A New Perspective on the Role of the Hippocampus in Traumatic Memory Formation David Diamond Medical Research, Veterans Hospital, Departments of Psychology, Molecular Pharmacology and Physiology, Center for Preclinical and Clinical Research on PTSD University of South Florida, Tampa, Florida
How does stress affect memory?
stress makes us forgetful Where is my car?
Dire Consequences When Our Memory Fails Us
but stress can also produce powerful flashbulb memories that can last a lifetime
Hippocampus The integrity of the hippocampus is essential for storing information about the details and events of our lives
Hippocampus but hippocampal functioning appears to be impaired by stress
Issues 1 Review 20 years of research showing unequivocally that hippocampal functioning is impaired by stress
1 Review 20 years of research showing unequivocally that hippocampal functioning is impaired by stress Issues 2 - #1 is wrong
1 Review 20 years of research showing unequivocally that hippocampal functioning is impaired by stress Issues 2 - #1 is wrong 3 Present a novel perspective on emotion and the hippocampus: it is both activated and inhibited by stress as a part of the process of making flashbulb or traumatic memories
Long-term Potentiation (LTP) A Physiological Model of Memory Baseline 1 hr After LTP Stimulation
Percent Change 150 100 50 0-50 LTP (in vitro) PB Potentiation (In Vitro) -10-5 0 5 10 15 20 25 30 Time (minutes) Diamond et al., (1988) J. Neurosci., 8:4079-4088
Post-doc project 1986: LTP Stimulation of the Hippocampus in Behaving Rats
Effects of PB Stimulation in the Awake Rat 1987 Progress Report: No LTP in the Awake Rat! 150 Percent Increase 100 50 0-50 -10-5 0 5 10 15 20 25 30 Time (minutes) Diamond and Rose, unpublished observations, 1986-1987
Behavioral and Neural Biology 4 8, 1 3 8-149 (1 9 8 7 )
Why is this stressful?
Novel Environments are Potentially Dangerous Scared rat
% Change Two Decades of Research: Stress Impairs LTP No Stress Stress 125 200 100 100 150 75 75 50 100 50 25 50 25 0 In Vivo Behaving Rat 0 In Vivo Anesthetized Rat 0 In Vitro Diamond et al (1990) Psychobiology, 18:273-281; Mesches et al., (1999) J Neurosci, 19:1-5 Diamond et al (1994) Behav Brain Res., 62: 1-9 Vouimba et al., (2006) Stress, 9:29-40
% Change Therefore, Stress Should Impair Hippocampus- Dependent Memory No Stress Stress 125 200 100 100 150 75 75 50 100 50 25 50 25 0 In Vivo Behaving Rat 0 In Vivo Anesthetized Rat 0 In Vitro Diamond et al (1990) Psychobiology, 18:273-281; Mesches et al., (1999) J Neurosci, 19:1-5 Diamond et al (1994) Behav Brain Res., 62: 1-9 Vouimba et al., (2006) Stress, 9:29-40
Memory Errors Memory Errors Stress Impairs Hippocampus-Dependent Memory in Rats 3 Memory for Food Memory for the Platform 3 2 1 No Stress Stress 2 1 0 0 Diamond et al (1996); Behav. Neurosci; Sandi et al (2005) Biological Psychiatry; Diamond et al (2008) Learning & Memory
Stress Impairs Hippocampus-Dependent Memory in People declarative memory (i.e., recognition, spatial memory and paragraph recall) was (impaired) by the stress challenge, whereas performance on hippocampus-independent tasks was unaffected
Consensus: Stress Impairs Hippocampal Functioning in Rats stress induces a shutdown of the hippocampus LeDoux, J. E. The Emotional Brain: The mysterious underpinnings of emotional life. New York: Simon and Schuster, 1996 under stressful conditions, emotional memory storage in the amygdala will be facilitated at the expense of hippocampal-dependent processing Akirav and Richter Levin, Dose-Response, (2006) 4:22-37.
Consensus: Stress Impairs Hippocampal Functioning in People high levels of stress impair the functioning of the hippocampus. A number of studies, with both humans and animals, have demonstrated this now well-accepted fact. Nadel and Jacobs, Current Directions in Psychological Science, (1998) 7:154-157. under conditions of extreme stress, the hippocampally based categorization system fails van der Kolk and Fisler, J. Traumatic Stress, (1995) 8:505-525.
