Extinction and discrimination in a Bayesian model of context fear conditioning (BaconX)

The extinction of contextual fear is commonly an essential requirement for successful exposure therapy for fear disorders. However, experimental work on extinction of contextual fear is limited, and there little or no directly relevant theoretical work. Here, we extend BACON, a neurocomputational model of context fear conditioning that provides plausible explanations for a number of aspects of context fear conditioning, to deal with extinction (calling the model BaconX). In this model, contextual representations are formed in the hippocampus and association of fear to them occurs in the amygdala. Representation creation, conditionability, and development of between-session extinction are controlled by degree of confidence (assessed by the Bayesian weight of evidence) that an active contextual representation is in fact that of the current context (i.e., is “valid”). The model predicts that: (1) extinction which persists between sessions will occur only if at a sessions end there is high confidence that the active representation is valid. It follows that the shorter the context placement-to-US (shock) interval (“PSI”) and the less is therefore learned about context, the longer extinction sessions must be for enduring extinction to occur, while too short PSIs will preclude successful extinction. (2) Short-PSI deficits can be rescued by contextual exposure even after conditioning has occurred. (3) Learning to discriminate well between a conditioned and similar safe context requires representations of each to form, which may not occur if PSI was too short. (4) Extinction-causing inhibition must be applied downstream of the conditioning locus for reasonable generalization properties to be generated. (5) Context change tends to cause return of extinguished contextual fear. (6). Extinction carried out in the conditioning context generalizes better than extinction executed in contexts to which fear has generalized (as done in exposure therapy). (7) BaconX suggests novel approaches to exposure therapy

Engram size varies with learning and reflects memory content and precision

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

Pedestrian Trajectory Prediction with Structured Memory Hierarchies

This paper presents a novel framework for human trajectory prediction based on multimodal data (video and radar). Motivated by recent neuroscience discoveries, we propose incorporating a structured memory component in the human trajectory prediction pipeline to capture historical information to improve performance. We introduce structured LSTM cells for modelling the memory content hierarchically, preserving the spatiotemporal structure of the information and enabling us to capture both short-term and long-term context. We demonstrate how this architecture can be extended to integrate salient information from multiple modalities to automatically store and retrieve important information for decision making without any supervision. We evaluate the effectiveness of the proposed models on a novel multimodal dataset that we introduce, consisting of 40,000 pedestrian trajectories, acquired jointly from a radar system and a CCTV camera system installed in a public place. The performance is also evaluated on the publicly available New York Grand Central pedestrian database. In both settings, the proposed models demonstrate their capability to better anticipate future pedestrian motion compared to existing state of the art.Comment: To appear in ECML-PKDD 201

Maladaptive Properties of Context-Impoverished Memories.

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

Prefrontal microcircuit underlies contextual learning after hippocampal loss

Specific brain circuits have been classically linked to dedicated functions. However, compensation following brain damage suggests that these circuits are capable of dynamic adaptation. Such compensation is exemplified by Pavlovian fear conditioning following damage to the dorsal hippocampus (DH). Although the DH normally underlies contextual fear and fear renewal after extinction, both can be learned in the absence of the DH, although the mechanisms and nature of this compensation are currently unknown. Here, we report that recruitment of alternate structures, specifically the infralimbic and prelimbic prefrontal cortices, is required for compensation following damage to the hippocampus. Disconnection of these cortices in DH-compromised animals and immediate early gene induction profiles for amygdala-projecting prefrontal cells revealed that communication and dynamic rebalancing within this prefrontal microcircuit is critical. Additionally, the infralimbic cortex normally plays a role in limiting generalization of contextual fear. These discoveries reveal that plasticity through recruitment of alternate circuits allows the brain to compensate following damage, offering promise for targeted treatment of memory disorders

Double Dissociation of Amygdala and Hippocampal Contributions to Trace and Delay Fear Conditioning

A key finding in studies of the neurobiology of learning memory is that the amygdala is critically involved in Pavlovian fear conditioning. This is well established in delay-cued and contextual fear conditioning; however, surprisingly little is known of the role of the amygdala in trace conditioning. Trace fear conditioning, in which the CS and US are separated in time by a trace interval, requires the hippocampus and prefrontal cortex. It is possible that recruitment of cortical structures by trace conditioning alters the role of the amygdala compared to delay fear conditioning, where the CS and US overlap. To investigate this, we inactivated the amygdala of male C57BL/6 mice with GABA A agonist muscimol prior to 2-pairing trace or delay fear conditioning. Amygdala inactivation produced deficits in contextual and delay conditioning, but had no effect on trace conditioning. As controls, we demonstrate that dorsal hippocampal inactivation produced deficits in trace and contextual, but not delay fear conditioning. Further, pre- and post-training amygdala inactivation disrupted the contextual but the not cued component of trace conditioning, as did muscimol infusion prior to 1- or 4-pairing trace conditioning. These findings demonstrate that insertion of a temporal gap between the CS and US can generate amygdala-independent fear conditioning. We discuss the implications of this surprising finding for current models of the neural circuitry involved in fear conditioning

Lmo4 in the Basolateral Complex of the Amygdala Modulates Fear Learning

Pavlovian fear conditioning is an associative learning paradigm in which mice learn to associate a neutral conditioned stimulus with an aversive unconditioned stimulus. In this study, we demonstrate a novel role for the transcriptional regulator Lmo4 in fear learning. LMO4 is predominantly expressed in pyramidal projection neurons of the basolateral complex of the amygdala (BLC). Mice heterozygous for a genetrap insertion in the Lmo4 locus (Lmo4gt/+), which express 50% less Lmo4 than their wild type (WT) counterparts display enhanced freezing to both the context and the cue in which they received the aversive stimulus. Small-hairpin RNA-mediated knockdown of Lmo4 in the BLC, but not the dentate gyrus region of the hippocampus recapitulated this enhanced conditioning phenotype, suggesting an adult- and brain region-specific role for Lmo4 in fear learning. Immunohistochemical analyses revealed an increase in the number of c-Fos positive puncta in the BLC of Lmo4gt/+ mice in comparison to their WT counterparts after fear conditioning. Lastly, we measured anxiety-like behavior in Lmo4gt/+ mice and in mice with BLC-specific downregulation of Lmo4 using the elevated plus maze, open field, and light/dark box tests. Global or BLC-specific knockdown of Lmo4 did not significantly affect anxiety-like behavior. These results suggest a selective role for LMO4 in the BLC in modulating learned but not unlearned fear

A Novel Form of Memory for Auditory Fear Conditioning at a Low-Intensity Unconditioned Stimulus

Fear is one of the most potent emotional experiences and is an adaptive component of response to potentially threatening stimuli. On the other hand, too much or inappropriate fear accounts for many common psychiatric problems. Cumulative evidence suggests that the amygdala plays a central role in the acquisition, storage and expression of fear memory. Here, we developed an inducible striatal neuron ablation system in transgenic mice. The ablation of striatal neurons in the adult brain hardly affected the auditory fear learning under the standard condition in agreement with previous studies. When conditioned with a low-intensity unconditioned stimulus, however, the formation of long-term fear memory but not short-tem memory was impaired in striatal neuron-ablated mice. Consistently, the ablation of striatal neurons 24 h after conditioning with the low-intensity unconditioned stimulus, when the long-term fear memory was formed, diminished the retention of the long-term memory. Our results reveal a novel form of the auditory fear memory depending on striatal neurons at the low-intensity unconditioned stimulus