Neurobiology of Memory Reconsolidation

Neurobiology of Memory Reconsolidation What is the current understanding of the neurobiology of memory reconsolidation and how will impact psychology. Abstract This essay is focusing on the neurobiology of memory reconsolidation, specifically on the molecular mechanisms of LTP and reconsolidation, and the crucial role synaptic plasticity plays in fear conditioning and its resultant implication for psychopathology specifically Posttraumatic stress disorder This essay is focusing on current understanding of the neurobiology of memory reconsolidation, specifically on the molecular mechanisms of LTP and reconsolidation, and its resultant implication for psychopathology specifically promising research using propranolol and d-cycloserine as a treatment of post-traumatic stress disorder. Memory consolidationis the process by which memories are stabilised after being acquired. Consolidation studies have traditionally focused on the hippocampus andsystems consolidation, whereshort term memories become long term memories and independent of thehippocampus over time (Pinel, 2011). The more recently discovered process of consolidation is synaptic consolidation, which occurs within the first few hours after learning, and requires protein synthesis and gene transcription (Pinel, 2011). Long term memories were once considered to be stable, but within the last decade, the discovery of reconsolidation, the process in which stored memories can be retrieved and held in labile short-term memory, has changed theory and research on memory (Pinel, 2011). The neurobiological process of synaptic memory consolidation is thought to be long-term potentiation (LTP), which is the prolonged strengthening of the synapse with increased signalling between two neurons (Sacktor, 2012). The model of LTP and synaptic consolidation, as first theorised by Hebb (Pinel, 2011), suggests that changes in membrane potential and alterations of synapticprotein synthesis such as activating Phosporylated Mitogen Activated Protein Kinase (MAPK),are achieved through activatingintracellular transduction cascades, such as glutamate activating the NMDA receptor so that calcium ions can enter the neuron. These molecular cascades triggertranscription factors such as CREBthat lead to changes ingene expression through RNA synthesis (Pinel, 2011). The result of the gene expression is the lasting structural remodelling of synapses. This complex process of the molecular cascade, expression and process of transcription factors, is susceptible to disruptions in the short ti me period immediately following memory induction (Nader, Schafe LeDoux, 2000a). The potential for memory to be distrupted during consolidation has been extensively researched using pharmacology and trauma. For example, in experiments on Pavlovian fear conditioning in rats, LTP and fear conditioning were blocked when NMDA-receptorantagonistswere administered (Nader et al, 2000b). This process ofLTPis regarded as a contributing factor tosynaptic plasticityand in the growth ofsynaptic strength, and is thought to underlie memory formation, as it affects memory when disrupted. It was previously thought that even though this long process of consolidation could be disrupted, once a memory was consolidated it could not be disrupted. This classic view has been revised over the last 15 years, with extensive research showing that consolidated memories, once retrieved, revert to a labile state where they can be disrupted and undergo another consolidation process, called reconsolidation. (Shwabe, 2014). Reconsolidation was first hypothesised after studies were done using electroconvulsive shock therapy to disrupt consolidated fear memory (Tronson Taylor, 2007). Nader’s (2000a) landmark research using Pavlovianfear conditioningon rats found that a consolidated fear memory can return to alabilestate, when the amygdalais infused with theprotein synthesis inhibitor anisomycin. Subsequent studies have also shown that post-retrieval treatment with protein synthesis inhibitors can lead to an amnestic state (Shwabe, 2014). It has been concluded therefore that cons olidated fear memory, when reactivated, enters a changeable state that requires de novo protein synthesisfor new consolidation or reconsolidation of the old memory (Shwabe, 2014). Since these breakthrough studies many more have found evidence supporting reconsolidation, and have explored its processes and implications. Reconsolidation research over the last decade has demonstrated that some, but not all memories can be strengthened, weakened, or updated thus providing an opportunity to modify some long term memories (Shwabe, 2014). This very limited essay will focus on a few of the important animal and human studies related to fear memory and reconsolidation theory and its implications for psychology. Fear conditioning, fear memory and extinction learning experiments, often use manipulations of theamygdala, due to its involvement in the encoding and memory of significant emotional experiences (Agren et al, 2012). Most of the research on reconsolidation has been done on animals, one of the first studies of human fear memory consolidation was by Kindt in 2009 in which healthy participants were first fear-conditioned and the fear was reactivated by a single presentation of a conditioned stimulus 24 hours later. Shortly before memory reactivation, participants received the beta-adrenergic receptor blocker propranolol during the proposed reconsolidation window, which resulted in substantial weakening of the behavioural fear response and the return of fear memory. Research by Schiller (2010) also explored fear memory activation and update mechanisms and extinction learning, and found the ventromedial prefrontal cortex (vmPFC) plays an important role (Schiller, 2013). Agren et al (2012) also demonstrated fear memory trace erasure in the amygdala of humans using behavioural manipulations. Using functional brain imaging, Agren and colleagues (2012) found that when reconsolidation was disrupted through extinction training, the fear memory was significantly weakened and the memory trace was erased in the