factor of activated T-cells (NFAT) nuclear translocation in the transition between reconsolidation and extinction. Accordingly, the hippocampal inhibition of both calcineurin and NFAT independently impaired memory extinction, whereas inhibition of NF-κB enhanced memory extinction. These findings represent the first insight into the molecular mechanisms that determine memory reprocessing after retrieval, supporting a transcriptional switch that directs memory toward reconsolidation or extinction. The precise molecular characterization of postretrieval processes has potential importance to the development of therapeutic strategies for fear memory disorders.
... These results are consistent with much of the work employing protein synthesis inhibitors (e.g., Berman & Dudai, 2001;Power et al., 2006;Rodriguez-Ortiz et al., 2008;Vianna et al., 2001). Protein synthesis inhibitors disrupt the translation of proteins into mRNA (Vianna, Muller-Igaz, Coitinho, Medina, & Izquierdo, 2003b). Vianna et al. (2003b) showed that infusion of anisomycin into the hippocampus prior to extinction trials in an inhibitory avoidance task produced blocking of extinction; however, infusion one or 3 h post-extinction did not disrupt memory for extinction. ...
... Protein synthesis inhibitors disrupt the translation of proteins into mRNA (Vianna, Muller-Igaz, Coitinho, Medina, & Izquierdo, 2003b). Vianna et al. (2003b) showed that infusion of anisomycin into the hippocampus prior to extinction trials in an inhibitory avoidance task produced blocking of extinction; however, infusion one or 3 h post-extinction did not disrupt memory for extinction. Unlike original consolidation, which typically requires two peaks of protein synthesis (Müller Igaz, Vianna, Medina, & Izquierdo, 2002), extinction appears to only require one immediately surrounding training (Vianna, Cammarota, Coitinho, Medina, & Izquierdo, 2003a). ...
... It is well known that specific transcriptional changes are required for many phases of LTM including consolidation, recall, or even for extinction processes (Flexner et al., 1963;Montarolo et al., 1986;Kida et al., 2002;Vianna et al., 2003;Berger-Sweeney et al., 2006;Bianchi et al., 2014;Alberini & Kandel, 2014). Previous little is known about lncRNAs localized to dendrites and their mechanism of function at the synapse. ...
LncRNAs are involved in critical processes for cell homeostasis and function. However, it remains largely unknown whether and how the transcriptional regulation of long noncoding RNAs results in activity-dependent changes at the synapse and facilitate formation of long-term memories. Here, we report the identification of a novel lncRNA, SLAMR, that becomes enriched in CA1- but not in CA3-hippocampal neurons upon contextual fear conditioning. SLAMR is transported to dendrites via the molecular motor KIF5C and recruited to the synapse in response to stimulation. Loss of function of SLAMR reduced dendritic complexity and impaired activity-dependent changes in spine structural plasticity. Interestingly, the gain of function of SLAMR enhanced dendritic complexity, and spine density through enhanced translation. Analyses of the SLAMR interactome revealed its association with CaMKIIα protein through a 220-nucleotide element and its modulation of CaMKIIα phosphorylation. Furthermore, loss-of-function of SLAMR in CA1 selectively impairs consolidation without altering acquisition, recall, and extinction of fear memory or spatial memory. Together, these results establish a new mechanism for activity dependent changes at the synapse and consolidation of contextual fear memory.
... Here, discriminating between aversive and appetitive forms of extinction learning may help extricate the role of specific brain structures in this process. The vast majority of studies of the neural basis of the extinction learning to date, have addressed this phenomenon from the perspective of aversive conditioning (Szapiro et al., 2003;Vianna et al., 2003;Cammarota et al., 2007;Kim and Richardson, 2009;Ernst et al., 2017) and suggest that the brain areas that encode fear conditioning might be the same as those involved in aversive extinction learning (Akirav and Maroun, 2007;Vlachos et al., 2011). Given its essential role in spatial, associative and context-dependent learning (for a review see McDonald and Mott, 2017), the hippocampus seems a likely location for the encoding of context-dependent extinction learning. ...
During extinction learning (EL), an individual learns that a previously learned behavior no longer fulfills its original purpose, or is no longer relevant. Recent studies have contradicted earlier theories that EL comprises forgetting, or the inhibition of the previously learned behavior, and indicate that EL comprises new associative learning. This suggests that the hippocampus is involved in this process. Empirical evidence is lacking however. Here, we used fluorescence in situ hybridization of somatic immediate early gene (IEG) expression to scrutinize if the hippocampus processes EL.
Rodents engaged in context-dependent EL and were also tested for renewal of (the original behavioral response to) a spatial appetitive task in a T-maze. Whereas distal and proximal CA1 subfields processed both EL and renewal, effects in the proximal CA1 were more robust consistent with a role of this subfield in processing context.
The lower blade of the dentate gyrus and the proximal CA3 subfields were particularly involved in renewal. Responses in the distal and proximal CA3 subfields suggest that this hippocampal subregion may also contribute to evaluation of the reward outcome. Taken together, our findings provide novel and direct evidence for the involvement of distinct hippocampal subfields in context-dependent EL and renewal.
... Successful memory extinction is defined by effective short-or long-lasting CR reduction towards the CS after repeated CS-alone presentations, rather than the mere experimental manipulation. As for CS-US memories, long-term extinction requires a period of consolidation where de novo mRNA and protein synthesis are required ( Vianna et al., 2003;Santini et al., 2004). ...
Associative long-term memories (LTMs) support long-lasting behavioural changes resulting from sensory experiences. Retrieval of a stable LTM by means of a large number of conditioned stimulus (CS) alone presentations produces inhibition of the original memory through extinction. Currently, there are two opposing hypotheses to account for the neural mechanisms supporting extinction. The unlearning hypothesis posits that extinction affects the original memory trace by reverting the synaptic changes supporting LTM. On the contrary, the new learning hypothesis proposes that extinction is simply the formation of a new associative memory that inhibits the expression of the original one. We propose that detailed analysis of extinction-associated molecular mechanisms could help distinguish between these hypotheses. Here we will review experimental evidence regarding the role of protein kinases and phosphatases on LTM formation and extinction. Even though kinases and phosphatases regulate both memory processes, their participation appears to be dissociated. LTM formation recruits kinases, but is constrained by phosphatases. Memory extinction presents a more diverse molecular landscape, requiring phosphatases and some kinases, but also being constrained by kinase activity. Based on the available evidence, we propose a new theoretical model for memory extinction: a neuronal segregation of kinases and phosphatases supports a combination of time-dependent reversible inhibition of the original memory (CS-US), with establishment of a new associative memory trace (CS-noUS).
... Mediante la administración de inhibidores de la arn polimerasa y del ribosoma en la cpfm, se ha demostrado que la transcripción y la síntesis de proteínas también son requeridas para el establecimiento de la extinción (Santini, Feyder, Gangarossa, Bateup, Greengard y Fisone, 2012). En la extinción parecen ser necesarios los mecanismos de transcripción y de traducción en una ventana más reducida de lo que ocurre en la consolidación, ya que se ha demostrado que la síntesis de proteínas es requerida alrededor del establecimiento de la extinción y no más allá de una hora (Vianna, Igaz, Coitinho, Medina e Izquierdo, 2003). ...
Las neuronas de la corteza prefrontal y su participación en la memoria.
... Reconsolidation disruption was demonstrated through the use of N-methyl-D-aspartate (NMDA) antagonists, like MK-801 (Ben Mamou, Gamache, & Nader, 2006;Flavell & Lee, 2013;Lee, Everitt, & Thomas, 2004;Winters, Tucci, & DaCosta-Furtado, 2009), and with beta-adrenergic receptor antagonists, like propranolol (Dêbiec & LeDoux, 2004;Kindt, Soeter, & Vervliet, 2009;Robinson, Ross, & Franklin, 2011). Another common method for inducing reconsolidation disruption involved administration of protein synthesis inhibitors-drugs, such as anisomycin and cycloheximide (CHX), which disrupted the translation of proteins into messenger RNA (Dêbiec, LeDoux, & Nader, 2002;Vianna, Igaz, Coitinho, Medina, & Izquierdo, 2003). Furthermore, a variety of learning and memory paradigms were used to examine reconsolidation (for reviews, see Nader & Einarsson, 2010;Nader & Hardt, 2009). ...
Reconsolidation theory has supported the notion that active memory is vulnerable to the effects of an amnesic agent. An extension of reconsolidation theory posits that active memory, while necessary for creating vulnerability in memory, is not sufficient. Prediction error (i.e., when expectation is inconsistent with reality) may be a key factor in the destabilization of memory. The present study examined the role of prediction error in appetitive memory reconsolidation. Rats learned to dig in cups of scented sand to retrieve buried sweet cereal rewards. Forty-eight hours following acquisition, a single reactivation trial was given during which a prediction error or no prediction error was included. The prediction error consisted of a single extinction trial, while the no prediction error condition consisted of an additional reinforced trial. Cycloheximide (CHX; 1 mg/kg) or vehicle (VEH: distilled water; 1 mg/kg) was administered intraperitoneally immediately following reactivation. One week following reactivation, rats received 2 nonreinforced test trials. Results showed longer latencies to dig for rats that received CHX following a prediction error (CHX/PE) compared to rats that received VEH (VEH/PE) or did not receive a prediction error (CHX/NoPE or VEH/NoPE). These results add to a growing literature demonstrating that protein synthesis is necessary in appetitive memory reconsolidation only when reactivation includes a prediction error.
