Recent research on changing fears has examined targeting reconsolidation. During reconsolidation, stored information is rendered labile after being retrieved. Pharmacological manipulations at this stage result in an inability to retrieve the memories at later times, suggesting they are erased or persistently inhibited. Unfortunately, the use of these pharmacological manipulations in humans can be problematic. Here we introduce a non-invasive technique to target the reconsolidation of fear memories in humans. We provide evidence that old fear memories can be updated with non-fearful information provided during the reconsolidation window. As a consequence, fear responses were no longer expressed, an effect that lasted at least a year and was selective only to reactivated memories without affecting others. These findings demonstrate the adaptive role of reconsolidation as a window of opportunity to rewrite emotional memories, and suggest a non-invasive technique that can be used safely in humans to prevent the return of fear.

Dysregulation of the fear system is at the core of many psychiatric disorders. Much progress has been made in uncovering the neural basis of fear learning through studies in which associative emotional memories are formed by pairing an initially neutral stimulus (conditioned stimulus, CS; e.g., a tone) to an unconditioned stimulus (US; e.g., a shock). Despite significant recent advances, the question of how to persistently weaken aversive CS-US associations, or dampen traumatic memories in pathological cases, remains a major dilemma. Two paradigms (blockade of reconsolidation and extinction) have been used in the laboratory to reduce acquired fear. Unfortunately, their clinical efficacy is limited: reconsolidation blockade typically requires potentially toxic drugs and extinction is not permanent. Here we describe a novel behavioral design, in rats, in which a fear memory is destabilized and reinterpretated as safe by presenting an isolated retrieval trial prior to an extinction session. This procedure permanently attenuates the fear memory without the use of drugs.

Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala-PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC-amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders.fear | Pavlovian conditioning | defense | learning E fforts to control maladaptive defensive reactions through extinction or exposure therapy are sometimes short-lived because these techniques do not significantly alter the threat memory itself, but rather regulate its expression via the prefrontal cortex's (PFC) inhibition of the amygdala (1, 2). Individual variation in the integrity of this amygdala-prefrontal circuitry has been linked to trait anxiety and posttraumatic stress disorder, suggesting that exposure-based techniques may be least effective in those who suffer from anxiety disorders (3-9).Recently, it has been shown in mice (10, 11), rats (12), and humans (13-16) that precisely timing behavioral extinction to coincide with memory reconsolidation can persistently inhibit the return of defensive reactions (but see refs. 17-19 for a discussion of boundary conditions). Reconsolidation is the state to which memories enter upon retrieval, which makes them prone to interference (20)(21)(22). Behavioral interference of reconsolidation using extinction has been linked to alterations in glutamate receptor function in the amygdala, which plays a critical role in memory plasticity (10,12). These findings are consistent with the suggestion that, in contrast to standar...

Humans and animals can learn that specific sensory cues in the environment predict aversive events through a form of associative learning termed fear conditioning. This learning occurs when the sensory cues are paired with an aversive event occuring in close temporal proximity. Activation of lateral amygdala (LA) pyramidal neurons by aversive stimuli is thought to drive the formation of these associative fear memories; yet, there have been no direct tests of this hypothesis. Here we demonstrate that viral-targeted, tissuespecific expression of the light-activated channelrhodopsin (ChR2) in LA pyramidal cells permitted optical control of LA neuronal activity. Using this approach we then paired an auditory sensory cue with optical stimulation of LA pyramidal neurons instead of an aversive stimulus. Subsequently presentation of the tone alone produced behavioral fear responses. These results demonstrate in vivo optogenetic control of LA neurons and provide compelling support for the idea that fear learning is instructed by aversive stimulus-induced activation of LA pyramidal cells.ear conditioning is a simple form of associative learning that provides a powerful model system to study associative plasticity and memory formation (1-4). During fear conditioning, a neutral stimulus [termed the conditioned stimulus (CS)], often an auditory tone, is paired repeatedly with an aversive stimulus [termed the unconditioned stimulus (US)] and animals learn that the CS predicts the occurrence of the US. When the CS is encountered after learning, animals emit a stereotyped group of adaptive responses, including behavioral freezing and associated physiological adjustments, which together are termed the fear response.The lateral nucleus of the amygdala (LA) is a site of associative plasticity, where US-evoked depolarization of LA pyramidal neurons is thought to instruct plasticity at synapses formed by CS inputs onto the same neurons (5-7). Several lines of indirect evidence support the idea that this plasticity occurs as a result of a Hebbian mechanism through which depolarization of LA pyramidal neurons by the shock US coincident with weaker activation of the same cells by auditory CS inputs results in fear learning (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). This hypothesis makes the strong prediction that pairing an auditory CS with direct activation of LA pyramidal neurons as an US should be sufficient, in the absence of a shock US, to support fear learning and memory formation. Here we tested this hypothesis by substituting the aversive US with optical stimulation (19,20) of LA pyramidal neurons during learning, and we report that physiological activation of these cells results in fear conditioning. ResultsThe light activated channelrhodopsin (ChR2) (19,20) has been used in other neural systems to activate specific cell populations and produce learning (21-23). We took advantage of this technology and targeted ChR2 to pyramidal cells by in vivo viralmediated gene transfer. We used an adeno-associated virus (AAV) to express a...

