"Consolidation theory posits that once a memory is consolidated, it remains consolidated. In contrast to this expectation, we will argue that memory retrieval can return a consolidated/fixed memory to an unstable state once again, from which the memory is then restabilized." Nader, K., Schafe, G. E., & Le Doux, J. E. (2000). The labile nature of consolidation theory. Nature, 1, 216–219. To be displayed later in lecture: <https://www.youtube.com/watch?v=HDXWBHCusqs> Psych 355, Miyamoto, Spr '18

Retrieval, Reconsolidation, & the Formation of Memories Psychology 355: Cognitive Psychology Instructor: John Miyamoto 05/07/2018: Lecture 07-1 Note: This Powerpoint presentation may contain macros that I wrote to help me create the slides. The macros aren’t needed to view the slides. You can disable or delete the macros without any change to the presentation.

Outline Memory consolidation is a process that involves multiple retrievals of memory representations. Memories are labile at time of retrieval. Memories can be changed by mental processes and events at time of retrieval. Fear conditioning in rats can be undone by blocking the reconsolidation of the fear memories. Retrieval of the emotional components of a traumatic memory can be reduced by blocking the reconsolidation of the emotional response to the memory. Psych 355, Miyamoto, Spr '18 Hypothesis: Memory Representations are Malleable at Time of Retrieval

Memory Representations Are Malleable At Time of Retrieval Hypothesis: When memories are retrieved, they are vulnerable to change. After retrieval, a memory must be reconsolidated (stored again in long-term memory). The reconsolidation preserves changes in a memory that occur during retrieval of the memory. Under special circumstances, when memories are retrieved, memories can be altered, even wiped out. Can these ideas be used to develop a treatment for PTSD? Psych 355, Miyamoto, Spr '18 Undoing Fear Conditioning in the Rat

Undoing Fear Conditioning in the Rat Nader, K., Schafe, G. E., & Le Doux, J. E. (2000). Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature, 406, 722-726. If a tone is paired with an electric shock, a rat will learn to freeze when it hears the tone (classical conditioning of fear). Administering anisomycin to a rat can cause it to fail to learn fear conditioning. Anisomycin – antibiotic that inhibits protein synthesis that is required in the formation of new memories. If memories can be changed at time of retrieval, can anisomycin be used to make a rat unlearn the fear conditioning that it previously learned? Psych 355, Miyamoto, Spr '18 Experimental Design (Diagram of Rat Learning or Unlearning)

Experimental Design Condition 1: Day 1: Tone + Shock + Drug Day 2: No drug; no tone; no shock Day 3: Does not freeze to tone (shows no learning) Day 1 Day 2 Day 3 Condition 2: Day 1: Tone + Shock Day 2: Drug; no tone; no shock Day 3: Freezes to tone (shows learning) Day 1 Day 2 Day 3 Conditions 1 & 3: In both conditions, rats learned to freeze on Day 1. Conditions 1 & 3: In both conditions, rats got anisomycin on Day 2. But rats in Condition 1 did not forget their learning on Day 1. Rats in Condition 3 did forget their learning. Why? Retrieval of learning on Day 2 made the learning from Day 1 vulnerable to loss (damage? unlearning?). Spring 2014: Garret Zieve (student) pointed out that we need one more condition: Condition *4*: Day 1: Tone + Shock Day 2: Tone (no shock) Day 3: Test tone alone. Need to verify that Day 2 tone alone does not extinguish the conditioning. You need Day 2 drug + tone (no shock) to decondiiton the rat. 5/20/2014: JM talked with Lauren Graham about Garret’s point. She says that the answer depends on the strength of the initial shock (stronger shock is harder to extinguish) and the number of extinction trials on Day 2, but if the Day 1 shock were strong enough and if there was only one extinction trial on Day 2, then indeed it would be well-known that without the drug on Day 2, the one extinction trial would not extinguish the fear conditioning from Day 2. Condition 3: Day 1: Tone + Shock Day 2: Drug + tone, no shock. Day 3: Does not freeze to tone (shows no learning) Day 1 Day 2 Day 3 Figure 7.20 Psych 355, Miyamoto, Spr '18 Repeat This Slide with Emphasis Rectangles

