Marie H. Monfils

Preventing the return of fear in humans using reconsolidation update mechanisms

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 that 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 are 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.

Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories

Reversing Pavlov Memories of fearful associations, such as hearing a tone before receiving a low-voltage shock, are labile when they are retrieved, such that the association can be extinguished or reconsolidated. Monfils et al. (p. 951, published online 2 April) demonstrate that applying a standard extinction treatment (sounding the tone multiple times in the absence of any shocks) within a window of time during which reconsolidation would normally occur has the effect of overwriting the original memory. Rats treated in this fashion display much lower levels of renewal (fear induced by sounding the tone once by itself), reinstatement (fear induced by giving the shock once by itself), and spontaneous recovery. Behavioral manipulations can reverse a learned fearful association in rats. 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 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 behavioral design in which a fear memory in rats is destabilized and reinterpreted as safe by presenting an isolated retrieval trial before an extinction session. This procedure permanently attenuates the fear memory without the use of drugs.

Brain-Derived Neurotrophic Factor: A Dynamic Gatekeeper of Neural Plasticity

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.

In Search of the Motor Engram: Motor Map Plasticity as a Mechanism for Encoding Motor Experience

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.

Optical activation of lateral amygdala pyramidal cells instructs associative fear learning

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, tissue-specific 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.

The aging hippocampus: a multi-level analysis in the rat.

In the current experiment we conducted a multi-level analysis of age-related characteristics in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344xBrown Norway hybrid (FBNF1) rats. We examined the relationships between aging, hippocampus, and memory using a combination of behavioral, non-invasive magnetic resonance imaging and spectroscopy, and postmortem neuroanatomical measures in the same rats. Aging was associated with functional deficits on hippocampus-dependent memory tasks, accompanied by structural alterations observed both in vivo (magnetic resonance imaging-hippocampal volume) and postmortem (dentate gyrus neuronal density and neurogenesis). Neuronal metabolic integrity, assessed by levels of N-acetylaspartate with magnetic resonance spectroscopy, was however, preserved. Further, our results suggest that neurogenesis (doublecortin) seems to be related to both performance deficits on hippocampus-dependent tasks and hippocampal volume reduction. The observed pattern of age-related alterations closely resembles that previously reported in humans and suggests FBNF1 rats to be a useful model of normal human aging.

Erasing Fear Memories with Extinction Training

Decades of behavioral studies have confirmed that extinction does not erase classically conditioned fear memories. For this reason, research efforts have focused on the mechanisms underlying the development of extinction-induced inhibition within fear circuits. However, recent studies in rodents have uncovered mechanisms that stabilize and destabilize fear memories, opening the possibility that extinction might be used to erase fear memories. This symposium focuses on several of these new developments, which involve the timing of extinction training. Extinction-induced erasure of fear occurs in very young rats, but is lost with the development of perineuronal nets in the amygdala that render fear memories impervious to extinction. Moreover, extinction administered during the reconsolidation phase, when fear memory is destabilized, updates the fear association as safe, thereby preventing the return of fear, in both rats and humans. The use of modified extinction protocols to eliminate fear memories complements existing pharmacological strategies for strengthening extinction.

Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat

Abstract Improving functional recovery following cerebral strokes in humans will likely involve augmenting brain plasticity. This study examined skilled forelimb behavior, neocortical evoked potentials, and movement thresholds to assess cortical electrical stimulation concurrent with rehabilitative forelimb usage following a focal ischemic insult. Adult rats were trained on a task that required skilled usage of both forelimbs. They then underwent an acute focal ischemic insult to the caudal forelimb area of sensorimotor cortex contralateral to their preferred forelimb. During the same procedure, they also received a stimulation electrode over the infarct area and two depth electrodes anterior to the lesion to record evoked potentials. One week following the surgery, rats received cortical stimulation during performance of the skilled task. Evoked potentials and movement thresholds were also determined. Functional assessment revealed that cortical stimulation resulted in superior performance compared to the no stimulation group, and this was initially due to a shift in forelimb preference. Cortical stimulation also resulted in enhanced evoked potentials and a reduction in the amount of current required to elicit a movement, in a stimulation frequency dependent manner. This study suggests that cortical stimulation, concurrent with rehabilitative training, results in better forelimb usage that may be due to augmented synaptic plasticity.

Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala.

When reactivated, memories enter a labile, protein synthesis–dependent state, a process referred to as reconsolidation. Here, we show in rats that fear memory retrieval produces a synaptic potentiation in the lateral amygdala that is selective to the reactivated memory, and that disruption of reconsolidation is correlated with a reduction of synaptic potentiation in the lateral amygdala. Thus, both retrieval and reconsolidation alter memories via synaptic plasticity at selectively targeted synapses.

Functional Organization of Adult Motor Cortex Is Dependent upon Continued Protein Synthesis

The functional organization of adult cerebral cortex is characterized by the presence of highly ordered sensory and motor maps. Despite their archetypical organization, the maps maintain the capacity to rapidly reorganize, suggesting that the neural circuitry underlying cortical representations is inherently plastic. Here we show that the circuitry supporting motor maps is dependent upon continued protein synthesis. Injections of two different protein synthesis inhibitors into adult rat forelimb motor cortex caused an immediate and enduring loss of movement representations. The disappearance of the motor map was accompanied by a significant reduction in synapse number, synapse size, and cortical field potentials and caused skilled forelimb movement impairments. Further, motor skill training led to a reappearance of movement representations. We propose that the circuitry of adult motor cortex is perpetually labile and requires continued protein synthesis in order to maintain its functional organization.