A New Perspective on the Role of the Hippocampus in Traumatic Memory Formation. David Diamond

Transcription

1 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

2 How does stress affect memory?

3 stress makes us forgetful Where is my car?

4 Dire Consequences When Our Memory Fails Us

5 but stress can also produce powerful flashbulb memories that can last a lifetime

6 Hippocampus The integrity of the hippocampus is essential for storing information about the details and events of our lives

7 Hippocampus but hippocampal functioning appears to be impaired by stress

8 Issues 1 Review 20 years of research showing unequivocally that hippocampal functioning is impaired by stress

9 1 Review 20 years of research showing unequivocally that hippocampal functioning is impaired by stress Issues 2 - #1 is wrong

10 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

11 Long-term Potentiation (LTP) A Physiological Model of Memory Baseline 1 hr After LTP Stimulation

12 Percent Change LTP (in vitro) PB Potentiation (In Vitro) Time (minutes) Diamond et al., (1988) J. Neurosci., 8:

13 Post-doc project 1986: LTP Stimulation of the Hippocampus in Behaving Rats

14 Effects of PB Stimulation in the Awake Rat 1987 Progress Report: No LTP in the Awake Rat! 150 Percent Increase Time (minutes) Diamond and Rose, unpublished observations,

15 Behavioral and Neural Biology 4 8, ( )

16 Why is this stressful?

17 Novel Environments are Potentially Dangerous Scared rat

18 % Change Two Decades of Research: Stress Impairs LTP No Stress Stress In Vivo Behaving Rat 0 In Vivo Anesthetized Rat 0 In Vitro Diamond et al (1990) Psychobiology, 18: ; 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

19 % Change Therefore, Stress Should Impair Hippocampus- Dependent Memory No Stress Stress In Vivo Behaving Rat 0 In Vivo Anesthetized Rat 0 In Vitro Diamond et al (1990) Psychobiology, 18: ; 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

20 Memory Errors Memory Errors Stress Impairs Hippocampus-Dependent Memory in Rats 3 Memory for Food Memory for the Platform No Stress Stress Diamond et al (1996); Behav. Neurosci; Sandi et al (2005) Biological Psychiatry; Diamond et al (2008) Learning & Memory

21 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

22 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.

23 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: under conditions of extreme stress, the hippocampally based categorization system fails van der Kolk and Fisler, J. Traumatic Stress, (1995) 8:

24 No Doubt About it: Stress Impairs Hippocampal Functioning

25 Problems With The Consensus View: The hippocampus serves a critical role in declarative memory our capacity to recall everyday facts and events

26 Problem # 1 - If stress impairs hippocampal functioning, how do we have such detailed, factual (declarative) memories of strong emotional experiences?

27 Problem #2: The Hippocampus is Necessary for Storing Fear- Related Memories

28 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: , 2003 Volker Koorz and Julietta U. Frey, J. Neurosci., 23: , 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

29 A Paradox: How Can Stress Enhance and Impair Hippocampal Functioning?

30 Toward a Resolution of the Paradox: Timing of Amygdala Stimulation and Corticosterone Influences Hippocampal LTP Amygdala

31 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

32 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

33 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

34 Tests of the Model

35 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

36 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: (2004) + _ sec - min minutes - hours hours - days

37 Plasticity State of the Hippocampus Stress Hippocampus-Dependent Learning Occurring During Phase 1 Should Be Enhanced + _ sec - min minutes - hours hours - days

38 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

39 Minimal (Weak) Water Maze Training (5 trials)

40 Brief Stress Before Minimal Training Should Enhance Long-term (24 hr) Memory Brief Stress (2 min) Minimal (Weak) Water Maze Training (5 trials)

41 Errors Minimal Training Under Control Conditions Produces Poor Long-term (24 hr) Memory No Stress Learning Trials hr Memory 24 hr Memory

42 Errors Influence of Brief (2 min) Stress on Learning and Memory No Stress Stress 2 min Cat Learning Trials hr Memory 24 hr Memory

43 Errors Brief Pre-Training Stress Enhanced 24 hr Memory Brief Stress (No Delay) No Stress * Stress 2 min Cat Learning Trials hr Memory 24 hr Memory

44 Errors How Will Brief Stress 30 min Before Training Affect Long-term (24 hr) Memory? Brief Stress (No Delay) No Stress * Stress 2 min Cat 30 min Learning Trials hr Memory 24 hr Memory

45 Errors Brief Stress 30 min Before Training Did Not Enhance Long-term (24 hr) Memory Brief Stress (30 min Delay) Brief Stress (No Delay) No Stress * Stress 2 min Cat 30 min Learning Trials hr Memory 24 hr Memory Diamond et al., Neural Plasticity, 2007

46 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

47 Extensive Training Under Control Conditions Produces Intact Long-term (24 hr) Memory Extensive Water Maze Training (18 trials)

48 Prolonged (30 min) Stress Before Extensive Training Should Impair Long-term (24 hr) Memory Prolonged Stress (30 min) Extensive Water Maze Training (18 trials)

49 Errors Extensive Training Produces Strong 24 hr Spatial Memory 4.0 No Stress hr 24 hr Day 1: 18 Trials (Blocks of 2 Trials) Day 2

50 Errors 30 Min of Cat Stress Should Impair Memory Consolidation 4.0 No Stress min of Cat hr 24 hr Day 1: 18 Trials (Blocks of 2 Trials) Day 2

51 Errors 30 minutes of Predator Stress Before Learning Impaired 24 Hour Memory 4.0 No Stress Stress Before Training min of Cat hr 24 hr Day 1: 18 Trials (Blocks of 2 Trials) Day 2 Diamond et al., Neural Plasticity, 2007

52 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).

53 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.

54 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

55 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