... 18 and 20, see Fig. 3.15b-c) suggests that motivational and sensorimotor processes underlying performance in the watermaze were intact. This was reported by others (Meiri and Rosenblum, 1998;Naghdi et al., 2003;Morris et al., 2006;Rodriguez-Ortiz et al., 2008), as well as the absence of effect of intra-hippocampal infusions of anisomycin (80 g/l per side) on activity/exploration in an open field and anxiety in an elevated plus maze (Vianna et al., 2003). Recently, however, new findings have added to the original scepticism and non-specific effects of anisomycin, such as apoptosis, have again been proposed to mediate anisomycin-induced amnesia rather than inhibition of protein synthesis per se Radulovic and Tronson, 2008;Qi and Gold, 2009). ...
In everybody’s lives, there are strong emotional or surprising events that, for being special,
are vividly remembered for a lifetime. Sometimes, these memories include one-shot images or
details of associated daily life events that, for being ordinary, should have been rapidly
forgotten. Why and how does the brain form and retain detailed memories of trivial events? The
synaptic tagging and capture (STC) hypothesis of memory formation (Frey & Morris, Nature
1997) provides a theoretical framework that might explain the formation of these flashbulb
memories at a cellular level. The hypothesis suggests that strong events, producing long-lasting
memories, might stabilise memory for weak events by up-regulating the synthesis of late-phase
plasticity-related proteins in neurons encoding memory traces for both events. This thesis tests
this prediction of the STC hypothesis during the formation of long-term place memory in
rodents.
First, two new behavioural tasks are developed which provide sensitive measures of rapidly
acquired place memory persistence - a new one-trial place memory task in the “event arena” and
a modified delayed matching-to-place (DMP) protocol in the watermaze. Persistence of place
memory is assessed and compared in these tasks. Given the important role of NMDA receptor
activation during STC mechanisms, the contribution of NMDA and AMPA receptor activation
in the hippocampus for the encoding and retrieval of place memory, respectively, is also
established. Finally, weak and strong encoding events, leading to the formation of either shortor
long-lasting place memory in the watermaze DMP task, are characterized. A second series of experiments investigates the possibility of synergistic interactions
between different encoding events that occur in two different watermazes. First, weak and
strong encoding events are arranged to occur within a short time-window to test behavioural
analogues of the “strong-before-weak” and “weak-before-strong” STC paradigms characterised
in electrophysiological experiments in rat hippocampal slices (Frey and Morris, 1997, 1998b).
Then, after establishing i) the time course and local specificity of protein synthesis inhibition by
intra-hippocampal infusion of anisomycin in vivo, ii) the dependence of long-term memory for
strong encoding events on protein synthesis in the hippocampus, and iii) the induction of
transcriptional and translational mechanisms in the hippocampus by strong encoding events, a
behavioural analogue of the “strong-before-strong” STC paradigm (Frey and Morris, 1997) is
also investigated.
The results of these experiments are supportive of i) a role for hippocampal NMDA
receptor-mediated synaptic plasticity in the encoding of rapidly acquired place memory; ii) a
role for hippocampal AMPA receptor-mediated synaptic transmission in both encoding and
retrieval of memory; and iii) a role for transcriptional and translational mechanisms in the
hippocampus in the stabilisation of place memory. However, no evidence could be found
supporting the involvement of synaptic tagging and capture mechanisms during the formation of
long-lasting place memory.
... Activity-dependent protein synthesis is important for synaptic plasticity and cognition (Krug et al. 1984;Katz and Shatz 1996;Sakata et al. 2013). Furthermore, changes in gene expression appear to be essential for memory extinction, as inhibition of gene transcription and protein synthesis interfere with memory extinction in an conditioned avoidance paradigm (Vianna et al. 2003). Thus loss of Slack channels could lead to defective activity-dependent protein synthesis, affecting molecular processes that are crucial for memory extinction and relearning. ...
Kcnt1 encoded sodium-activated potassium channels (Slack channels) are highly expressed throughout the brain where they modulate the firing patterns and general excitability of many types of neurons. Increasing evidence suggests that Slack channels may be important for higher brain functions such as cognition and normal intellectual development. In particular, recent findings have shown that human Slack mutations produce very severe intellectual disability and that Slack channels interact directly with the Fragile X mental retardation protein (FMRP), a protein that when missing or mutated results in Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism in humans. We have now analyzed a recently developed Kcnt1 null mouse model in several behavioral tasks to assess which aspects of memory and learning are dependent on Slack. We demonstrate that Slack deficiency results in mildly altered general locomotor activity, but normal working memory, reference memory, as well as cerebellar control of motor functions. In contrast, we find that Slack channels are required for cognitive flexibility, including reversal learning processes and the ability to adapt quickly to unfamiliar situations and environments. Our data reveal that hippocampal-dependent spatial learning capabilities require the proper function of Slack channels.
© 2015 Bausch et al.; Published by Cold Spring Harbor Laboratory Press.
... Using contextual fear conditioning as a task, these windows occur immediately or 4 hours after acquisition for memory tested 24 hours later [9,10], or 12 hours after training for memory tested a week later [11]. Processes that follow retrieval of the memory trace (extinction or reconsolidation) also require transcription and protein synthesis [12][13][14][15]. Several studies have used genome-wide approaches such as microarrays to describe changes in coding and noncoding gene expression after memory acquisition or synaptic activity [16][17][18][19][20]. ...
Background
A fundamental question in neuroscience is how memories are stored and retrieved in the brain. Long-term memory formation requires transcription, translation and epigenetic processes that control gene expression. Thus, characterizing genome-wide the transcriptional changes that occur after memory acquisition and retrieval is of broad interest and importance. Genome-wide technologies are commonly used to interrogate transcriptional changes in discovery-based approaches. Their ability to increase scientific insight beyond traditional candidate gene approaches, however, is usually hindered by batch effects and other sources of unwanted variation, which are particularly hard to control in the study of brain and behavior.
Results
We examined genome-wide gene expression after contextual conditioning in the mouse hippocampus, a brain region essential for learning and memory, at all the time-points in which inhibiting transcription has been shown to impair memory formation. We show that most of the variance in gene expression is not due to conditioning and that by removing unwanted variance through additional normalization we are able provide novel biological insights. In particular, we show that genes downregulated by memory acquisition and retrieval impact different functions: chromatin assembly and RNA processing, respectively. Levels of histone 2A variant H2AB are reduced only following acquisition, a finding we confirmed using quantitative proteomics. On the other hand, splicing factor Rbfox1 and NMDA receptor-dependent microRNA miR-219 are only downregulated after retrieval, accompanied by an increase in protein levels of miR-219 target CAMKIIγ.
Conclusions
We provide a thorough characterization of coding and non-coding gene expression during long-term memory formation. We demonstrate that unwanted variance dominates the signal in transcriptional studies of learning and memory and introduce the removal of unwanted variance through normalization as a necessary step for the analysis of genome-wide transcriptional studies in the context of brain and behavior. We show for the first time that histone variants are downregulated after memory acquisition, and splicing factors and microRNAs after memory retrieval. Our results provide mechanistic insights into the molecular basis of cognition by highlighting the differential involvement of epigenetic mechanisms, such as histone variants and post-transcriptional RNA regulation, after acquisition and retrieval of memory.
Keywords: Learning and memory; gene expression; normalization of unwanted variance; histone variants; microRNAs
... The behavioral phenomenon of extinction is deWned as a decrease in the conditioned response (CR) resulting from repeated CS presentations (Pavlov, 1927). This decrease of the CR is thought to be based on new learning ("the CS is not followed by the US") that leads to extinction memory via a protein synthesis-dependent consolidation process (Berman & Dudai, 2001;Bouton & Moody, 2004;Pedreira & Maldonado, 2003;Power, Berlau, McGaugh, & Steward, 2006;Santini, Ge, Ren, Pena de Ortiz, & Quirk, 2004;Vianna, Igaz, Coitinho, Medina, & Izquierdo, 2003;Vianna, Szapiro, McGaugh, Medina, & Izquierdo, 2001). Hence, the same experience an animal has had, the unreinforced exposure to the learned stimulus, results in two behavioral phenomena (reduction of the CR and stabilization of the CR). ...
... The role of hippocampal protein synthesis in fear extinction has been widely studied. Using an inhibitory avoidance paradigm it was found that intra-hippocampal (dorsal CA1 region) administration of the protein synthesis inhibitor anisomycin, performed either before Vianna et al., 2001Vianna et al., , 2003 or immediately after (Luft et al., 2006;Power et al., 2006;Vianna et al., 2001) the first extinction session, blocks extinction of this fear memory task. Instead, the treatment is ineffective when given 1 or 3 h after the first extinction session . ...
Fear memory is a motivational system essential for organisms survival having a central role in organization of defensive behaviors to threat. In the last years there has been a growing interest on conditioned fear memory reconsolidation and extinction, two specific phases of memorization process, both induced by memory retrieval. Understanding the mechanisms underlying these two mnemonic processes may allow to work out therapeutic interventions for treatment of human fear and anxiety disorders, such as specific phobias and post-traumatic stress disorder. Based on the use of one-trial conditioning paradigms, which allow to follow the evolution of a mnemonic trace in its various phases, the present paper has attempted to reorganize the current literature relative to the rodents highlighting both the role of several brain structures in conditioned fear memory reconsolidation and extinction and the selective cellular processes involved. A crucial role seems to be play by medial prefrontal cortex, in particular by prelimbic and infralimbic cortices, and by distinct connections between them and the amygdala, hippocampus and entorhinal cortex.
