Panels, Mini-Panels and Study Groups
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Neuropsychopharmacology (2011) 36, S1–S74 & 2011 American College of Neuropsychopharmacology. All rights reserved 0893-133X/11 www.neuropsychopharmacology.org S1 Monday, December 5, 2011 interruption in the behavioral response from which memory is inferred. Some studies that assessed memory at longer times after infusion used repeated testing (Migues, 2010) which can have a profound impact on the stability of memory over time. The current Panel Session study tested whether PKMz inhibition in the amygdala permanently Memory Erasure: Mechanisms and Potential Utility in disrupts olfactory mediated fear memory by testing the retention of fear memory at various intervals after PKMz blockade. Psychiatry Methods: Rats were trained to fear an odor by pairing it with a footshock. 7 days later they were infused with a PKMz antagonist into the amygdala and tested for fear-potentiated startle to the Memory as a New Therapeutic Target odor after either 2 hrs, 48 hrs or 15 later. In another experiment Karim Nader* they were tested 1 day and then again 10 days later. Results: Fear memory was disrupted when the injection-to-interval McGill University, Montreal, Canada was 2 hr, 48 hr but not 15 days. It was also blocked when the same Background: Traditionally, new memories were thought to be rats were tested 1 day and then 10 days later, perhaps due to a stabilized (consolidated) once in the brain. We tested whether facilitation of extinction produced by the 1 day test that involved recall/reactivation of a consolidated memory causes it to become tests trials with the odor not followed by shock. unstable again and require another round of re-stabilization. I will Conclusions: These results do not support the suggestion that discuss some of the evidence for the existence of this memory PKMæ activity underlies permanent memory storage of fear process and its clinical implications. memories in the amygdala. However, PKMz inhibition does have Methods: We use a number of behavioral tasks that have been long lasting effects when infused into a cortical area (Shema et al., relatively well described for their consolidation mechanisms. We 2007) and we are currently testing whether infusion of the then test whether the representations stored there, when recalled, inhibitor into the piriform cortex might have a long-lasting effect. can return them to a state that is susceptible to amnesic treatments Disclosure: M. Davis, None. again. In addition, we examine how molecular correlates of long- term memory change when a memory impaired. Results: Reconsolidation has been reported across appetitive and Disrupting Fear Memories: Retrieval, Reconsolidation and the aversive paradigms, in species as simple as c. elegans to humans, Passage of Time and using a wide range of amnesic treatments. The behavioral Cristina Alberini* impairments in reconsolidation can be relatively specific to the reactivated memory, generalizes across contexts and can be very Mount Sinai School of Medicine, New York, USA long lasting making. Reconsolidation is not ubiquitous for all memories. There are experimental parameters that determine Background: It is becoming increasingly clear that the processes when a memory will and will not undergo reconsolidation. of memory formation and storage are exquisitely dynamic. Understanding of how these constraints are manifested in the Elucidating the nature and temporal evolution of the biological brain will be critical for guiding us to optimize the chances of changes that accompany encoding, storage and retrieval is key successful translational application of these findings. for identifying means that can be used to disrupt the storage Conclusions: The clinical implications of reconsolidation are that or retention of memories associated to pathological states. For it may be possible to treat psychopathologies such as post- example, traumatic experiences may lead to debilitating psychia- traumatic stress disorder (PTSD), addiction, chronic pain, tric disorders including acute stress disorder and posttraumatic kindling, and obsessive compulsive disorder. For example, in the stress disorder, which are strongly associated with the reexperien- case of PTSD if we could impair reconsolidation of their traumatic cing of the trauma through intrusive memories and nightmares. memory this should in turn weaken the traumatic memory. In the Retrieval or reactivation of an apparently consolidated memory first study to test the results of challenging reconsolidation of can render the memory labile again, and reconsolidation is the traumatic memories in long-standing PTSD, the strength of the process that mediated its restabilization. traumatic memory was indeed reduced. This demonstrates the Methods: