RESUMEN
It is widely accepted that fear memories are consolidated through protein synthesis-dependent changes in the basolateral amygdala complex (BLA). However, recent studies show that protein synthesis is not required to consolidate the memory of a new dangerous experience when it is similar to a prior experience. Here, we examined whether the protein synthesis requirement for consolidating the new experience varies with its spatial and temporal distance from the prior experience. Female and male rats were conditioned to fear a stimulus (S1, e.g., light) paired with shock in stage 1 and a second stimulus (S2, e.g., tone) that preceded additional S1-shock pairings (S2-S1-shock) in stage 2. The latter stage was followed by a BLA infusion of a protein synthesis inhibitor, cycloheximide, or vehicle. Subsequent testing with S2 revealed that protein synthesis in the BLA was not required to consolidate fear to S2 when the training stages occurred 48â h apart in the same context; was required when they were separated by 14â d or occurred in different contexts; but was again not required if S1 was re-presented after the delay or in the different context. Similarly, protein synthesis in the BLA was not required to reconsolidate fear to S2 when the training stages occurred 48â h apart but was required when they occurred 14â d apart. Thus, the protein synthesis requirement for consolidating/reconsolidating fear memories in the BLA is determined by similarity between present and past experiences, the time and place in which they occur, and reminders of the past experiences.
Asunto(s)
Complejo Nuclear Basolateral , Consolidación de la Memoria , Ratas , Masculino , Femenino , Animales , Complejo Nuclear Basolateral/fisiología , Consolidación de la Memoria/fisiología , Inhibidores de la Síntesis de la Proteína/farmacología , Cicloheximida/farmacología , Miedo/fisiologíaRESUMEN
Activity in the basolateral amygdala complex (BLA) is needed to encode fears acquired through contact with both innate sources of danger (i.e., things that are painful) and learned sources of danger (e.g., being threatened with a gun). However, within the BLA, the molecular processes required to consolidate the two types of fear are not the same: protein synthesis is needed to consolidate the first type of fear (so-called first-order fear) but not the latter (so-called second-order fear). The present study examined why first- and second-order fears differ in this respect. Specifically, it used a range of conditioning protocols in male and female rats, and assessed the effects of a BLA infusion of the protein synthesis inhibitor, cycloheximide, on first- and second-order conditioned fear. The results revealed that the differential protein synthesis requirements for consolidation of first- and second-order fears reflect differences in what is learned in each case. Protein synthesis in the BLA is needed to consolidate fears that result from encoding of relations between stimuli in the environment (stimulus-stimulus associations, typical for first-order fear) but is not needed to consolidate fears that form when environmental stimuli associate directly with fear responses emitted by the animal (stimulus-response associations, typical for second-order fear). Thus, the substrates of Pavlovian fear conditioning in the BLA depend on the way that the environment impinges upon the animal. This is discussed with respect to theories of amygdala function in Pavlovian fear conditioning, and ways in which stimulus-response associations might be consolidated in the brain.
Asunto(s)
Complejo Nuclear Basolateral , Aprendizaje , Femenino , Ratas , Masculino , Animales , Amígdala del Cerebelo/fisiología , Complejo Nuclear Basolateral/fisiología , Condicionamiento Clásico/fisiología , Miedo/fisiologíaRESUMEN
This study examined the effect of danger on consolidation of neutral information in two regions of the rat (male and female) medial temporal lobe: the perirhinal cortex (PRh) and basolateral amygdala complex (BLA). The neutral information was the association that forms between an auditory stimulus and a visual stimulus (labeled S2 and S1) across their pairings in sensory preconditioning. We show that, when the sensory preconditioning session is followed by a shocked context exposure, the danger shifts consolidation of the S2-S1 association from the PRh to the BLA; and does so by interacting with processes involved in encoding of the S2-S1 pairings. Specifically, we show that the initial S2-S1 pairing in sensory preconditioning is encoded in the BLA and not the PRh; whereas the later S2-S1 pairings are encoded in the PRh and not the BLA. When the sensory preconditioning session is followed by a context alone exposure, the BLA-dependent trace of the early S2-S1 pairings decays and the PRh-dependent trace of the later S2-S1 pairings is consolidated in memory. However, when the sensory preconditioning session is followed by a shocked context exposure, the PRh-dependent trace of the later S2-S1 pairings is suppressed and the BLA-dependent trace of the initial S2-S1 pairing is consolidated in memory. These findings are discussed with respect to mutually inhibitory interactions between the PRh and BLA, and the way that these regions support memory in other protocols, including recognition memory in people.SIGNIFICANCE STATEMENT The perirhinal cortex (PRh) and basolateral amygdala complex (BLA) process the pairings of neutral auditory and visual stimuli in sensory preconditioning. The involvement of each region in this processing is determined by the novelty/familiarity of the stimuli as well as events that occur immediately after the preconditioning session. Novel stimuli are represented in the BLA; however, as these stimuli are repeatedly presented without consequence, they come to be represented in the PRh. Whether the BLA- or PRh-dependent representation is consolidated in memory depends on what happens next. When nothing of significance occurs, the PRh-dependent representation is consolidated and the BLA-dependent representation decays; but when danger is encountered, the PRh-dependent representation is inhibited and the BLA-dependent representation is selected for consolidation.