Copyright © 2015. Published by Elsevier Ltd.
... Divergent results have also been reported regarding the effects of PSIs on extinction, a form of learning in which subjects decrease the intensity or frequency of responses to a cue that no longer predicts a consequence [9,10]. In many studies, PSIs have been found to interfere with extinction [11][12][13][14][15][16][17][18][19][20][21], although it has also been reported that PSIs facilitate [18,22] or have no effect [23,24] on this type of learning. ...
... In this context, extinction may be considered as a new form of learning, involving memory formation although preserving the original memory trace. Many studies have tried to explain neural basis underlying this stage in terms of conditioning [6,[8][9][10]; however, the neural substrates of a previously acquired spatial memory task remain elusive. The extinction of spatial learning evaluated in the Morris water maze has been studied at a behavioral level [3,4] and used in a despairand depression-like model [2,[11][12][13]. ...
... All drugs were purchased from Sigma (Italy) and injected in a quantity of 0.3 ll/side. All drug doses were chosen on the basis of the current literature (Tinsley et al. 2009;Vianna et al. 2003). Pre-training and post-training injection protocols were used to analyze the effects of the drugs on WM and LTM, respectively (see Supplementary methods reported in Online Resource 1 for a detailed description of the procedure). ...
Memory capacity (MC) refers to the number of elements one can maintain for a short retention interval. The molecular mechanisms underlying MC are unexplored. We have recently reported that mice as well as humans have a limited MC, which is reduced by hippocampal lesions. Here, we addressed the molecular mechanisms supporting MC. GluA1 AMPA-receptors (AMPA-R) mediate the majority of fast excitatory synaptic transmission in the brain and are critically involved in memory. Phosphorylation of GluA1 at serine residues S831 and S845 is promoted by CaMKII and PKA, respectively, and regulates AMPA-R function in memory duration. We hypothesized that AMPA-R phosphorylation may also be a key plastic process for supporting MC because it occurs in a few minutes, and potentiates AMPA-R ion channel function. Here, we show that knock-in mutant mice that specifically lack both of S845 and S831 phosphorylation sites on the GluA1 subunit had reduced MC in two different behavioral tasks specifically designed to assess MC in mice. This demonstrated a causal link between AMPA-R phosphorylation and MC. We then showed that information load regulates AMPA-R phosphorylation within the hippocampus, and that an overload condition associated with impaired memory is paralleled by a lack of AMPA-R phosphorylation. Accordingly, we showed that in conditions of high load, but not of low load, the pharmacological inhibition of the NMDA–CaMKII–PKA pathways within the hippocampus prevents memory as well as associated AMPA-R phosphorylation. These data provide the first identified molecular mechanism that regulates MC.
Electronic supplementary material
The online version of this article (doi:10.1007/s00429-014-0927-1) contains supplementary material, which is available to authorized users.
... The one-trial, step-down avoidance inhibitory (IA) apparatus consisted of a white wood box (50 × 25 × 25 cm), the floor of which consisted of parallel 1.0-mm diameter stainless steel bars spaced at 1.0 cm apart. The left end of the floor was covered by a 7-cm wide, 2.5-cm high wood platform [30][31][32]. ...
Background
Flavonoids, which have been identified in a variety of plants, have been demonstrated to elicit beneficial effects on memory. Some studies have reported that flavonoids derived from Erythrina plants can provide such beneficial effects on memory. The aim of this study was to identify the flavonoids present in the stem bark crude extract of Erythrina falcata (CE) and to perform a bioactivity-guided study on conditioned fear memory.
Methods
The secondary metabolites of CE were identified by high performance liquid chromatography combined with a diode array detector, electrospray ionization tandem mass spectrometry (HPLC-DAD-ESI/MSn) and nuclear magnetic resonance (NMR). The buthanolic fraction (BuF) was obtained by partitioning. Subfractions from BuF (BuF1 – BuF6) and fraction flavonoidic (FfA and FfB) were obtained by flash chromatography. The BuF3 and BuF4 fractions were used for the isolation of flavonoids, which was performed using HPLC-PAD. The isolated substances were quantified by HPLC-DAD and their structures were confirmed by nuclear magnetic resonance (NMR). The activities of CE and the subfractions were monitored using a one-trial, step-down inhibitory avoidance (IA) task to identify the effects of these substances on the acquisition and extinction of conditioned fear in rats.
Results
Six subclasses of flavonoids were identified for the first time in CE. According to our behavioral data, CE, BuF, BuF3 and BuF4, the flavonoidic fractions, vitexin, isovitexin and 6-C-glycoside-diosmetin improved the acquisition of fear memory. Rats treated with BuF, BuF3 and BuF4 were particularly resistant to extinction. Nevertheless, rats treated with FfA and FfB, vitexin, isovitexin and 6-C-glycoside-diosmetin exhibited gradual reduction in conditioned fear response during the extinction retest session, which was measured at 48 to 480 h after conditioning.
Conclusions
Our results demonstrate that vitexin, isovitexin and diosmetin-6-C-glucoside and flavonoidic fractions resulted in a significant retention of fear memory but did not prevent the extinction of fear memory. These results further substantiate that the treatment with pure flavonoids or flavanoid-rich fractions might represent potential therapeutic approaches for the treatment of neurocognitive disorders, improvement of memory acquisition and spontaneous recovery of fear.
... Substantial evidence indicates that extinction depends on the glutamate NMDA receptor-linked signalling pathway, gene expression and protein synthesis in the hippocampus (Myers and Davis, 2002;Szapiro et al., 2003;Vianna et al., 2003). To determine whether NMDA receptors in the DH are involved in CPA extinction, we examined the effect of a microinjection of AP-5 into the DH on the CPA extinction. ...
... In fact, extinction may be understood as new learning involving new memory formation, although preserving the original memory trace and it would be also associated with decreased responding in memory tasks [10]. Former studies have tried to explain neural basis underlying this process in terms of conditioning [8,[11][12][13]. ...
... That is, there is a fast and excitatory phase in which the plasticity is improved, which corresponds with the acquisition of the information; conversely, in the slower or inhibitory phase, the plasticity is reduced and corresponds the initial stage of consolidation, in which the irrelevant or less-significant events are masked (Richter-Levin, 2004). Just like Hp, the AC is also involved in the acquisition or retrieval or fear memory (Hall et al., 2001;Schafe et al., 2001;Bucherelli et al., 2006), and both are involved in its extinction (Vianna et al., 2003;Sotres-Bayon et al., 2007). Thus, although the neural substrates that underlie the consolidation, retrieval or excitation of fear memory could be the same, efforts have focused on determining whether they share the same mechanisms (Abel and Lattal, 2001;Cammarota et al., 2004a). ...
Our group previously demonstrated that short-term treatment with a standardized extract of Ginkgo biloba (EGb) changed fear-conditioned memory by modulating gene expression in the hippocampus, amygdaloid complex and prefrontal cortex. Although there are few controlled studies that support the long-term use of EGb for the prevention and/or treatment of memory impairment, the chronic use of Ginkgo is common. This study evaluated the effects of chronic treatment with EGb on the conditioned emotional response, assessed by the suppression of ongoing behavior and in the modulation of gene and protein expression. Male adult Wistar rats were treated over 28 days and assigned to five groups (n = 10) as follows: positive control (4 mg kg−1 Diazepam), negative control (12% Tween 80), EGb groups (0.5 and 1.0 g kg−1) and the naïve group. The suppression of the licking response was calculated for each rat in six trials. Our results provide further evidence for the efficacy of EGb on memory. For the first time, we show that long-term treatment with the highest dose of EGb improves the fear memory and suggests that increased cAMP-responsive element-binding protein (CREB)-1 and glial fibrillary acidic protein (GFAP) mRNA and protein (P < 0.001) in the dorsal hippocampus and amygdaloid complex and reduced growth and plasticity-associated protein 43 (GAP-43) (P < 0.01) in the hippocampus are involved in this process. The fear memory/treatment-dependent changes observed in our study suggest that EGb might be effective for memory enhancement through its effect on the dorsal hippocampus and amygdaloid complex.
... The hippocampus is known to play an important role in various forms of learning and spatial/contextual memory and in memory consolidation/retrieval (Neves et al., 2008). The hippocampus is also involved in extinction behavior as evidenced by impairments in context-dependent extinction of fear conditioning that results from inactivation of this brain region (Corcoran and Maren, 2001; Corcoran et al., 2005; Ji and Maren, 2005) and cellular substrate inhibition (Szapiro et al., 2003; Vianna et al., 2003; Power et al., 2006). Similarly, studies have also implicated the hippocampus in the extinction of drug-related behaviors. ...
Theories of drug addiction that incorporate various concepts from the fields of learning and memory have led to the idea that classical and operant conditioning principles underlie the compulsiveness of addictive behaviors. Relapse often results from exposure to drug-associated cues, and the ability to extinguish these conditioned behaviors through inhibitory learning could serve as a potential therapeutic approach for those who suffer from addiction. This review will examine the evidence that extinction learning alters neuronal plasticity in specific brain regions and pathways. In particular, subregions of the prefrontal cortex (PFC) and their projections to other brain regions have been shown to differentially modulate drug-seeking and extinction behavior. Additionally, there is a growing body of research demonstrating that manipulation of neuronal plasticity can alter extinction learning. Therefore, the ability to alter plasticity within areas of the PFC through pharmacological manipulation could facilitate the acquisition of extinction and provide a novel intervention to aid in the extinction of drug-related memories.