amygdala. Additional important recent research providing support for memory updating used Pavlovian fear conditioning manipulations and micro density heat map measures of fear memory on the lateral amygdala of rats, and found that the memory recapitulated not only in the same location but in new areas during reconsolidation (Bergstrom, McDonald, Dey, Tang, Selwyn Johnson, 2013). These, and many more important studies using different experimental manipulations, suggest that memory is labile and updated after reactivation, and that more or less the same areas are recruited for reconsolidation that are involved in initial memory formation. The potential ability to modify established emotional memories through the processes of memory updating, reconsolidationand extinction of conditioned fear memories has important implications for the treatment of many mental disorders, including anxiety disorders, such as post-traumatic stress disorder. Posttraumatic stress disorder is classified as ananxiety disorderin the DSM iV, characteristic symptoms of PTSD are strong traumatic memories that are continuously retrieved in an intrusive manner, causing re-experiencing of the original trauma (Schwabe, 2014).Research is focusing on testing pharmacological treatments and behavioural interventions that target memory reconsolidation in PTSD populations. One drug being researched in neurobiology for the treatment of PTSD is propranolol, the b-adrenergic receptor antagonist that has effects on protein synthesis. The idea that propranolol could be a useful treatment in PTSD stemmed from studies showing that this drug can disrupt the reconsolidation of fear conditioning in animal models and humans (Kindt, 2009). There is some evidence of success with propranolol, such as in pilot studies by Pitman (2002) and Vaiva (2003) which found that immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. In recent experiments using propranolol, patients with chronic PTSD were asked to prepare a written script of their personal traumatic experience that caused the PTSD. Each patient then received either propranolol or a placebo (Brunet et al, 2008). One week later, all patients underwent a procedure where there physiological arousal was tested as the script was read. The results showed that psychophysiological responding was significantly lower in patients who had received propranolol a week earlier than in patients who were administered a placebo. These findings were replicated and extended in three open-label studies where PTSD symptoms were significantly lower than at pretreatment (Brunet et al, 2011). In these promising studies on the effect of post-retrieval propranolol in chronic PTSD it is ambiguous as to whether the benefits were from propranolol enhancement or the psychological intervention; And whether propranolol enhanced extinction consolidation or blocked memory reconsoli dation. (de Kleine et al, 2013). Some of these studies also lacked the appropriate control groups that would be required to conclude that the observed effects are due to changes in memory reconsolidation, however, these findings suggest that postretrieval manipulations with propranolol might be a promising tool in the treatment of PTSD, even when the trauma is decades old. d-cycloserine (DCS) is another pharmacological intervention being recently researched in reconsolidation and PTSD due to it being a partial NMDA receptor agonist and extinction enhancer (De Kliene, 2014). Research on using exposure therapy with DCS for PTSD suggests that it could be promising (De Kliene, 2014). Exposure therapy is established as an effective form of fear extinction training in PTSD through the repeated exposure of the trauma memory, and its emotional processing (De Kliene, 2014). De Kleine, Hendriks, Kusters, Broekman, and van Minnen (2012) investigated the effect of DCS on exposure therapy on a female civilian population and found no overall enhancement effects, but a stronger treatment response. However, a second study on a male veteran population found a significant enhancement (Litz et al, 2012). Some criticisms of these studies were the possibility that DCS might have undesirable effects when there is no in session fear extinction, and the need for more research and better administration of the drug (De Kleine, 2014). Sheeringa (2014) researched the effect of d-cycloserine with cognitive behaviour therapy on pediatric posttraumatic stress using a randomized placebo-controlled d-cycloserine. So far, DCS has only shown as extinction effect when used with behavioural training such as exposure therapy and CBT. This study did not show a greater effect on reducing PTSD symptoms, but did show preliminary evidence for improving attention of participants. Another promising study currently in press looked at whether DCS enhanced psychotherapy when used with virtual reality trauma exposure therapy (Difede, 2014). The pilot trial was randomized, placebo-controlled, and double-blind and found significantly greater PTSD remission rates for DCS group, with larger between groups effect sizes (Difede, 2014). Understanding the processes of reconsolidation and the crucial role synaptic plasticity plays in fear conditioning does have exciting and important implication for psychopathology specifically PTSD. There are still barriers and boundary conditions to be understood and overcome for example, memory age and strength. In Posttraumatic stress disorder, unwanted memories need to be retrieved and destabilized before they can be modified during reconsolidation. One of the barriers particular to PTSD is that researchers have proposed that younger and weaker memories are more likely to be modified after reconsolidation than older and stronger memories which are less likely to be modified (Wihchet, 2011). Further boundary conditions highlighted by Shwabe at al (2014) is the context in which the reactivation takes place, and the presence of new information at reactivation of the memories. Therefore, more research is needed to understand exactly when memories do and do not undergo reconsolidation in order to use reconsolidation as a treatment for disorders such as PTSD.