No Doubt About it: Stress Impairs Hippocampal Functioning
Problems With The Consensus View: The hippocampus serves a critical role in declarative memory our capacity to recall everyday facts and events
Problem # 1 - If stress impairs hippocampal functioning, how do we have such detailed, factual (declarative) memories of strong emotional experiences?
Problem #2: The Hippocampus is Necessary for Storing Fear- Related Memories
Problem #3: Stress Can Enhance LTP! Dopamine-dependent facilitation of LTP induction in hippocampal CA1 by exposure to spatial novelty Shaomin Li, William K. Cullen, Roger Anwyl & Michael J. Rowan Nature Neurosci., 6:526-531, 2003 Volker Koorz and Julietta U. Frey, J. Neurosci., 23:7281-7287, 2003 Exposure to handling and cold water increased the duration of LTP More examples: Seidenbecher et al., 1997; Frey, 2001; Li et al., 2003; Straube et al., 2003; Davis et al., 2004; Almaguer-Melian et al., 2005; Uzakov et al., 2005; Ahmed et al., 2006
A Paradox: How Can Stress Enhance and Impair Hippocampal Functioning?
Toward a Resolution of the Paradox: Timing of Amygdala Stimulation and Corticosterone Influences Hippocampal LTP Amygdala
Plasticity State of the Hippocampus Stress Temporal Dynamics Model of the Involvement of the Hippocampus in Emotional Memory Processing + _ sec - min minutes - hours hours - days
Plasticity State of the Hippocampus Stress Phase 1: Flashbulb Memory Processing, Increased Glu, Ca 2+ Influx Stress Onset Cocktail NE, CRH, ACTH, CORT, DA, ACh + _ LTP and Memory sec - min minutes - hours hours - days
Plasticity State of the Hippocampus Phase 1: Flashbulb Memory Processing, Increased Glu, Ca 2+ Influx Stress Onset Cocktail NE, CRH, ACTH, CORT, DA, ACh + _ Phase 2: NMDA-R Sensitivity GR Activation sec - min minutes - hours hours - days Stress LTP and Memory
Tests of the Model
Plasticity State of the Hippocampus Stress There Should be an Enhancement of Memory for Events Occurring in Phase 1 (Trauma Onset) + _ sec - min minutes - hours hours - days
Plasticity State of the Hippocampus Stress most intrusive memories represented stimuli that predicted the onset of the trauma Hackman, et al., J. Traumatic Stress, 17:231-240 (2004) + _ sec - min minutes - hours hours - days
Plasticity State of the Hippocampus Stress Hippocampus-Dependent Learning Occurring During Phase 1 Should Be Enhanced + _ sec - min minutes - hours hours - days
Plasticity State of the Hippocampus Stress Experiences that would normally be forgotten will be remembered if they occur in Phase 1 + _ sec - min minutes - hours hours - days
Minimal (Weak) Water Maze Training (5 trials)
Brief Stress Before Minimal Training Should Enhance Long-term (24 hr) Memory Brief Stress (2 min) Minimal (Weak) Water Maze Training (5 trials)
Errors Minimal Training Under Control Conditions Produces Poor Long-term (24 hr) Memory 5.0 4.5 4.0 No Stress 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Learning Trials 1-4 1 hr Memory 24 hr Memory
Errors Influence of Brief (2 min) Stress on Learning and Memory 5.0 4.5 4.0 No Stress 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Stress 2 min Cat Learning Trials 1-4 1 hr Memory 24 hr Memory
Errors Brief Pre-Training Stress Enhanced 24 hr Memory 5.0 4.5 4.0 Brief Stress (No Delay) No Stress 3.5 3.0 2.5 2.0 1.5 1.0 * 0.5 0.0 Stress 2 min Cat Learning Trials 1-4 1 hr Memory 24 hr Memory
Errors How Will Brief Stress 30 min Before Training Affect Long-term (24 hr) Memory? 5.0 4.5 4.0 Brief Stress (No Delay) No Stress 3.5 3.0 2.5 2.0 1.5 1.0 * 0.5 0.0 Stress 2 min Cat 30 min Learning Trials 1-4 1 hr Memory 24 hr Memory