... 300 It is thought to be a form of learning in which the animal no longer associates the conditioned stimulus as being linked to the unconditioned stimulus, but instead to the absence of malaise. 301,302 As in the formation of other taste memory traces, protein synthesis in the basolateral nuclei of the amygdala, as well as the GABA type B receptor subunit 1 and b-adrenergic receptors, is important. 296,[303][304][305] The process thus appears to be independent of muscarinic receptors and mitogen-activated protein kinase. ...
Personal experience, learned eating behaviors, hormones, neurotransmitters, and genetic variations affect food consumption. The decision of what to eat is modulated by taste, olfaction, and oral textural perception. Taste, in particular, has an important input into food preference, permitting individuals to differentiate nutritive and harmful substances and to select nutrients. To be perceived as taste, gustatory stimuli have to contact specialized receptors and channels expressed in taste buds in the oral cavity. Gustatory information is then conveyed via afferent nerves to the central nervous system, which processes the gustatory information at different levels, resulting in stimulus recognition, integration with metabolic needs, and control of ingestive reflexes. This review discusses physiological factors influencing the decision of what to eat, spanning the bow from the recognition of the nutritive value of food in the oral cavity, over the feedback received after ingestion, to processing of gustatory information to the central nervous system.
http://www.sciencedirect.com/science/article/pii/B9780123983978000150
... Past experiments examining the effects of protein synthesis inhibitors on memory have often examined the effects on memory for tasks that involve relatively high footshock intensities or other high-stress conditions, e.g. habituation to a loud conspecific distress cry, taste aversion training, fear extinction [e.g.: [55][56][57][58][59][60][61][62][63]. There are also reports of impairment of extinction in appetitive tasks [50,64], and it will be important to assess the nature of neurobiological bases of arousal in these conditions. ...
This experiment examined the effects on memory of interactions of cycloheximide dose and training foot shock intensity. Mice received injections of cycloheximide (120 mg/kg, s.c.) or saline 30 min prior to inhibitory avoidance training with shock intensities of 100, 150, 250 or 300 μA (1 s duration). Memory was tested 48 h later. The saline control mice showed increasing memory latencies as a function of shock intensity. The ability of cycloheximide to impair memory increased as the training shock intensity increased. In a second experiment, mice were trained with a 200 μA (1 s duration) shock and received injections of saline or cycloheximide at one of several doses (30, 60 or 120 mg/kg). Under these training conditions, cycloheximide enhanced memory in an inverted-U dose-response manner. These findings are consistent with prior findings suggesting that protein synthesis inhibitors act on memory by altering modulators of memory formation as a secondary consequence of the inhibition of protein synthesis rather than by interfering with training-initiated synthesis of proteins required for memory formation.
... In this case, hippocampal dentate spine density was increased 6 h after training and returned to basal levels at 72 h after training. Not only is the hippocampus involved in acquisition of conditioned responses, but also in the process of extinction, i.e., in the learned diminution of the conditioned responses following withholding of the unconditioned or reinforcing stimuli (Szapiro et al., 2003; Vianna et al., 2003; Dillon et al., 2008). However, there is a conspicuous lack of information regarding spine formation in this type of learning, and still less regarding extinction of enhanced learning. ...
Numerous reports indicate that learning and memory of conditioned responses are accompanied by genesis of dendritic spines in the hippocampus, although there is a conspicuous lack of information regarding spine modifications after behavioral extinction. There is ample evidence that treatments that typically produce amnesia become innocuous when animals are submitted to a procedure of enhanced training. We now report that extinction of inhibitory avoidance (IA), trained with relatively low foot-shock intensities, induces pruning of dendritic spines along the length of the apical dendrites of hippocampal CA1 neurons. When animals are trained with a relatively high foot-shock there is a high resistance to extinction, and pruning in the proximal and medial segments of the apical dendrite are seen, while spine count in the distal dendrite remains normal. These results indicate that pruning is involved in behavioral extinction, while maintenance of spines is a probable mechanism that mediates the protecting effect against amnesic treatments produced by enhanced training.
... Thus, in the IA task the animal learns that a specific place should be avoided since it is associated with an aversive event. Additionally, there are different experimental approach which use inhibitory passive avoidance learning in the rat to asses hippocampus dependent learning [2,40,3]. It is known that this kind of learning triggers biochemical events in the hippocampus that are necessary for the retention of this task [20]. ...
In this work we investigated how the neurosteroid allopregnanolone can modulate learning and memory processes. For this purpose, we used ovariectomized (OVX) rats subcutaneously injected with oestradiol benzoate (E) alone or E and progesterone (P). Then, rats were injected in dorsal hippocampus with allopregnanolone or vehicle. Animals were tested in inhibitory avoidance task (IA task). After behavioural test hippocampal mRNA expression and enzymatic activity of 3α-HOR, the enzyme responsible of allopregnanolone synthesis, were analysed. In IA task OVX-EP rats spent less time on platform, compared to those OVX or OVX-E. Regression analyses revealed that there was a significant negative relationship between E-P infusion and performance in this task. Pre-training allopregnanolone administration to OVX-EP rats increased the time spent on the platform. Interestingly, when enzymatic activity of 3α-HOR was tested, OVX-EP rats showed a significant decrease in the enzymatic activity, compared with OVX and OVX-E rats. In addition, OVX-EP group showed a significant increase in the enzymatic activity after intrahippocampal infusion of allopregnanolone. On the other hand, when mRNA expression of 3α-HOR was analysed no differences were observed when the hippocampal allopregnanolone injection was done. These results suggest that E and P have amnesic effects on female rats, being reversed by allopregnanolone through its modulation on hippocampal 3α-HOR activity.
... The step-down test apparatus was made according to a previous report (Vianna et al., 2001(Vianna et al., , 2003. Briefly, rats were placed in 25 cm × 22 cm × 30 cm acrylic training apparatus in which the floor is a series of parallel bronze bars spaced 0.8 cm apart. ...
To investigate the effects of chronic aluminum (Al) exposure on memory of rats by recording long-term potentiation (LTP) induction in CA1 region of Schaffer collateral (SC) of hippocampus and observing the changes of key LTP induction-related kinases.
Forty weaned Wistar rats were divided into 4 groups ad libitum, each group 10 rats. Three groups were fed with 0.2%, 0.4% and 0.6% AlCl(3) in drinking water for three months individually to set up the aluminum exposure models and the rest group was the control. After behavioral test, electrophysiological recordings were made at area CA1 from hippocampal SC branch followed by biochemical examination for several key kinases involved in LTP induction and formation.
Chronic exposure of Al significantly decrease the activities of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) and reduced the expression levels of extracellular signal-regulated kinases (ERK1/2) and Ca(2+)-calmodulin dependent protein kinase II (CaMKII) in hippocampus, attenuating the population spike (PS) amplitude of LTP from the hippocampal CA1 region, causing impaired memory abilities of rats.
Aluminum accumulation in the hippocampus affects several crucial kinases involved in LTP induction and formation, resulting in impairment of memory.
... Although it is widely accepted that the hippocampus plays a role in contextual encoding and retrieval of fear extinction memories (Corcoran, Desmond, Frey, & Maren, 2005; Corcoran & Maren, 2001; Corcoran & Quirk, 2007; Maren & Hobin, 2007 ), since contextual fear acquisition (Maren, Aharonov, & Fanselow, 1997) and extinction occurs in hippocampus-lesioned animals (Frohardt, Guarraci, & Bouton, 2000), a deeper investigation about the role of this cerebral structure in contextual fear memory has been demanded (see Maren, 2008 for a review). Extinction depends on specific molecular events: gene expression , protein synthesis and activation of the N-methyl-D-aspartate receptor (NMDAr) (Cammarota et al., 2005; Lin, Yeh, Lu, & Gean, 2003; Vianna, Igaz, Coitinho, Medina, & Izquierdo, 2003 ). For instance , the administration of D-cycloserine, an agonist of the NMDAr, facilitates fear extinction in distinct memory tasks (Gabriele & Packard, 2007; Langton & Richardson, 2008; Yamamoto et al., 2008). ...
Polyamines, such as spermidine and spermine, have been reported to improve memory retention through the activation of N-methyl-d-aspartate receptors (NMDAr). However whether polyamine agonists and antagonists alter extinction remains unclear. In the current study, we investigated whether spermidine and polyamine antagonists that selectively block the NR2B subunit at the NMDAr alter the extinction of contextual conditioned fear in male Wistar rats. The bilateral intra-hippocampal administration of exogenous spermidine (2 nmol/site) immediately after, but not 6h after extinction training, facilitated the extinction of fear conditioning. The injection of the NMDAr antagonists arcaine (0.2 nmol/site), ifenprodil (20 nmol/site) and traxoprodil (0.2 nmol/site), disrupted fear extinction and, at doses that had no effect per se, reversed the facilitatory effect of spermidine on fear extinction. These results suggest that exogenous and endogenous polyamines facilitate the extinction of contextual conditioned fear through activation of NR2B subunit-containing NMDAr in the hippocampus. Since extinction-based exposure therapy is widely used as treatment for a number of anxiety-related disorders, including phobias and post-traumatic stress, the currently reported facilitation of extinction by polyaminergic agents suggest these compounds as putative candidates for drug development.
