Prereactivation propranolol fails to reduce skin conductance reactivity to prepared fear‐conditioned stimuli

Pharmacologic blockade of memory reconsolidation has been demonstrated in fear‐conditioned rodents and humans and may provide a means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder. Studying the efficacy of potential interventions in clinical populations is challenging, creating a need for paradigms within which candidate reconsolidation‐blocking interventions can be readily tested. We used videos of biologically prepared conditioned stimuli (tarantulas) to test the efficacy of propranolol in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, subsequent propranolol failed to reduce reactivity to the reactivated conditioned stimulus. These results are consistent with other recent findings and point to a need for testing other candidate drugs.     

Peripheral bacterial endotoxin administration triggers both memory consolidation and reconsolidation deficits in mice

Peripherally administered inflammatory stimuli, such as lipopolysaccharide (LPS), induce the synthesis and release of proinflammatory cytokines and chemokines in the periphery and the central nervous system, and trigger a variety of neurobiological responses. Indeed, prior reports indicate that peripheral LPS administration in rats disrupts contextual fear memory consolidation processes, potentially due to elevated cytokine expression. We used a similar, but partially olfaction-based, contextual fear conditioning paradigm to examine the effects of LPS on memory consolidation and reconsolidation in mice. Additionally, interleukin-1β (IL-1β), brain-derived neurotrophic factor (BDNF), and zinc finger (Zif)-268 mRNA expression in the hippocampus and the cortex, along with peripheral cytokines and chemokines, were assessed. As hypothesized, LPS administered immediately or 2 h, but not 12 h, post-training impaired memory consolidation processes that support the storage of the conditioned contextual fear memory. Additionally, as hypothesized, LPS administered immediately following the fear memory trace reactivation session impaired memory reconsolidation processes. Four hours post-injection, both central cytokine and peripheral cytokine and chemokine levels were heightened in LPS-treated animals, with a simultaneous decrease in BDNF, but not Zif-268, mRNA. Collectively, these data reinforce prior work showing LPS- and cytokine-related effects on memory consolidation, and extend this work to memory reconsolidation.     

Emotional face processing in post-traumatic stress disorder after reconsolidation impairment using propranolol: A pilot fMRI study

Individuals with post-traumatic stress disorder (PTSD) exhibit exaggerated emotional reactions to threatening stimuli, which may represent deregulated fear-conditioning, associated with long-term adaptations in the sympathetic nervous system. Within a repeated measures design, functional magnetic resonance imaging (fMRI) was employed to investigate neural responses to threat in PTSD participants (N = 7), during the presentation of emotional facial expressions. Scans were separated by 6 weekly reconsolidation impairment treatment sessions, consisting of traumatic memory reactivation under the influence of propranolol. Greater activation before versus after treatment emerged in the thalamus and amygdala during fearful versus neutral face processing. Furthermore, participants showed greater activation after versus before treatment in the right anterior cingulate, during fearful relative to happy face processing. PTSD symptoms significantly improved (d = 1.75), post-treatment. These preliminary results suggest that aberrant emotional responding is modulated by noradrenergic plasticity within the amygdala-prefrontal cortex circuit, a neural substrate for the pharmacological treatment of PTSD.     

Understanding posttraumatic stress disorder through fear conditioning,extinction and reconsolidation

Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. NEUROSCI BIOBEHAV REV −Posttraumatic stress disorder (PTSD) is a psychopathology characterized by exacerbation of fear response. A dysregulated fear response may be explained by dysfunctional learning and memory, a hypothesis that was proposed decades ago. A key component of PTSD is fear conditioning and the study of this phenomenon in laboratory has expanded the understanding of the underlying neurobiological changes in PTSD. Furthermore, traumatic memories are strongly present even years after the trauma and maintenance of this memory is usually related to behavioral and physiological maladaptive responses. Persistence of traumatic memory may be explained by a dysregulation of two memory processes: extinction and reconsolidation. The former may explain the over-expression of fear responses as an imbalance between traumatic and extinction memory. The latter, in turn, explains the maintenance of fear responses as a result of enhancing trauma-related memories. Thus, this review will discuss the importance of fear conditioning for the establishment of PTSD and how failure in extinction or abnormal reconsolidation may contribute to the maintenance of fear response overtime.     