Errors Brief Stress 30 min Before Training Did Not Enhance Long-term (24 hr) Memory 5.0 4.5 4.0 Brief Stress (30 min Delay) Brief Stress (No Delay) No Stress 3.5 3.0 2.5 2.0 1.5 1.0 * 0.5 0.0 Stress 2 min Cat 30 min Learning Trials 1-4 1 hr Memory 24 hr Memory Diamond et al., Neural Plasticity, 2007
Plasticity State of the Hippocampus 30 Minutes of Stress Should Impair Hippocampal Functioning + New Learning Occurring When the Hippocampus is in Phase 2 Should Lead to Impaired Memory Storage _ 30 min sec - min minutes - hours hours - days
Extensive Training Under Control Conditions Produces Intact Long-term (24 hr) Memory Extensive Water Maze Training (18 trials)
Prolonged (30 min) Stress Before Extensive Training Should Impair Long-term (24 hr) Memory Prolonged Stress (30 min) Extensive Water Maze Training (18 trials)
Errors Extensive Training Produces Strong 24 hr Spatial Memory 4.0 No Stress 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 1 2 3 4 5 6 7 8 9 1 hr 24 hr Day 1: 18 Trials (Blocks of 2 Trials) Day 2
Errors 30 Min of Cat Stress Should Impair Memory Consolidation 4.0 No Stress 3.5 3.0 2.5 2.0 1.5 1.0 0.5 30 min of Cat 0.0 1 2 3 4 5 6 7 8 9 1 hr 24 hr Day 1: 18 Trials (Blocks of 2 Trials) Day 2
Errors 30 minutes of Predator Stress Before Learning Impaired 24 Hour Memory 4.0 No Stress Stress Before Training 3.5 3.0 2.5 2.0 1.5 1.0 0.5 30 min of Cat 0.0 1 2 3 4 5 6 7 8 9 1 hr 24 hr Day 1: 18 Trials (Blocks of 2 Trials) Day 2 Diamond et al., Neural Plasticity, 2007
Summary: How Does Stress Affect the Hippocampus? Temporal Dynamics Model: 1 The onset of stress enhances hippocampal memory storage processes for a relatively brief period of time (Phase 1: seconds - minutes).
Summary: How Does Stress Affect the Hippocampus? Temporal Dynamics Model: 1 The onset of stress enhances hippocampal memory storage processes for a relatively brief period of time (Phase 1: seconds - minutes). 2 Phase 1 is followed by a relatively prolonged plasticity refractory period (Phase 2), in which the induction of new plasticity, and therefore new memory consolidation, is impaired.
Summary: How Does Stress Affect the Hippocampus? Temporal Dynamics Model: 1 The onset of stress enhances hippocampal memory storage processes for a relatively brief period of time (Phase 1: seconds - minutes). 2 Phase 1 is followed by a relatively prolonged plasticity refractory period (Phase 2), in which the induction of new plasticity, and therefore new memory consolidation, is impaired. amygdala 3 Speculation: The onset of a stressful experience activates hippocampal and amygdala plasticity, for only a brief period of time, which underlies the unique features of traumatic (flashbulb) memories: time-restricted to trauma onset, lack of context, temporally fragmented
Acknowledgments Greg Rose LTP in Behaving Rats* Monika Fleshner Corticosterone* Ron Mervis Dendritic Spine Plasticity Gal Richter-Levin LTP in the Amygdala Carmen Sandi NCAMs and Memory Carmen Muñoz Tianeptine, LTP and Memory Cheryl Conrad Spine Plasticity and Stress-Sex Interactions Karim Alkhadi CaMKII and Memory Bob Spencer c-fos, BDNF, Stress and Memory Electrophysiology Berrilyn Branch Catherine Bennett Michael Mesches Karen Heman Rose-Marie Vouimba Behavioral Testing Collin Park James Woodson Vernon Haynes Adam Campbell Phil Zoladz Josh Halonen Funding Govt.: ONR, NIMH, VA; Pharmaceuticals: Servier, Merz, Allergan