The regulation of fear memories is critical for adaptive behaviors and dysregulation of these processes is implicated in trauma- and stress-related disorders. Treatments for these disorders include pharmacological interventions as well as exposure-based therapies, which rely upon extinction learning. Considerable attention has been directed toward elucidating the neural mechanisms underlying fear and extinction learning. In this review, we will discuss historic discoveries and emerging evidence on the neural mechanisms of the adaptive regulation of fear and extinction memories. We will focus on neural circuits regulating the acquisition and extinction of Pavlovian fear conditioning in rodent models, particularly the role of the medial prefrontal cortex and hippocampus in the contextual control of extinguished fear memories. We will also consider new work revealing an important role for the thalamic nucleus reuniens in the modulation of prefrontal-hippocampal interactions in extinction learning and memory. Finally, we will explore the effects of stress on this circuit and the clinical implications of these findings.
Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events. This study assessed the role of these systems in the hippocampus for the extinction memory process by submitting male Wistar rats to fear-motivated step-down inhibitory avoidance (IA). The post-extinction session administration of the nicotinic and muscarinic cholinergic receptor antagonists, mecamylamine and scopolamine, respectively, both at doses of 2µg/µl/side, and rapamycin, an mTOR inhibitor (0.02µg/µl/side), into the CA1 region of the dorsal hippocampus, impaired the IA extinction memory. Furthermore, the nicotinic and muscarinic cholinergic receptor agonists, nicotine and muscarine, respectively, had a dose-dependent effect on the IA extinction memory when administered intra-CA1, immediately after the extinction session. Nicotine (0.6µg/µl/side) and muscarine (0.02µg/µl/side), respectively, had no effect, while the higher doses (6 and 2µg/µl/side, respectively) impaired the IA extinction memory. Interestingly, the co-administration of muscarine at the lower dose blocked the impairment that was induced by rapamycin. This effect was not observed when nicotine at the lower dose was co-administered. These results have demonstrated the participation of the cholinergic receptors and mTOR in the hippocampus for IA extinction, and that the cholinergic agonists had a dose-dependent effect on the IA extinction memory. This study provides insights related to the behavioural aspects and the neurobiological properties underlying the early stage of fear-motivated IA extinction memory consolidation and suggests that there is hippocampal muscarinic receptor participation independent of mTOR in this memory process.
Long-term memory has been associated with morphological changes in the brain, which in turn tightly correlate with changes in synaptic efficacy. Such plasticity is proposed to rely on dendritic spines as a neuronal canvas on which these changes can occur. Given the key role of actin cytoskeleton dynamics in spine morphology, major regulating factors of this process such as Cofilin 1 (Cfl1) and LIM kinase (LIMK), an inhibitor of Cfl1 activity, are prime molecular targets that may regulate dendritic plasticity. Using a contextual fear conditioning paradigm in mice, we found that pharmacological induction of depolymerization of actin filaments through the inhibition of LIMK causes an impairment in memory reconsolidation, as well as in memory consolidation. On top of that, Cfl1 activity is inhibited and its mRNA is downregulated in CA1 neuropil after re-exposure to the training context. Moreover, by pharmacological disruption of actin cytoskeleton dynamics, the process of memory extinction can either be facilitated or impaired. Our results lead to a better understanding of the role of LIMK, Cfl1 and actin cytoskeleton dynamics in the morphological and functional changes underlying the synaptic plasticity of the memory trace.
Formation of long-term memories (LTMs) can be disturbed during a discrete time window after learning with amnestic agents. It has been concluded that LTMs undergo a labile phase of memory fixation, termed consolidation, and that an LTM, once consolidated, is stable. Since the late 1960s it is known that retrieving a memory in combination with the application of a consolidation inhibitor disturbs memory retention in a later memory test. This observation is nowadays interpreted along the consolidation theory. It is proposed that retrieval makes the consolidated memory labile and that a second consolidation round is required to stabilize the retrieved memory. This second round of consolidation is targeted by the inhibitor, resulting in a decrease of the conditioned response at a later memory test. Accordingly, the process in question is called reconsolidation. Meanwhile, the neuronal and molecular bases of reconsolidation in vertebrates and invertebrates are studied intensively, and it is under dispute whether this hypothesis holds true.
The functional organization of neural circuits that underlies learning and memory is defined by very specific synaptic contacts. Under normal conditions, the synaptic contacts between neurons can be modified by experience in order to establish other brain responses. In most cases such modifications tend to promote re-adaptation, although they can also lead to aberrant behaviour. Whatever the case, a wide range of changes can occur in nerve tissue at different levels of organization, tending to maintain an adequate balance between the individual's activity and their environmental demands. The adaptation of nerve cells to novel or adverse conditions, whether effective or not, is known as neuroplasticity. Experimental studies of plasticity in the nervous system have shown that the ability to acquire new information from the environment (learning) and to evoke stored information (memory) is closely related to structural changes in neuronal cytoarchitecture, specifically in the synaptic contacts mediated by dendritic spines. Dynamic modifications to the molecular components of both pre- and post-synaptic synaptic elements involved in plasticity underlie and define these cytoarchitectonic changes.
Estrogen receptors (ER) can be activated by their natural ligand estradiol (E2), although several cytoplasmic and nuclear ERs have been identified that may be activated in a different manner, such as ER-a66 and ER-ß. The cloning of human ER-a66 led to the identification of variants of this receptor, including the ER-a46 splice variant and more recently, the novel ERa-36 variant. On the other hand, five splice variants of ER-ß have also been identified named Erb1, Erb2, Erb1d3, Erb2d3 and Erb1d4, possibly with distinct biological activities. Both ER-a and ER-ß receptors are expressed extensively in the brain, and even in the spinal cord. Furthermore, ER-a/ER-ß receptor expression overlaps in several brain regions, although often to a different extent, and the functional role of such an overlapping distribution is still unclear. While ER-a plays a key role in the regulation of reproductive behavior and neuroendocrine activity, ER-ß is more strongly involved in non-reproductive psychoneural processes of a cognitive nature, such as learning and memory. In fact, ER-ß expression predominates over ERa in several cognition-related brain regions, such as the hippocampus and prefrontal cortex. Nevertheless, both ER-a and ER- ß are thought to modulate the excitatory synaptic activity underlying the transmission of cognitive information at dendritic spines, both in the hippocampus and prefrontal cortex. In this sense they favor and protect the integrity of learning- and mnemonic-associated information to yield adequate behavioral patterns, although the precise role of the αand β ERs in these events has yet to be elucidated. In addition, ER activation could have a distinct cognitive significance depending on the origin of E2 synthesis (i.e., gonadal or locally in the brain).
Memory could be conceptualized as the capability to encode, store and retrieve information to guide behavior. Memory may be stored in different manners depending on synaptic characteristics for information processing, which may modulate synchronization of firing of neuronal assemblies. This book focuses on some of the mechanisms that modulate the synaptic activity underlying both the organization and expression of memory. Thus, memory is viewed from the point of view of its synaptic determinants. This book is the integrated compilation of a large body of experimental evidence related to some cellular and subcellular events underlying plastic changes of neural circuits forming the memory traces related to some memory systems. Moreover, this view of memory is considered from both a normal viewpoint and from that of some atypical situations.
Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after experiencing trauma. Actual therapies do not help majority of patients with PTSD. Moreover, extinguished fear memories usually reappear in the individuals when exposed to trauma cues. New drugs to reduce the impact of conditioned cues in eliciting abnormal fear responses are urgently required. Cotinine, the main metabolite of nicotine, decreased anxiety and depressive-like behavior, and enhanced fear extinction in mouse models of PTSD. Cotinine, considered a positive modulator of the α7 nicotinic acetylcholine receptor (α7nAChR), enhances fear extinction in rodents in a manner dependent on the activity of the nAChRs. Cotinine stimulates signaling pathways downstream of α7nAChR including the protein kinase B (Akt)/glycogen synthase kinase 3β (GSK3β pathway and the extracellular signal-regulated kinases (ERKs). The stimulation of these factors promotes synaptic plasticity and the extinction of fear. In this review, we discuss the hypothesis that cotinine relieves PTSD symptoms and facilitates fear memory extinction by promoting brain plasticity through the positive modulation of presynaptic nAChRs and its effectors in the brain.
Fragile X syndrome (FXS) is the most common genetic cause for intellectual disability. Fmr1 knockout (KO) mice are an established model of FXS. Chronic pharmacological inhibition of metabotropic glutamate receptor 5 (mGlu5) in these mice corrects multiple molecular, physiological, and behavioral phenotypes related to patients' symptoms. To better understand the pathophysiology of FXS and the effect of treatment, brain activity was analyzed using functional magnetic resonance imaging in relation to learning and memory performance.
Wild-type (WT) and Fmr1 KO animals receiving chronic treatment with the mGlu5 inhibitor CTEP or vehicle were evaluated consecutively for 1) learning and memory performance in the inhibitory avoidance and extinction test, and 2) for the levels of brain activity using continuous arterial spin labeling based functional magnetic resonance imaging. Neural activity patterns were correlated with cognitive performance using a multivariate regression analysis. Furthermore, mGlu5 receptor expression in brains of untreated mice was analyzed by autoradiography and saturation analysis using [(3)H]-ABP688.
Chronic CTEP treatment corrected the learning deficit observed in Fmr1 KO mice in the inhibitory avoidance and extinction test and prevented memory extinction in WT and Fmr1 KO animals. Chronic CTEP treatment normalized perfusion in the amygdala and the lateral hypothalamus in Fmr1 KO mice and furthermore decreased perfusion in the hippocampus and increased perfusion in primary sensorimotor cortical areas. No significant differences in mGlu5 receptor expression levels between Fmr1 WT and KO mice were detected.