Experimental Design Condition 1: Day 1: Tone + Shock + Drug Day 2: No drug; no tone; no shock Day 3: Does not freeze to tone (shows no fear conditioning) Day 1 Day 2 Day 3 Condition 2: Day 1: Tone + Shock Day 2: Drug; (No Tone; No Shock) Day 3: Freezes to tone (shows fear conditioning) Day 1 Day 2 Day 3 Conditions 1 & 3: In both conditions, rats learned to freeze on Day 1. Conditions 1 & 3: In both conditions, rats got anisomycin on Day 2. But rats in Condition 1 did not forget their learning on Day 1. Rats in Condition 3 did forget their learning. Why? Retrieval of learning on Day 2 made the learning from Day 1 vulnerable to loss (damage? unlearning?). Spring 2014: Garret Zieve (student) pointed out that we need one more condition: Condition *4*: Day 1: Tone + Shock Day 2: Tone (no shock) Day 3: Test tone alone. Need to verify that Day 2 tone alone does not extinguish the conditioning. You need Day 2 drug + tone (no shock) to decondiiton the rat. 5/20/2014: JM talked with Lauren Graham about Garret’s point. She says that the answer depends on the strength of the initial shock (stronger shock is harder to extinguish) and the number of extinction trials on Day 2, but if the Day 1 shock were strong enough and if there was only one extinction trial on Day 2, then indeed it would be well-known that without the drug on Day 2, the one extinction trial would not extinguish the fear conditioning from Day 2. Condition 3: Day 1: Tone + Shock Day 2: Tone + Drug (No Shock) Day 3: Does not freeze to tone (shows no fear conditioning) Day 1 Day 2 Day 3 Figure 7.20 Psych 355, Miyamoto, Spr '18 Summary of Experimental Findings

Summary of Experimental Findings Condition 1: Day 1: Tone + Shock + Drug Day 2: No drug; no tone; no shock Day 3: Does not freeze to tone (shows no fear conditioning) Combining drug with tone & shock on Day 1 prevents fear conditioning. Condition 2: Day 1: Tone + Shock Day 2: Drug; (No Tone; No Shock) Day 3: Freezes to tone (shows fear conditioning) Drug on Day 2 does not undo fear conditioning. Conditions 1 & 3: In both conditions, rats learned to freeze on Day 1. Conditions 1 & 3: In both conditions, rats got anisomycin on Day 2. But rats in Condition 1 did not forget their learning on Day 1. Rats in Condition 3 did forget their learning. Why? Retrieval of learning on Day 2 made the learning from Day 1 vulnerable to loss (damage? unlearning?). Condition 3: Day 1: Tone + Shock Day 2: Tone + Drug (No Shock) Day 3: Does not freeze to tone (shows no fear conditioning) Combining drug with retrieval of fear conditioning on Day 2 undoes fear conditioning. Psych 355, Miyamoto, Spr '18 Interpretation - Retrieval Makes Day 1 Learning Vulnerable to Change

Interpretation Retrieval makes the fear conditioning from Day 1 vulnerable to change. Combining retrieval with drug prevents reconsolidation of memory of fear conditioning, thereby causing loss of conditioning. Condition 3 displayed to the right: Nader et al. (2000) state that the memory trace is "labile" during retrieval, i.e., its form can be changed at that time. Day 1 Day 2 Day 3 Conditions 1 & 3: In both conditions, rats learned to freeze on Day 1. Conditions 1 & 3: In both conditions, rats got anisomycin on Day 2. But rats in Condition 1 did not forget their learning on Day 1. Rats in Condition 3 did forget their learning. Why? Retrieval of learning on Day 2 made the learning from Day 1 vulnerable to loss (damage? unlearning?). Psych 355, Miyamoto, Spr '18 Using Fragility of Memories During Retrieval to Treat PTSD

Using the Fragility of Memories During Retrieval to Treat PTSD Brunet, A., Orr, S. P., Tremblay, J., Robertson, K., Nader, K., & Pitman, R. K. (2008). Effect of post- retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. Journal of Psychiatric Research, 42, 503-506. Post-traumatic stress disorder (PTSD): Strong fear and stress responses are evoked by reminders of the initial traumatic event. Hypothesis: Fear and stress conditioning in PTSD patients can be reduced or eliminated by techniques that are similar to Nader et al.'s demonstration that rats can lose their fear conditioning. Study used propranolol, a drug that is used to prevent traumatic memories if administered immediately following a traumatic event. Propranolol reduces the fear & stress conditioning of trauma. By itself, propranolol will not reduce PTSD in someone who already has PTSD. It can be used to prevent PTSD if it is administered within several hours of a traumatic experience. Doing so, reduces physiological measures of fear and stress that accompany future retrieval of memories of the traumatic experience. The Goldstein textbook contains a misprint. The drug is referred to as “probanolol” but it should be “propranolol.” Psych 355, Miyamoto, Spr '18 Brunet et al.'s Subjects Were PTSD Patients

Brunet et al.'s Study of PTSD Subjects PTSD patients: Childhood sexual abuse, motor vehicle accident, rape, being taken hostage. Comorbid mental disorders included: major depressive disorder, panic disorder, social phobia, bulimia, generalized anxiety disorder. Two scripts were prepared for each patient that described the events that produced the trauma for that patient. 19 PTSD patients were randomly assigned to either a TREATMENT Condition or a CONTROL Condition. (Conditions described on next slide.) Related paper on use of corticosteroids to mitigate or block PTSD: E:\pprs\Neuro\ZoharJ Hydrocortisone After Trauma Alters Traj o PTSD.pdf Psych 355, Miyamoto, Spr '18 Diagram that Shows the Experimental and Control Conditions

