Stress-Induced Out-of-Context Activation of Memory Karel Jezek, Benjamin B. Lee, Eduard Kelemen, Katharine M. McCarthy, Bruce S. McEwen, Andre A. Fenton PLOS BIOLOGY | December 2010 ZHANG Zicong, Feb 14, 2011

Introduction Inappropriate recollections and responses in stressful conditions are hallmarks of post- traumatic stress disorder (PTSD) and other anxiety and mood disorders, but how stress contributes to the disorders is unclear. The possibility that stress itself might promote inappropriate associations between unrelated memories and events has not been explored. The authors demonstrate that a single stressful experience can activate already consolidated memories outside of their appropriate context. 2

Section 1 3 (A) Experiment 1a—Appetitive left/right discrimination training (B) Experiment 1b—Circulating corticosterone levels in trunk blood at different stages of repeated experiment 1a were collected Summary: Stressful forced swim enhanced the expression of 24-h-old memory.

4 Section 1 (C) Experiment 2a—Aversive left/right discrimination training (D) Experiment 2b—Experiment 2a was repeated, extending the interval between swim and the retention test to 6 d Summary: The enhancement of the expression of memory did not depend on whether learning was appetitive or aversive. The memory enhancement was long lasting for at lease 6 d.

Section 1 5 (E) Experiment 3a—Aversive left/right discrimination training using the intensive training protocol (+ 30 trials). Retention was tested on Day 3 by reversal learning. (F) Experiment 3b—Rats were forced to swim 24h before intensive training to examine whether swim impairs learning abilities. Summary: Memory acquired on Day 1 interfered reversal learning on Day 3. Stressful swim enhanced Day 1 memory, resulting in higher errors in reversal learning. Swim neither improved nor impaired the ability to learn the task.

Summary of Section 1 Stressful forced swim enhanced the expression of memory. The phenomenon is robust, persisting at least 6 d. It was observed for both aversive and appetitive conditioning, for weak and strong memories, and whether memory was assessed by extinction or reversal tests. Whether the day-old memory is undergoing cellular consolidation at the time of swim? 6

Section 2 7 Experiment 4—Electro-convulsive shock (ECS) blocked the swim-induced enhancement of memory. In ECS or delECS (5h) group, ECS was delivered immediately or 5 h after swim. ECS: amnesic treatment Summary: The results suggest that the swim activated a stable memory, making it transiently sensitive to amnestic treatment ECS.

Section 2 8 (A) Experiment 5—Propranolol, blocker of the adrenergic component of stress, caused amnesia of inhibitory avoidance memory only if it was administered after the forced swim. (B) Experiment 6—Dexamethasone, a potent suppressant of the hypothalamic-pituitary-adrenal (HPA) axis, blocks the swim-induced enhancement of memory. Summary: Activation of both the adrenergic and HPA components of stress are crucial for the phenomenon.

Section 2 9 Experiment 7—Swim-induced interhemispheric transfer (IHT) of lateralized memory. The training protocol is administered under unilateral cortical spreading depression (CSD) (shading), which led to the formation of a lateralized memory. The IHT only occurred in Lat-Sw group. Summary: The swim modified discrimination memory by enhancing its expression, by switching it from a consolidated to a labile state, and by modifying what part of the brain could retrieve it, a progress thought to require synapse-specific plasticity.

Summary of Section 2 Stressful swim made conditioned avoidance susceptible to amnestic treatment, and activation of both adrenergic and HPA components of stress are crucial for the phenomenon. Stressful swim activated memory. OCAM: Out-of-Context activation of memory. The triggering experience did not need to have any physical contextual elements in common with the experience of the memory encoding or retrieval. Hippocampal dysfunction impairs episodic encoding and recall. Whether is the hippocampus necessary for OCAM? 10

Section 3 11 (A) Experiment 8a—Bilateral TTX inactivation of dorsal hippocampus in the D1- TTX group (1 h before learning) did not influence left/right discrimination learning in the Y-maze task compared with saline controls (B) Experiment 8b—The TTX injection did not impair retrieval. Summary: Acquisition and retrieval of left/right discrimination does not depend on dorsal hippocampus.

Section 3 12 (C) Experiment 9—Hippocampus was necessary for the swim-induced enhancement of memory. Experiment 10—The swim-induced inter-hemispheric transfer of lateralized memory required hippocampal function. Summary: Swim-induced memory enhancement and IHT of lateralized memory requires hippocampus function.

Summary of Section 3 Left/right discrimination memory could be acquired and recalled independently of the hippocampus. The hippocampus was necessary for the swim- induced memory enhancement. OCAM required a functional hippocampus during the swim. 13

Discussion OCAM affects memory storage rather than its retrieval. Whether is stress-induced activation of memory biochemically identical to consolidation and reconsolidation? The hippocampus modifies recent memories that are stored elsewhere in the brain and is a site along with amygdala for the combined roles of stress and arousal in mediating memory modulation. 14

Hypothesis Stress-triggered memory activation creates a condition where multiple memories coactivate, and through mechanisms of synaptic plasticity that include both long-term potentiation and depression, consolidation and reconsolidation, their subsequent expression is enhanced. 15