Chronic mGlu5 inhibition corrected the learning deficits and partially normalized the altered brain activity pattern in Fmr1 KO mice.
Fear memory retrieval can lead to either reconsolidation (accompanied or not by strengthening of the memory trace) or extinction. Here, we show that non-reinforced retrieval of inhibitory avoidance (IA) conditioning can induce memory strengthening assessed in a subsequent retention test trial. Infusion of the protein synthesis inhibitor cycloheximide or the mTOR inhibitor rapamycin into the rat basolateral complex of the amygdala (BLA) after a reactivation (retrieval) session impaired retrieval-induced strengthening. Intra-BLA infusion of the mRNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) after retrieval had no effect. These findings provide the first evidence suggesting that non-reinforced IA retrieval can lead to memory strengthening through a mechanism dependent on protein synthesis and mTOR activity in the BLA.
The aerial respiratory behaviour of Lymnaea can be operantly conditioned to form a long-term memory (LTM) that will persist for >24hrs. LTM formation is dependent on altered gene activity and new protein synthesis, with the N-methyl-D-aspartate (NMDA) receptors, mitogen activated protein kinase (MAPK), and protein kinase C (PKC) pathways playing a critical role. LTM can also undergo extinction, whereby the original memory is temporarily masked by a new memory. Here we investigate if the formation of an extinction memory uses similar molecular pathways to those required for LTM formation. We find that the formation of the extinction memory can be blocked by inhibitors of NMDA receptors, PKC, and MAPK suggesting that extinction memory formation uses similar mechanisms to that of 'normal' memory formation.
Metabolites of the commonly used imidazole fungicide prochloraz are androgen receptor antagonists. They have been shown to block androgen-driven development and compromise reproductive function. We tested the effect of prochloraz on cognitive behavior following exposure to this fungicide during the perinatal period. Pregnant Wistar rats were administered a 200mg/kg dose of prochloraz on gestational day (GD) 7, GD11, and GD15. The social recognition test (SRT) was performed on 7-week-old male rat offspring. We found an increase in pregnancy length and a significantly reduced pup weight on PND15 and PND40 but no effect of prenatal prochloraz exposure on social investigation or acquisition of social-olfactory memory.
Abstract Memories are fragile and easily forgotten at first, but after a consolidation period of hours to weeks, are inscribed in our brains as stable traces, no longer vulnerable to conventional amnesic treatments. Retrieval of a memory renders it labile, akin to the early stages of consolidation. This phenomenon has been explored as memory reactivation, in the sense that the memory is temporarily 'deconsolidated', allowing a short time window for amnesic intervention. This window closes again after reconsolidation, which restores the stability of the memory. In contrast to this 'transient deconsolidation' and the short-spanned amnesic effects of consolidation blockers, some specific treatments can disrupt even consolidated memory, leading to apparent amnesia. We propose the term 'amnesic deconsolidation' to describe such processes that lead to disruption of consolidated memory and/or consolidated memory traces. We review studies of these 'amnesic deconsolidation' treatments that enhance memory extinction, alleviate relapse, and reverse learning-induced plasticity. The transient deconsolidation that memory retrieval induces and the amnesic deconsolidation that these regimes induce both seem to dislodge a component that stabilizes consolidated memory. Characterizing this component, at both molecular and network levels, will provide a key to developing clinical treatments for memory-related disorders and to defining the consolidated memory trace.
Ginkgo biloba extract, EGb761, is widely used as herbal supplements throughout Western society. It has been used in the treatment of various common geriatric complaints including short-term memory loss. Our previous study has shown that acute systemic administration of EGb761 enhanced extinction of fear-potentiated startle (FPS) in rats. Little is known about the behavioral effects of hippocampally administered EGb761 on the extinction of FPS.
The current study was performed to evaluate the involvement of the dorsal hippocampus (DH) in the EGb761 facilitation effect on the extinction of FPS.
Male adult SD rats were used. EGb761 (28 ng/side, bilaterally) was infused into DH bilaterally 10 min prior to extinction training. Animals were then tested for FPS 24 h later. Results showed that intra-hippocampal infusion of EGb761 prior to extinction training facilitated extinction, which was not due to impairments of expression of conditioned fear. Intra-hippocampal injection of ERK1/2 inhibitor PD98059 partially attenuates the above EGb761 effect. Therefore, acute EGb761 administration modulated extinction of conditioned fear, which might be mediated by more than one signal cascade.
These results suggest that DH may participate in the facilitation effect of EGb761 on the extinction of conditioned fear. In addition to ERK1/2, another signal cascade may also be involved in the EGb761 facilitation effect on extinction.
Several lines of evidence suggest that initial acquisition of learned behavior involves multiple memory systems. In particular, lesions of the hippocampus impair the acquisition of cognitive or relational memory, but do not impair the acquisition of stimulus-response habits. Extinction behavior also involves new learning, and therefore it is possible that multiple forms of memory may also underlie extinction. We examined this hypothesis by training rats in a task in which extinction behavior could putatively be acquired by either a cognitive or habit memory system. Adult male Long-Evans rats were initially trained to run in a straight alley maze for food reward. Following training they were placed into one of two extinction conditions. In one condition rats were allowed to run to an empty goal box (i.e. response extinction). In a second condition rats were placed into an empty goal box without making a running response (i.e. latent or non-response extinction). Prior to each daily session of extinction training, rats received intra-hippocampal infusions of either the local anesthetic bupivacaine (0.75% solution/0.5 ul), or saline. Rats receiving saline infusions displayed extinction behavior in both the response and non-response conditions. In contrast, rats receiving intra-hippocampal infusions ofbupivacaine extinguished normally in the response condition, but did not display nonresponse extinction. This latent extinction effect was enhanced by decreasing the amount of time between the last extinction trial and the probe trial. Additionally, administering extinction training and probe trials in different contexts did not appear to prevent latent extinction, however large variability may be masking this effect. The new context administered during extinction prevented latent extinction in some animals, but not others. These findings suggest that, similar to initial acquisition, the learning that occurs during extinction also involves multiple memory systems. Specifically, the hippocampus may selectively mediate extinction under conditions in which new stimulus-response learning is prevented.
Data derived from in vitro preparations indicate that NMDA receptors play a critical role in synaptic plasticity in the CNS. More recently, in vivo pharmacological manipulations have suggested that an NMDA-dependent process may be involved in specific forms of behavioral plasticity. All of the work thus far has focused on the possible role of NMDA receptors in the acquisition of responses. However, there are many examples in the behavioral literature of learning-induced changes that involve the reduction or elimination of a previously acquired response. Experimental extinction is a primary example of the elimination of a learned response. Experimental extinction is well described in the behavioral literature, but has not received the same attention in the neurobiological literature. As a result, the neural mechanisms that underlie this important form of learning are not at all understood. In the present experiments, the fear-potentiated startle paradigm was employed to begin to investigate neural mechanisms of extinction. The results show that infusion of the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (AP5) into the amygdala, a limbic structure known to be important for fear conditioning, dose-dependently blocked extinction of conditioned fear. Control experiments showed that the blockade of extinction was neither the result of the permanent disruption of amygdaloid function nor the result of decreased sensitivity of the animals to the conditioned stimulus. Infusion of AP5 into the interpositus nucleus of the cerebellum, a control site, did not block extinction. Finally, intra-amygdala infusion of a selected dose of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione did not block extinction of conditioned fear. These results, together with a previous report from our laboratory (Miserendino et al., 1990), demonstrate the importance of the amygdala in the elaboration of conditioned fear and suggest that an NMDA-dependent process might underlie the extinction of conditioned fear.
We have studied the effect of training conditions on hippocampal protein synthesis-dependent processes in consolidation of the inhibitory avoidance task. Adult male Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.4 mA foot shock, 24 hr training-test interval). Fifteen minutes before or 0, 3, or 6 hr after training, animals received a 0.8-microl intrahippocampal infusion of the protein-synthesis inhibitor anisomycin (80 microg) or vehicle (PBS, pH 7.4). The infusion of anisomycin impaired retention test performance in animals injected 15 min before and 3 hr after the training session, but not at 0 or 6 h post-training. Pretraining with a low foot shock intensity (0.2 mA) 24 hr before training, prevented the amnestic effect of anisomycin injected at 15 min before or 3 hr after training. However, simple pre-exposure to the inhibitory avoidance apparatus did not alter the amestic effects of anisomycin. The results suggest that hippocampal protein synthesis is critical in two periods, around the time of, and 3 hr after training. A prior weak training session, however, which does not itself alter step-down latencies, is sufficient to prevent the amnestic effect of anisomycin, suggesting that even if not behaviorally detectable, weak training must be sufficient to produce some lasting cellular expression of the experience.
Recent studies implicate the hippocampus in contextual memory retrieval. The present experiments explore this possibility by examining the impact of reversible inactivation of the dorsal hippocampus (DH) on the context-specific expression of extinction. In experiment 1, rats were conditioned to fear a tone conditional stimulus (CS) and subsequently extinguished either in the same context as conditioning or in a novel context. A third group of rats underwent fear conditioning but did not receive extinction. After extinction, conditional fear to the tone CS was assessed in the conditioning context by measuring freezing. Rats extinguished in the conditioning context exhibited low levels of freezing, whereas those extinguished in a different context and those that received no extinction showed high levels of freezing. This indicates that the expression of extinction is context-specific. In experiment 2, the context-specific expression of extinction was disrupted by infusion of muscimol, a GABA(A) receptor agonist, into the DH. Rats that received muscimol infusions into the DH showed little freezing to the tone CS, regardless of whether the CS had been extinguished in the testing context or another context. In experiment 3, intrahippocampal muscimol infusions did not disrupt the expression of conditional freezing to the tone CS in rats that did not receive extinction. Thus, muscimol infusion into the DH produced a selective impairment in the context-specific expression of extinction. These results extend findings from other behavioral paradigms and provide additional support for a role for the hippocampus in contextual memory retrieval.