Lack of neurotensin type 1 receptor facilitates contextual fear memory depending on the memory strength

Neurotensin is known to have antipsychotic-like behavioral and neurochemical effects, but its participation in fear memory has not been fully elucidated. Here, we report that a lack of type 1 neurotensin receptor (Ntsr1) increases the behavioral fear response elicited by weak fear memory. Adult Ntsr1-knockout (KO) mice and their wild-type (WT) littermates were compared in contextual fear conditioning. The mice were exposed twice for 3 min to the context 24 and 48 h after conditioning (first and second exposure, respectively), and freezing response of mice at the exposure was measured to evaluate fear memory. Ntsr1-KO mice showed a higher freezing rate than WT mice at both first and second exposures under the condition where a relatively weak unconditioned stimulus (footshock) was applied and thus elicited a relatively lower freezing rate. The difference in the first exposure between Ntsr1-KO and WT mice disappeared under the condition where a more intense unconditioned stimulus was used. The enhancement of freezing response in Ntsr1-KO mice at second exposure was abolished by propranolol, a β-adrenergic blocker that suppresses fear memory reconsolidation, and suppressed by MK-801, an NMDA receptor antagonist. These results suggest that Ntsr1 plays inhibitory roles in weak fear memory.     

Delayed extinction fails to reduce skin conductance reactivity to fear‐conditioned stimuli

A brief 10‐min time delay between an initial and subsequent exposure to extinction trials has been found to impair memory reconsolidation in fear‐conditioned rodents and humans, providing a potential means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder (PTSD). The present study used videos of biologically prepared, conditioned stimuli (tarantulas) to test the efficacy of delayed extinction in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, the delayed‐extinction intervention failed to reduce reactivity to the conditioned stimulus paired with the extinction delay. These results are partially consistent with other recent, mixed findings and point to a need for testing other candidate interventions designed to interfere with the reconsolidation process.     

Erasing fear for an imagined threat event

Although memory for emotionally arousing and stressful experiences is strong and resistant to change, recent years have witnessed rapidly emerging evidence for the plasticity of fear memories. Upon retrieval a memory may be rendered labile and vulnerable to the disruptive effects of amnestic agents. This process is referred to as "disrupting reconsolidation" and may point to a novel therapeutic strategy for the permanent reduction of fear in patients suffering from anxiety disorders. However, the fear-reducing effects are thus far only demonstrated for freezing reactions in rodents and autonomic fear responding in humans. If disrupting reconsolidation will be of value for clinical practice, it should also target the subjective feelings of anxiety. Using an instructed fear-learning paradigm in humans, we here tested whether disrupting reconsolidation would diminish the subjective feelings of anxiety for a noxious event that was anticipated but never actually experienced. Beta-adrenergic receptor blockade during reconsolidation strongly diminished the behavioral expression of the instructed fear memory (i.e., startle responding) as well as the subjective feelings of anxiety 24h later, yet without affecting both the physiological and cognitive component of the anticipation of threat (i.e., skin conductance responding, expectancy ratings). Together, the present findings suggest that the various memory traces of a learned fear association do not necessarily undergo reconsolidation in harmony. Considering that patients with anxiety disorders (1) often fear objects and situations that they have never actually experienced, and (2) primarily suffer from the subjective feelings of anxiety, the present findings may have important ramifications for psychotherapy.     

恐惧记忆的再巩固及其干预措施分析

目前,记忆再巩固过程中进行药物干预可引起遗忘的研究受到广泛的关注,尤其是副作用较小的普萘洛尔以及RU38486,在以恐惧记忆为核心特征的精神障碍如PTSD、恐惧症的治疗中显示了良好的应用前景。另外,联合再巩固与消退特征的无创干预技术也是未来临床治疗关注的焦点。