Asunto(s)
Complejo Nuclear Basolateral , Miedo , Femenino , Ratas , Masculino , Animales , Condicionamiento Psicológico , Lóbulo Temporal , Reconocimiento en PsicologíaRESUMEN
Memories are rarely acquired under ideal conditions, rendering them vulnerable to profound omissions, errors, and ambiguities. Consistent with this, recent work using context fear conditioning has shown that memories formed after inadequate learning time display a variety of maladaptive properties, including overgeneralization to similar contexts. However, the neuronal basis of such poor learning and memory imprecision remains unknown. Using c-fos to track neuronal activity in male mice, we examined how these learning-dependent changes in context fear memory precision are encoded in hippocampal ensembles. We found that the total number of c-fos-encoding cells did not correspond with learning history but instead more closely reflected the length of the session immediately preceding c-fos measurement. However, using a c-fos-driven tagging method (TRAP2 mouse line), we found that the degree of learning and memory specificity corresponded with neuronal activity in a subset of dentate gyrus cells that were active during both learning and recall. Comprehensive memories acquired after longer learning intervals were associated with more double-labeled cells. These were preferentially reactivated in the conditioning context compared with a similar context, paralleling behavioral discrimination. Conversely, impoverished memories acquired after shorter learning intervals were associated with fewer double-labeled cells. These were reactivated equally in both contexts, corresponding with overgeneralization. Together, these findings provide two surprising conclusions. First, engram size varies with learning. Second, larger engrams support better neuronal and behavioral discrimination. These findings are incorporated into a model that describes how neuronal activity is influenced by previous learning and present experience, thus driving behavior.SIGNIFICANCE STATEMENT Memories are not always formed under ideal circumstances. This is especially true in traumatic situations, such as car accidents, where individuals have insufficient time to process what happened around them. Such memories have the potential to overgeneralize to irrelevant situations, producing inappropriate fear and contributing to disorders, such as post-traumatic stress disorder. However, it is unknown how such poorly formed fear memories are encoded within the brain. We find that restricting learning time results in fear memories that are encoded by fewer hippocampal cells. Moreover, these fewer cells are inappropriately reactivated in both dangerous and safe contexts. These findings suggest that fear memories formed at brief periods overgeneralize because they lack the detail-rich information necessary to support neuronal discrimination.
Asunto(s)
Aprendizaje/fisiología , Memoria/fisiología , Animales , Condicionamiento Clásico , Giro Dentado/fisiología , Discriminación en Psicología , Antagonistas de Estrógenos/farmacología , Miedo/psicología , Hipocampo/fisiología , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Modelos Psicológicos , Neuronas/fisiología , Proteínas Proto-Oncogénicas c-fos/genética , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologíaRESUMEN
Rodents require a minimal time period to explore a context prior to footshock to display plateau-level context fear at test. To investigate whether this rapid fear plateau reflects complete memory formation within that short time-frame, we used the immediate-early gene product Arc as an indicator of hippocampal context memory formation-related activity. We found that hippocampal Arc expression continued to increase well past the minimal time required for plateau-level fear. This raises the possibility that context fear conditioning occurs more rapidly than complete memory formation. Thus, animals may be able to condition robustly to both complete and incomplete contextual representations.
Asunto(s)
Miedo , Hipocampo/metabolismo , Memoria/fisiología , Complejo Relacionado con el SIDA/genética , Complejo Relacionado con el SIDA/metabolismo , Animales , Condicionamiento Clásico , Electrochoque/efectos adversos , Reacción Cataléptica de Congelación/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
Cognitive-behavioral testing in preclinical models of Alzheimer's disease has failed to capture deficits in goal-directed action control. Here, we provide the first comprehensive investigation of goal-directed action in a transgenic mouse model of Alzheimer's disease. Specifically, we tested outcome devaluation performance in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press left and right levers for pellet and sucrose outcomes, respectively (counterbalanced), over 4 d. On test, mice were prefed one of the outcomes to satiety and given a choice between levers. Devaluation performance was intact for 36-week-old wild-types of both sexes, who responded more on the valued relative to the devalued lever (Valued > Devalued). By contrast, devaluation was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. After additional lever press training (i.e., 8-d lever pressing in total), devaluation was intact for all mice, demonstrating that the initial deficits were not a result of a nonspecific impairment in reward processing, depression, or locomotor activity in J20 or aging mice. Follow-up analyses revealed that microglial expression in the dorsal CA1 region of the hippocampus was associated with poorer outcome devaluation performance on initial, but not later tests. Together, these data demonstrate that goal-directed action is initially impaired in J20 mice of both sexes and in aging male mice regardless of genotype, and that this impairment is related to neuroinflammation in the dorsal CA1 hippocampal region.
Asunto(s)
Enfermedad de Alzheimer , Ratones , Masculino , Humanos , Femenino , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Objetivos , Ratones Transgénicos , Hipocampo/metabolismo , Modelos Animales de EnfermedadRESUMEN
The context in which sudden fearful events occur can be poorly encoded into memory. Yet, the consequences of the resulting context-impoverished memories remain unknown. We demonstrate that restricting the time available for context encoding during contextual fear conditioning causes maladaptively overgeneralized and inextinguishable fear. However, post-conditioning context exposure enables further context encoding through hippocampal reconsolidation-dependent memory updating. Updating in the conditioning context alleviates overgeneralization and restores capacity for extinction. However, updating in a similar safe context erroneously shifts fear from the dangerous to the safe context. We argue that these phenomena can be explained by uncertainty about where events occurred. Moreover, we show that a hippocampal-neocortical neurocomputational model based on this assumption successfully simulates and explains our observations. These findings reveal that context-impoverished memories are maladaptive and can be improved or distorted after recall, with implications for basic memory theory, memory distortion, and treatment of disorders like post-traumatic stress disorder.