The rat insular cortex (IC) subserves the memory of conditioned taste aversion (CTA), in which a taste is associated with
malaise. When the conditioned taste is unfamiliar, formation of long-term CTA memory depends on muscarinic and β-adrenergic
receptors, mitogen-activated protein kinase (MAPK), and protein synthesis. We show that extinction of CTA memory is also dependent
on protein synthesis and β-adrenergic receptors in the IC, but independent of muscarinic receptors and MAPK. This resembles
the molecular signature of the formation of long-term memory of CTA to a familiar taste. Thus, memory extinction shares molecular
mechanisms with learning, but the mechanisms of learning anew differ from those of learning the new.
Five Pavlovian magazine approach experiments with rat subjects examined the mechanisms by which reconditioning restores extinguished responding. Experiments 1, 2, and 3 found that retraining did not destroy the spontaneous recovery with the passage of time that is characteristic of extinguished stimuli. Experiments 4 and 5 found evidence that retaining after extinction enhanced the strength of the originally trained associations. Together these results suggest that, just as extinction does not destroy original acquisition but superimposes some decremental process, so retraining does not destroy that decremental process but instead superimposes further associative learning.
Previous results indicate that intra-amygdala infusions of NMDA receptor antagonists block the extinction of conditioned fear. Mitogen-activated protein kinase (MAPK) can be activated by NMDA receptor stimulation and is involved in excitatory fear conditioning. Here, we evaluate the role of MAPK within the basolateral amygdala in the extinction of conditioned fear. Rats received 10 light-shock pairings. After 24 hr, fear was assessed by eliciting the acoustic startle reflex in the presence of the conditioned stimulus (CS) (CS-noise trials) and also in its absence (noise-alone trials). Rats subsequently received an intra-amygdala or intrahippocampal infusion of either 20% DMSO or the MAPK inhibitor PD98059 (500 ng/side) followed 10 min later by 30 presentations of the light CS without shock (extinction training). After 24 hr, they were again tested for fear-potentiated startle. PD98059 infusions into the basolateral amygdala but not the hippocampus significantly reduced extinction, which was otherwise evident in DMSO-infused rats. Control experiments indicated that the effect of intra-amygdala PD98059 could not be attributed to lasting damage to the amygdala or to state dependency. These results suggest that a MAPK-dependent signaling cascade within or very near the basolateral amygdala plays an important role in the extinction of conditioned fear.
Evidence that protein synthesis inhibitors induce amnesia in a variety of species and learning paradigms indicates that the consolidation of newly acquired information into stable memories requires the synthesis of new proteins. Because extinction of a response also requires acquisition of new information, extinction, like original learning, would be expected to require protein synthesis. The present experiments examined the involvement of protein synthesis in the hippocampus in the extinction of a learned fear-based response known to involve the hippocampus. Rats were trained in a one-trial inhibitory avoidance task in which they received footshock after stepping from a small platform to a grid floor. They were then given daily retention tests without footshock. The inhibitory response (e.g., remaining on the platform) gradually extinguished with repeated testing over several days. Footshock administered in a different context, instead of a retention test, prevented the extinction. Infusions of the protein synthesis inhibitor anisomycin (80 microg) into the CA1 region of the hippocampus (bilaterally) 10 min before inhibitory avoidance training impaired retention on all subsequent tests. Anisomycin infused into the hippocampus immediately after the 1st retention test blocked extinction of the response. Infusions administered before the 1st retention test induced a temporary (i.e., 1 day) reduction in retention performance and blocked subsequent extinction. These findings are consistent with other evidence that anisomycin blocks both the consolidation of original learning and extinction.
NMDA receptor antagonists block conditioned fear extinction when injected systemically and also when infused directly into the amygdala. Here we evaluate the ability of d -cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine-recognition site on the NMDA receptor complex, to facilitate conditioned fear extinction after systemic administration or intra-amygdala infusions.
Rats received 10 pairings of a 3.7 sec light and a 0.4 mA footshock (fear conditioning). Fear-potentiated startle (increased startle in the presence vs the absence of the light) was subsequently measured before and after 30, 60, or 90 presentations of the light without shock (extinction training). Thirty non-reinforced light presentations produced modest extinction, and 60 or 90 presentations produced nearly complete extinction (experiment 1). DCS injections (3.25, 15, or 30 mg/kg) before 30 non-reinforced light exposures dose-dependently enhanced extinction (experiment 2) but did not influence fear-potentiated startle in rats that did not receive extinction training (experiment 3). These effects were blocked by HA-966, an antagonist at the glycine-recognition site (experiment 4). Neither DCS nor HA-966 altered fear-potentiated startle when injected before testing (experiment 5). The effect of systemic administration was mimicked by intra-amygdala DCS (10 μg/side) infusions (experiment 6).
These results indicate that treatments that promote NMDA receptor activity after either systemic or intra-amygdala administration promote the extinction of conditioned fear.
Information storage in the brain is a temporally graded process involving different memory types or phases. It has been assumed for over a century that one or more short-term memory (STM) processes are involved in processing new information while long-term memory (LTM) is being formed. It has been repeatedly reported that LTM requires de novo RNA synthesis around the time of training. Here we show that LTM formation of a one-trial inhibitory avoidance training in rats, a hippocampal-dependent form of contextual fear conditioning, depends on two consolidation periods requiring synthesis of new mRNAs. By injecting the RNA polymerase II inhibitors 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole or alpha-amanitin into the CA1 region of the dorsal hippocampus at various times before and after training, we found that hippocampal gene expression is critical in two time windows: around the time of training and 3-6 hr after training. Interestingly, these two periods of sensitivity to transcriptional inhibitors are similar to those observed using the protein synthesis inhibitor anisomycin. These findings underscore the parallel dependence of LTM formation of contextual fear on mRNA and protein synthesis in the hippocampus and suggest that the two time periods of anisomycin-induced amnesia depend at least in part on new mRNA synthesis.
A paperback edition of the translation by Anrep, first published in 1927 by the Oxford University Press, containing a series of 23 lectures on the research of Pavlov's laboratory in the 1st quarter of the 20th century. From Psyc Abstracts 36:05:5CG30P. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The effect of a sublethal dose of alpha-amanitin given intraventricularly to rats on retention of passive and active avoidance conditioning has been studied, together with the effect on brain RNA and protein synthesis in vivo. The toxin brings about a significant impairment of retention of both passive and active conditioning in rats poisoned 6 hr or 24 before training. Brain RNA synthesis is decreased at 6 hr after poisoning, whilst protein synthesis decreases at a later stage (not before 12 hr after poisoning). Thus in rats poisoned with alpha-amanitin memory consolidation is impaired when RNA synthesis is decreased, and before protein synthesis is affected.
Injection of α amanitin into a cerebral ventricle reduced the ability of male mice to retain a passive avoidance response without affecting spontaneous locomotor activity or performance of a previously learned task. α Amanitin inhibited the brain form II DNA dependent RNA polymerase in a dose dependent manner up to 10 μg, at which dose a maximum of 98% inhibition was observed as determined by assay of brain nuclei at the time of training. The effect observed on passive avoidance retention is only seen at maximal (98%) inhibition. Furthermore, the inhibition of brain form II polymerase is transient, indicating that α amanitin is effective in vivo only when virtually 100% inhibition of this enzyme is attained. The liver form II polymerase was also inhibited after cerebroventricular injection, indicating that a significant amount of the α amanitin reached peripheral circulation. A 50% inhibition of liver form II polymerase was measured within 15 min. However, intraperitoneal injection of 10 μg of α amanitin did not produce significant inhibition of brain form II polymerase, and retention of a passive avoidance response was not affected.
Recent data have demonstrated a biochemical sequence of events in the rat hippocampus that is necessary for memory formation of inhibitory avoidance behavior. The sequence initially involves the activation of three different types of glutamate receptors followed by changes in second messengers and biochemical cascades led by enhanced activity of protein kinases A, C, and G and calcium-calmodulin protein kinase II, followed by changes in glutamate receptor subunits and binding properties and increased expression of constitutive and inducible transcription factors. The biochemical events are regulated early after training by hormonal and neurohumoral mechanisms related to alertness, anxiety, and stress, and 3-6 h after training by pathways related to mood and affect. The early modulation is mediated locally by GABAergic, cholinergic, and noradrenergic synapses and by putative retrograde synaptic messengers, and extrinsically by the amygdala and possibly the medial septum, which handle emotional components of memories and are direct or indirect sites of action for several hormones and neurotransmitters. The late modulation relies on dopamine D1, beta-noradrenergic, and 5HT1A receptors in the hippocampus and dopaminergic, noradrenergic, and serotoninergic pathways. Evidence indicates that hippocampal activity mediated by glutamate AMPA receptors must persist during at least 3 h after training in order for memories to be consolidated. Probably, this activity is transmitted to other areas, including the source of the dopaminergic, noradrenergic, and serotoninergic pathways, and the entorhinal and posterior parietal cortex. The entorhinal and posterior parietal cortex participate in memory consolidation minutes after the hippocampal chain of events starts, in both cases through glutamate NMDA receptor-mediated processes, and their intervention is necessary in order to complete memory consolidation. The hippocampus, amygdala, entorhinal cortex, and parietal cortex are involved in retrieval in the first few days after training; at 30 days from training only the entorhinal and parietal cortex are involved, and at 60 days only the parietal cortex is necessary for retrieval. Based on observations on other forms of hippocampal plasticity and on memory formation in the chick brain, it is suggested that the hippocampal chain of events that underlies memory formation is linked to long-term storage elsewhere through activity-dependent changes in cell connectivity.