We use the fear-based task inhibitory avoidance and feasibility of targeting reconsolidation therapeutically. a variety of molecular or pharmacological interferences in rats Disclosure: K. Nader, None. to study the mechanisms and functions of fear memory reconsolidation. Results: We found that inhibitory avoidance reconsolidation evolves with the age of the memory: Young memories (one week Temporary, but not Permanent, Disruption of Fear Potentiated old) are sensitive to post-retrieval disruption, but older memories Startle Following PKMf Inhibition in the Amygdala Michael Davis* (2 weeks old) are resistant. Furthermore, we found that retrievals of older memories lead preferentially to extinction rather than Emory University, Atlanta, USA reconsolidation. Furthermore, an effective reconsolidation disrup- tion of inhibitory avoidance was found with the glucocorticoid Background: Maintenance of late-phase LTP can be blocked by antagonist RU38486 but not with the b-adrenergic antagonist disruption of protein kinase Mz (PKMz), implying that memories propranolol. may be maintained by this persistently active kinase (Sacktor, 1993; Conclusions: We conclude that the main function of reconsolida- Ling, 2002). Inhibition of PKMz can also disrupt memory for tion is to contribute to a lingering consolidation process and, in various tasks (Shema, 2007; Serrano, 2008; Migues, 2010). How- fact, mediate memory strengthening. These results have important ever, many of these experiments assessed memory shortly after implications for framing the optimal parameters to be used in infusion, raising the possibility that apparent memory erasure may therapeutic settings. instead reflect a disruption in retrieval of the memory or an Disclosure: C. Alberini, None. ACNP 50th Annual Meeting Abstracts S2 Selectively Erasing a Fear Memory in Mice experts have provided numerous recommendations on how DSM-5 Sheena Josselyn* can address current gaps in our understanding of psychiatric disorders. This includes providing a revised chapter organization Hospital for Sick Children, Toronto, Canada that integrates findings from neuroscience and better reflects Background: Over 40 million adult Americans suffer from some our current knowledge of underlying interrelationships between sort of anxiety disorder, making these disorders amongst the most similar disorders; calling greater attention to meta-issues that prevalent mental illnesses. As inappropriate or excessive fear and/ cross all diagnostic categories, like those related to developmental or anxiety is a core feature of these disorders, a more thorough lifespan, gender, and culture; consideration of categorical versus understanding of how the brain encodes and stores fear memories dimensional approaches to diagnosis; and integration of diagnostic will likely facilitate the development of more targeted treatments. severity measures with disorder criteria. Methods: The primary goal of our research is to understand how Conclusions: The goal of DSM-5 is to provide a representation of fear memories are encoded and stored in the brain. Identifying the psychiatric disorders consistent with the state of the science, while physical basis of a memory within the brain (the memory trace) ensuring that patients receive the best care possible. has been a long-standing challenge for scientists since Lashley’s Disclosure: D. Kupfer, Part 1: N/A, Part 2: American Psychiatric ‘‘search for the engram’’ in the 1950’s. My lab applied more Association - Consultant. modern molecular techniques in our search for the elusive engram. Instead of deleting an entire brain region, we used a more targeted network approach in which we specifically ablated only those New Approaches to Psychiatric Diagnosis: The NIMH Research neurons in a structure thought to be involved in a fear memory. Domain Criteria Project Specifically, we used an inducible diphtheria-toxin system to Bruce Cuthbert* ablate a defined population of neurons in the lateral amygdala (LA, a critical fear center in the brain) of mice. NIMH, Bethesda, USA Results: Selectively inducing cell death in neurons in a small Background: The purpose of this presentation is to give a brief population of LA neurons (those with increased levels of the overview of the RDoC project, explain its major features, and transcription factor CREB) after learning blocked subse- outline the goals for the project in contributing to NIMH’s future quent expression of that fear memory. Importantly, ablating research portfolio in the neurobiology of mental disorders. a similar portion of random neurons had no effect and mice Methods: N/A could re-acquire a memory. The resulting memory loss Results: While the DSM and ICD diagnostic frameworks represent produced by ablating LA neurons with high levels of CREB was current consensus thinking