Cued fear memory generalization increases over time

Neuropharmacology, 2007

Much of the research on long-term potentiation (LTP) is motivated by the question of whether changes in synaptic strength similar to LTP underlie learning and memory. Here we discuss findings from studies on fear conditioning, a form of associative learning whose neural circuitry is relatively well understood, that may be particularly suited for addressing this question. We first review the evidence suggesting that fear conditioning is mediated by changes in synaptic strength at sensory inputs to the lateral nucleus of the amygdala. We then discuss several outstanding questions that will be important for future research on the role of synaptic plasticity in fear learning. The results gained from these studies may shed light not only on fear conditioning, but may also help unravel more general cellular mechanisms of learning and memory.

Proceedings of the National Academy of Sciences, 2009

Mammals evolved a potent fear-motivated defensive system capable of single-trial fear learning that shows no forgetting over the lifespan of the animal. The basolateral amygdala complex (BLA) is considered an essential component of this conditional fear learning system. However, recent studies challenge this view and suggest that plasticity within other brain regions (i.e., central nucleus of the amygdala) may be crucial for fear conditioning. In the present study, we examine the mnemonic limits of contextual fear conditioning in the absence of the BLA using overtraining and by measuring remote fear memories. After excitotoxic lesions of the BLA were created, animals underwent overtraining and were tested at recent and remote memory intervals. Here we show that animals with BLA lesions can learn normal levels of fear. However, this fear memory loses its adaptive features: it is acquired slowly and shows substantial forgetting when remote memory is tested. Collectively, these finding...

PLOS ONE, 2015

Fear memories can be attenuated by reactivation followed by disrupted reconsolidation. Using functional magnetic resonance imaging we recently showed that reactivation and reconsolidation of a conditioned fear memory trace in the basolateral amygdala predicts subsequent fear expression over two days, while reactivation followed by disrupted reconsolidation abolishes the memory trace and suppresses fear. In this follow-up study we demonstrate that the behavioral effect persists over 18 months reflected in superior reacquisition after undisrupted, as compared to disrupted reconsolidation, and that neural activity in the basolateral amygdala representing the initial fear memory predicts return of fear. We conclude that disrupting reconsolidation have long lasting behavioral effects and may permanently erase the fear component of an amygdala-dependent memory.

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 isnotrequired 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 consolidation of the new experience varies with its spatial and temporal distance from the prior experience. In each experiment, rats were conditioned to fear a stimulus (S1, e.g., light) across its pairings 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. Finally, rats were tested for fear to S2. Critically, protein synthesis in the BLA wasnotrequired to consolidate fear to S2 when the two training stages occurred 48 hours apart ...

Cell and Tissue Research, 2002

The amygdala modulates memory consolidation and the storage of emotionally relevant information in other brain areas, and itself comprises a site of neural plasticity during aversive learning. These processes have been intensively studied in Pavlovian fear conditioning, a leading aversive learning paradigm that is dependent on the structural and functional integrity of the amygdala. The rapidness and persistence, and the relative ease, with which this conditioning paradigm can be applied to a great variety of species have made it an attractive model for neurochemical and electrophysiological investigations on memory formation. In this review we summarise recent studies which have begun to unravel cellular processes in the amygdala that are critical for the formation of long-term fear memory and have identified molecular factors and mechanisms of neural plasticity in this brain area.

2019

SummaryThe formation and extinction of fear memories represent two forms of learning that each engage the hippocampus and amygdala. How cell populations in these areas contribute to fear relapse, however, remains unclear. Here, we demonstrate that, in male mice, cells active during fear conditioning in the dentate gyrus of hippocampus exhibit decreased activity during extinction and are re-engaged after contextual fear relapse. In vivo calcium imaging reveals that relapse drives population dynamics in the basolateral amygdala to revert to a network state similar to the state present during fear conditioning. Finally, we find that optogenetic inactivation of neuronal ensembles active during fear conditioning in either the hippocampus or amygdala is sufficient to disrupt fear expression after relapse. These results suggest that fear relapse triggers a partial re-emergence of the original fear memory representation, providing new insight into the neural substrates of fear relapse.