A novel property of hippocampal LTP, 'variable persistence', has recently been described that is, we argue, relevant to the role of LTP in information storage. Specifically, new results indicate that a particular pattern of synaptic activation can give rise, either to a relatively short-lasting LTP, or to a longer-lasting LTP as a function of the history of activation of the neuron. This has led to the idea that the induction of LTP is associated with the setting of a'synaptic tag' at activated synapses, whose role is to sequester plasticity-related proteins that then serve to stabilize temporary synaptic changes and so extend their persistence. In this article, we outline the synaptic tag hypothesis, compare predictions it makes with those of other theories about the persistence of LTP, and speculate about the cellular identity of the tag. In addition, we outline the requirement for aminergic activation to induce late LTP and consider the functional implications of the synaptic tag hypothesis with respect to long-term memory.
The transcriptional inhibitor 5, 6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB) is an adenosine analog that has been shown to cause premature transcriptional termination and thus has been a useful tool to identify factors important for transcriptional elongation. Here, we establish an efficient system for studying DRB-sensitive steps of transcriptional elongation. In addition, we establish two novel effects of DRB not previously reported: intron stabilization and the induction of long transcripts by a mechanism other than premature termination. We found that DRB had a biphasic effect on T-cell receptor-beta (TCRbeta) transcripts driven by a tetracycline (tet)-responsive promoter in transfected HeLa cells. In the first phase, DRB caused a rapid decrease (within five minutes) of pre-mRNA and its spliced intron (IVS1(Cbeta1)), consistent with the known ability of DRB to inhibit transcription. In the second phase (which began ten minutes to two hours after treatment, depending on the dose), DRB dramatically increased the levels of IVS1(Cbeta1)-containing transcripts by a mechanism requiring de novo RNA synthesis. DRB induced the appearance of short 0.4 to 0.8 kb TCRbeta transcripts in vivo, indicating DRB enhances premature transcriptional termination. A approximately 475 nt prematurely terminated transcript (PT) was characterized that terminated at an internal poly(A) tract in the intron IVS1(Cbeta1). We identified three other effects of DRB. First, we observed that DRB induced the appearance of heterodisperse TCRbeta transcripts that were too long ( approximately 1 kb to >8 kb) to result from the type of premature termination events previously described. Their production was not promoter-specific, as we found that long transcripts were induced by DRB from both the tet-responsive and beta-actin promoters. Second, DRB upregulated full-length normal-sized c-myc mRNA, which provided further evidence that DRB has effects besides regulation of premature termination. Third, DRB stabilized lariat forms of the intron IVS1(Cbeta1), indicating that DRB exerts post-transcriptional actions. We propose that our model system will be useful for elucidating the factors that regulate RNA decay and transcriptional elongation in vivo.
'New' memories are initially labile and sensitive to disruption before being consolidated into stable long-term memories. Much evidence indicates that this consolidation involves the synthesis of new proteins in neurons. The lateral and basal nuclei of the amygdala (LBA) are believed to be a site of memory storage in fear learning. Infusion of the protein synthesis inhibitor anisomycin into the LBA shortly after training prevents consolidation of fear memories. Here we show that consolidated fear memories, when reactivated during retrieval, return to a labile state in which infusion of anisomycin shortly after memory reactivation produces amnesia on later tests, regardless of whether reactivation was performed 1 or 14 days after conditioning. The same treatment with anisomycin, in the absence of memory reactivation, left memory intact. Consistent with a time-limited role for protein synthesis production in consolidation, delay of the infusion until six hours after memory reactivation produced no amnesia. Our data show that consolidated fear memories, when reactivated, return to a labile state that requires de novo protein synthesis for reconsolidation. These findings are not predicted by traditional theories of memory consolidation.
Rats were implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus, the entorhinal cortex, anterior cingulate cortex, posterior parietal cortex, or the basolateral complex of the amygdala. The animals were trained in one-trial step-down inhibitory avoidance and tested 24 h later. Prior (10 min) to the retention test, through the cannulae, they received 0.5 microl infusions of a vehicle (2% dimethylsulfoxide in saline), or of the following drugs dissolved in the vehicle: the glutamate NMDA receptor blocker, aminophosphonopentanoic acid (AP5, 2.0 or 5.0 microg), the AMPA receptor blocker, 6,7-dinitroquinoxaline-2,3 (1H,4H)dione (DNQX, 0.4 or 1.0 microg), the metabotropic receptor antagonist, methylcarboxyphenylglycine (MCPG, 0.5 or 2.5 microg), the inhibitor of cAMP-dependent protein kinase (PKA), Rp-cAMPs (0.1 or 0.5 microg), the PKA stimulant, Sp-cAMPs (0.5 microg), or the inhibitor of the mitogen-activated protein kinase (MAPK), PD098059 (10 or 50 microM). All these drugs, at the same doses, had been previously found to alter long-term memory formation of this task. Here, retrieval test performance was blocked by DNQX, MCPG, Rp-cAMPs and PD098059 and enhanced by Sp-cAMPs infused into CA1 or the entorhinal cortex. The drugs had similar effects when infused into the parietal or anterior cingulate cortex, except that in these two areas AP5 also blocked retrieval, and in the cingulate cortex DNQX had no effect. Infusions into the basolateral amygdala were ineffective except for DNQX, which hindered retrieval. None of the treatments that affected retrieval had any influence on performance in an open field or in a plus maze; therefore, their effect on retention testing can not be attributed to an influence on locomotion, exploration or anxiety. The results indicate that the four cortical regions studied participate actively in, and are necessary for, retrieval of the one-trial avoidance task. They require metabotropic and/or NMDA glutamate receptors and PKA and MAPK activity. In contrast, the basolateral amygdala appears to participate only through a maintenance of its regular excitatory transmission mediated by glutamate AMPA receptors.
Recent findings have significantly advanced our understanding the mechanisms of memory formation. Most of these advances stemmed from behavioural pharmacology research involving, particularly, the localized infusion of drugs with specific molecular actions into specific brain regions. This approach has revealed brain structures involved in different memory types and the main neurotransmitter systems and sequence of metabolic cascades that participate in memory consolidation. Biochemical studies and, in several cases, studies of genetically manipulated animals, in which receptors or enzymes affected by the various drugs were absent or overexpressed, have complemented the pharmacological research. Although most studies have concentrated on the involvement of the hippocampus, many have also investigated the entorhinal cortex, other regions of the cortex, and the amygdala. Behavioural pharmacology has been of crucial importance in establishing the major neurohumoral and hormonal systems involved in the modulation of memory formation. These systems act on specific steps of memory formation in the hippocampus and in the entorhinal, parietal, and cingulate cortex. A specialized system mediated by the basolateral amygdaloid nucleus, and involving several neuromodulatory systems, is activated by emotional arousal and serves to regulate memory formation in other brain regions. The core mechanisms involved in the formation of explicit (declarative) memory are in many respects similar to those of long-term potentiation (LTP), particularly in the hippocampus. However, there are also important differences between memory formation and LTP. Memory formation involves numerous modulatory influences, the co-participation of various brain regions other than the hippocampus, and some properties that are specific to memory and absent in LTP (i.e. flexibility of response). We discuss the implications of these similarities and differences for understanding the neural bases of memory.
One of the most remarkable aspects of an animal's behavior is the ability to modify that behavior by learning, an ability that reaches its highest form in human beings. For me, learning and memory have proven to be endlessly fascinating mental processes because they address one of the fundamental features of human activity: our ability to acquire new ideas from experience and to retain these ideas over time in memory. Moreover, unlike other mental processes such as thought, language, and consciousness, learning seemed from the outset to be readily accessible to cellular and molecular analysis. I, therefore, have been curious to know: What changes in the brain when we learn? And, once something is learned, how is that information retained in the brain? I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells.
Pavlovian conditioning involves the association of initially neutral conditioned stimuli (CS) with unconditioned stimuli (US) that elicit a response. In contextual fear conditioning in rodents, the CS is the context of a training apparatus and the US is a foot shock. Retrieval of memory of the training is tested by presenting the CS alone. But a retrieval test also initiates extinction of the conditioned response. That is, presentation of the CS alone results in new learning, i.e., the CS no longer predicts the US. Here we report that extinction is triggered by two hippocampal signaling pathways underlying retrieval (the cAMP-dependent protein kinase and the mitogen-activated protein kinase pathways) and two other mechanisms that become activated at the same time and are not necessary for retrieval (N-methyl-D-aspartate glutamatergic receptors and the calcium/calmodulin-dependent protein kinase II signaling pathway). Thus, the molecular mechanisms underlying acquisition and/or consolidation of the memory for extinction are similar to those described for the acquisition and/or consolidation of the original contextual fear.
Retrieval of memory for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus
- Vianna