Brunet et al.'s Study: Treatment and Control Conditions Patient hears recorded description of traumatic experience Patient is injected with propranolol. Patient is injected with placebo. 7 Days Related paper on use of corticosteroids to mitigate or block PTSD: E:\pprs\Neuro\ZoharJ Hydrocortisone After Trauma Alters Traj o PTSD.pdf Patient hears another recorded description of traumatic experience Measure anxiety Psych 355, Miyamoto, Spr '18 Analogy Btwn Treatment of PTSD Treatment and Conditioning

Analogy Between PTSD Treatment & Conditioning HUMAN RAT Traumatic experience Tone + shock conditioning in the rat Listen to taped description Rat hears tone without the shock of traumatic experience Injection of propranolol Injection of anisomycin immediately after recall immediately after rat hears tone ? Later, will the human seem to have unlearned the fear conditioning to the traumatic memories? Later, the rat seems to have unlearned the fear conditioning to the tone. Psych 355, Miyamoto, Spr '18 Experimental Results

Grey = placebo group; Black = propranolol group Brunet et al. Results Tensing of Frowning Muscles Heart Rate Skin Conductance Corrugator EMG Y-Axis: Z-Scores Relative to Base Rate Patients report symptom improvement. Grey = placebo group; Black = propranolol group Result: Therapy reduces original fear conditioning. Psych 355, Miyamoto, Spr '18 Same Slide Without Emphasis Rectangles

Grey = placebo group; Black = propranolol group Brunet et al. Results Tensing of Frowning Muscles Heart Rate Skin Conductance Corrugator EMG Y-Axis Are Z-Scores Relative to Base Rate Patients report symptom improvement. Grey = placebo group; Black = propranolol group Result: Therapy reduces original fear conditioning. Psych 355, Miyamoto, Spr '18 Show Video of Treatment for Arachnaphobia.

PBS NOVA- MEMORY HACKERS, 2016 Merel Kindt's treatment of arachnaphobia <https://www.youtube.com/watch?v=HDXWBHCusqs> On YouTube under title "Psychology- Merel Kindt's Studies" Karim Nader's TED Talk https://www.youtube.com/watch?v=Dan68pTqpxQ Describes "erasing memories". Somewhat dry but it explains the ideas behind reconsolidation and therapy in a clear way. Old link to NOVA program: <https://www.youtube.com/watch?v=xS_OiKvoqbo This link no longer works 5/6/2018. Psych 355,, Miyamoto, Spr '18 Memories Are Malleable At Time of Retrieval

Malleability of Memories at Time of Retrieval Learned associations can be lost during retrieval and reconsolidation. Rats unlearned tone-shock connection Humans unlearn (to some degree) the association between a traumatic memory and the emotional response. Psych 355, Miyamoto, Spr '18 This Slide + Retrieval Strengthens Memory (Consolidation/Reconsolidation)

Malleability of Memories at Time of Retrieval Learned associations can be lost during retrieval and reconsolidation. Consolidation & reconsolidation – Memories can be strengthened during retrieval. Thinking about something produces better future recall. Practice testing (retrieval) produces better future recall. Thinking about a memory makes it more primed, i.e., more easily retrieved as an associate of something else. Psych 355, Miyamoto, Spr '18 This Slide + Query: Do These Facts Contradict Each Other? - END

Malleability of Memories at Time of Retrieval Learned associations can be lost during retrieval and reconsolidation. Consolidation & reconsolidation – Memories can be strengthened during retrieval. Do these results contradict each other? Stored representations can change during retrieval and reconsolidation. Usually the change makes the memory stronger, better organized, more linked to other memories. The memory becomes more primed, i.e., more easily retrieved as an associate of something else. The opposite can also happen, E.g., rats unlearn their fear conditioning, or humans become desensitized to memories of trauma. (This is a special case that is based on the use of drugs that would not normally be present.) E.g., while we think about past events, i.e., during retrieval, we may distort the facts or even falsify what was once a true memory. Psychologists believe that this happens to everyone. No! Psych 355, Miyamoto, Spr '18 END

"Consolidation theory posits that once a memory is consolidated, it remains consolidated. In contrast to this expectation, we will argue that memory retrieval can return a consolidated/fixed memory to an unstable state once again, from which the memory is then restabilized." Nader, K., Schafe, G. E., & Le Doux, J. E. (2000). The labile nature of consolidation theory. Nature, 1, 216–219. To be displayed later in lecture: <https://www.youtube.com/watch?v=HDXWBHCusqs> Psych 355, Miyamoto, Spr '18