Motor skill acquisition occurs through modification and organization of muscle synergies into effective movement sequences. The learning process is reflected neurophysiologically as a reorganization of movement representations within the primary motor cortex, suggesting that the motor map is a motor engram. However, the specific neural mechanisms underlying map plasticity are unknown. Here the authors review evidence that 1) motor map topography reflects the capacity for skilled movement, 2) motor skill learning induces reorganization of motor maps in a manner that reflects the kinematics of acquired skilled movement, 3) map plasticity is supported by a reorganization of cortical microcircuitry involving changes in synaptic efficacy, and 4) motor map integrity and topography are influenced by various neurochemical signals that coordinate changes in cortical circuitry to encode motor experience. Finally, the role of motor map plasticity in recovery of motor function after brain damage is discussed.

Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family of structurally related proteins that promote neuronal differentiation and survival during development, is a potent modulator of synaptic plasticity. Changes in BDNF expression, release and neuromodulatory activity, mediated by both epigenetic and post-translational mechanisms, have been associated with many pathological conditions and developmental experiences, such as maternal deprivation and environmental enrichment. Much effort has been devoted to studying plasticity in the hippocampus, a structure traditionally associated with learning and memory, yet there is increasing empirical support for the contribution of another structure--the amygdala--to BDNF-induced changes. Because the amygdala is a critical site for emotional memory formation, and many emotional and neurodevelopmental pathologies have been linked to amygdala-based abnormalities, considerable efforts have been devoted to the characterization of its circuitry. Here we review the role of BDNF as a biochemical integrator of convergent cellular signals, and as a central driver of neural plasticity. We conclude by emphasizing the importance of characterizing BDNF signaling cascades in behaviorally-relevant networks, to identify potential drug targets for novel therapeutic interventions.

Fear learning is associated with changes in synapse strength in the lateral amygdala (LA). To examine changes in LA dendritic spine structure with learning, we used serial electron microscopy to reconstruct dendrites after either fear or safety conditioning. The spine apparatus, a smooth endoplasmic reticulum (sER) specialization found in very large spines, appeared more frequently after fear conditioning. Fear conditioning was associated with larger synapses on spines that did not contain a spine apparatus, whereas safety conditioning resulted in smaller synapses on these spines. Synapses on spines with a spine apparatus were smaller after safety conditioning but unchanged with fear conditioning, suggesting a ceiling effect. There were more polyribosomes and multivesicular bodies throughout the dendrites from fear conditioned rats, indicating increases in both protein synthesis and degradation. Polyribosomes were associated with the spine apparatus under both training conditions. We conclude that LA synapse size changes bidirectionally with learning and that the spine apparatus has a central role in regulating synapse size and local translation. T he lateral amygdala (LA) fear circuit provides a unique model for investigating the synaptic basis of memory. The LA is critical for the acquisition and storage of auditory fear conditioning, a robust behavioral paradigm in which animals learn to associate a previously neutral tone with an aversive stimulus, such as a footshock (1, 2). In conditioned inhibition, tones and shocks are arranged such that the tone predicts the absence of the shock; the tone thus becomes associated with safety and suppresses fear (3). Tone-evoked physiological responses in the LA are strengthened with fear conditioning and weakened with conditioned inhibition, suggesting that LA synapse strength encodes the fear response to the tone (1, 2, 4-6).Auditory inputs to LA cells form synapses on dendritic spines, tiny compartments that may allow local regulation of synaptic transmission and structure (7-12). Experimentally-induced changes in synaptic strength such as long-term potentiation (LTP) and depression (LTD) alter spine size in immature hippocampus in vitro, with LTP generally associated with larger spines and LTD with smaller spines (13-16). Although LTP and LTD are considered models of learning, it is unknown whether spine structure is affected by associative learning in the adult animal. To address this question, we took advantage of the known effects of fear learning on LA synaptic strength and used serial section transmission electron microscopy (ssTEM) to reconstruct spiny dendrites from adult rat LA after either fear conditioning or conditioned inhibition training.Enlarged spines have been proposed as a locus for information storage, with smaller spines representing memory capacity (10,17). Very large spines typically contain a spine apparatus, a membranous organelle that has been reported to be involved in learning and synaptic plasticity (18). We found that the effects of learnin...

Fear memories are notoriously difficult to erase, often recovering over time. The longstanding explanation for this finding is that, in extinction training, a new memory is formed that competes with the old one for expression but does not otherwise modify it. This explanation is at odds with traditional models of learning such as Rescorla-Wagner and reinforcement learning. A possible reconciliation that was recently suggested is that extinction training leads to the inference of a new state that is different from the state that was in effect in the original training. This solution, however, raises a new question: under what conditions are new states, or new memories formed? Theoretical accounts implicate persistent large prediction errors in this process. As a test of this idea, we reasoned that careful design of the reinforcement schedule during extinction training could reduce these prediction errors enough to prevent the formation of a new memory, while still decreasing reinforcement sufficiently to drive modification of the old fear memory. In two Pavlovian fear-conditioning experiments, we show that gradually reducing the frequency of aversive stimuli, rather than eliminating them abruptly, prevents the recovery of fear. This finding has important implications for theories of state discovery in reinforcement learning.