Science

Memories become labile when recalled. In humans and rodents alike, reactivated fear memories can be attenuated by disrupting reconsolidation with extinction training. Using functional brain imaging, we found that, after a conditioned fear memory was formed, reactivation and reconsolidation left a memory trace in the basolateral amygdala that predicted subsequent fear expression and was tightly coupled to activity in the fear circuit of the brain. In contrast, reactivation followed by disrupted reconsolidation suppressed fear, abolished the memory trace, and attenuated fear-circuit connectivity. Thus, as previously demonstrated in rodents, fear memory suppression resulting from behavioral disruption of reconsolidation is amygdala-dependent also in humans, which supports an evolutionarily conserved memory-update mechanism.

Psychopharmacology, 2019

Rationale The precise neural circuitry that encodes fear memory and its extinction within the brain are not yet fully understood. Fearful memories can be persistent, resistant to extinction, and associated with psychiatric disorders, especially post-traumatic stress disorder (PTSD). Here, we investigated the microtopography of neurons activated during the recall of an extinguished fear memory, as well as the influence of time on this microtopography. Methods We used the plasticity-related phosphorylated mitogen-activated protein kinase (pMAPK) to identify neurons activated in the recall of consolidated and extinguished auditory Pavlovian fear memories in rats. Quantitatively matched brain regions were used to investigate activity in the amygdala and prefrontal cortex. Results Recall of a consolidated, nonextinguished auditory fear memory resulted in a significantly greater number of activated neurons located in the dorsolateral subdivision of the lateral amygdala (LADL) when recalled 24 h after consolidation but not when recalled 7 days later. We found that the recall of an extinction memory was associated with pMAPK activation in the ventrolateral subdivision of the lateral amygdala (LAVL). Next, we showed that the pattern of pMAPK expression in the prelimbic cortex differed spatially following temporal variation in the recall of that memory. The deep and superficial layers of the pre-limbic cortex were engaged in recent recall of a fear memory, but only the superficial layers were recruited if the recall occurred 7 days later. Conclusions Collectively, our findings demonstrate a functional microtopography of auditory fear memory during consolidation and extinction at the microanatomical level within the lateral amygdala and medial prefrontal cortex.

Frontiers in Behavioral Neuroscience, 2013

Changes in neuronal connectivity occurring upon the formation of aversive memory were examined in C57BL/6 (C57) mice 24 h after they were trained for tone fear conditioning (TFC) and contextual fear conditioning (CFC). Although TFC and CFC are amenable to distinct learning systems each involving a specific neural substrate, we found that mice trained in the two protocols showed the same increase in spine density and spine size in class I basolateral amygdala (BLA) and in dorsal hippocampus CA1 pyramidal neurons. Our findings suggest that, because of their remarkably functional hippocampus, C57 mice might engage this region in any fear situation they face. These observations raise a point relevant to aversive memory studies, i.e., how the peculiarity of memory in certain individuals impacts on the components of the fear circuitry. It is suggested that enhanced connectivity in brain regions dispensable for specific forms of learning could considerably increase the resistance of aversive memory traces to treatments aimed at disrupting them.

Learning & Memory, 2007

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine whether these extinction-related changes undergo further plasticity as the memory of extinction becomes more remote. Changes in synaptic efficacy in both vHPC-mPFC and MD-mPFC inputs were consequently analyzed when the memory was either 1 d or 7 d old. Increases of synaptic efficacy in the vHPC-mPFC pathway were observed when the memory was 1 d old, but not 7 d after initial extinction. In contrast, potentiation of synaptic efficacy in the MD-mPFC pathway increased over time. In rats that received low-frequency vHPC stimulation immediately after extinction, both vHPC-mPFC and MD-mPFC inputs failed to develop potentiation, and the recall of extinction (both recent and remote memories) was impaired. These findings suggest that post-extinction potentiation in vHPC-mPFC inputs may be necessary for both the recall of recent memory and post-extinction potentiation in the MD-mPFC inputs. This late potentiation process may be required for the recall of remote extinction memory.