Persistence of Amygdala‐Hippocampal Connectivity and Multi‐Voxel Correlation Structures During Awake Rest After Fear Learning Predicts Long‐Term Expression of Fear

&NA; After encoding, memories undergo a process of consolidation that determines long‐term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning “offline” periods. However, no human studies to date have investigated such processes, particularly in relation to long‐term expression of fear. We tested 24 participants using functional MRI on 2 consecutive days in a fear conditioning paradigm involving 1 habituation block, 2 acquisition blocks, and 2 extinction blocks on day 1, and 2 re‐extinction blocks on day 2. Conditioning blocks were preceded and followed by 4.5‐min rest blocks. Strength of spontaneous recovery of fear on day 2 served as a measure of long‐term expression of fear. Amygdala connectivity primarily with hippocampus increased progressively during postacquisition and postextinction rest on day 1. Intraregional multi‐voxel correlation structures within amygdala and hippocampus sampled during a block of differential fear conditioning furthermore persisted after fear learning. Critically, both these main findings were stronger in participants who exhibited spontaneous recovery 24 h later. Our findings indicate that neural circuits activated during fear conditioning exhibit persistent postlearning activity that may be functionally relevant in promoting consolidation of the fear memory.

[1]  Karl J. Friston,et al.  Amygdala–Hippocampal Involvement in Human Aversive Trace Conditioning Revealed through Event-Related Functional Magnetic Resonance Imaging , 1999, The Journal of Neuroscience.

[2]  J. D. McGaugh Memory--a century of consolidation. , 2000, Science.

[3]  H. Steven Scholte,et al.  Associative Learning Increases Trial-by-Trial Similarity of BOLD-MRI Patterns , 2011, The Journal of Neuroscience.

[4]  Erno J. Hermans,et al.  Fear bradycardia and activation of the human periaqueductal grey , 2013, NeuroImage.

[5]  C. Pavlides,et al.  Influences of hippocampal place cell firing in the awake state on the activity of these cells during subsequent sleep episodes , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[6]  R. Dolan,et al.  Encoding of emotional memories depends on amygdala and hippocampus and their interactions , 2004, Nature Neuroscience.

[7]  Daniela Popa,et al.  Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep , 2010, Proceedings of the National Academy of Sciences.

[8]  R. Henson,et al.  Awake reactivation predicts memory in humans , 2013, Proceedings of the National Academy of Sciences.

[9]  Jeff H. Duyn,et al.  Large-scale spontaneous fluctuations and correlations in brain electrical activity observed with magnetoencephalography , 2010, NeuroImage.

[10]  G. Buzsáki,et al.  Selective suppression of hippocampal ripples impairs spatial memory , 2009, Nature Neuroscience.

[11]  Edwin M. Robertson,et al.  The Resting Human Brain and Motor Learning , 2009, Current Biology.

[12]  Raffael Kalisch,et al.  Single dose of l-dopa makes extinction memories context-independent and prevents the return of fear , 2013, Proceedings of the National Academy of Sciences.

[13]  B. McNaughton,et al.  Reactivation of Hippocampal Cell Assemblies: Effects of Behavioral State, Experience, and EEG Dynamics , 1999, The Journal of Neuroscience.

[14]  G H Glover,et al.  Image‐based method for retrospective correction of physiological motion effects in fMRI: RETROICOR , 2000, Magnetic resonance in medicine.

[15]  N. Daw,et al.  Rethinking Extinction , 2015, Neuron.

[16]  N. Tzourio-Mazoyer,et al.  Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain , 2002, NeuroImage.

[17]  P. Frankland,et al.  The organization of recent and remote memories , 2005, Nature Reviews Neuroscience.

[18]  J. Born,et al.  Maintaining memories by reactivation , 2007, Current Opinion in Neurobiology.

[19]  G. Quirk,et al.  Fear extinction as a model for translational neuroscience: ten years of progress. , 2012, Annual review of psychology.

[20]  A. Ylinen,et al.  Reciprocal Connections between the Amygdala and the Hippocampal Formation, Perirhinal Cortex, and Postrhinal Cortex in Rat: A Review , 2000, Annals of the New York Academy of Sciences.

[21]  Laura A. Atherton,et al.  Memory trace replay: the shaping of memory consolidation by neuromodulation , 2015, Trends in Neurosciences.

[22]  Archana Venkataraman,et al.  Intrinsic functional connectivity as a tool for human connectomics: theory, properties, and optimization. , 2010, Journal of neurophysiology.

[23]  B. McNaughton,et al.  Reactivation of hippocampal ensemble memories during sleep. , 1994, Science.

[24]  Norman M. Weinberger,et al.  Physiological Memory in Primary Auditory Cortex: Characteristics and Mechanisms , 1998, Neurobiology of Learning and Memory.

[25]  Joseph E LeDoux,et al.  Preventing the return of fear in humans using reconsolidation update mechanisms , 2010, Nature.

[26]  Gary H. Glover,et al.  Breath holding reveals differences in fMRI BOLD signal in children and adults , 2005, NeuroImage.

[27]  B. McNaughton,et al.  Preferential Reactivation of Motivationally Relevant Information in the Ventral Striatum , 2008, The Journal of Neuroscience.

[28]  Denis Paré,et al.  Lasting increases in basolateral amygdala activity after emotional arousal: implications for facilitated consolidation of emotional memories. , 2005, Learning & memory.

[29]  Karl J. Friston,et al.  Unified segmentation , 2005, NeuroImage.

[30]  Joseph E LeDoux,et al.  Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement , 2013, Proceedings of the National Academy of Sciences.

[31]  Nikolaus Weiskopf,et al.  A Stable Sparse Fear Memory Trace in Human Amygdala , 2011, The Journal of Neuroscience.

[32]  Joseph E LeDoux,et al.  Fear conditioning induces associative long-term potentiation in the amygdala , 1997, Nature.

[33]  R. Cabeza,et al.  Interaction between the Amygdala and the Medial Temporal Lobe Memory System Predicts Better Memory for Emotional Events , 2004, Neuron.

[34]  Daniel S. Margulies,et al.  Functional connectivity of the human amygdala using resting state fMRI , 2009, NeuroImage.

[35]  Pan Feng,et al.  Altered resting-state brain activity at functional MRI during automatic memory consolidation of fear conditioning , 2013, Brain Research.

[36]  M. Kindt,et al.  Beyond extinction: erasing human fear responses and preventing the return of fear , 2009, Nature Neuroscience.

[37]  H. Lachnit,et al.  Differential conditioning of anticipatory pupillary dilation responses in humans , 2002, Biological Psychology.

[38]  Erno J. Hermans,et al.  How the amygdala affects emotional memory by altering brain network properties , 2014, Neurobiology of Learning and Memory.

[39]  M. Fanselow,et al.  Modality-specific retrograde amnesia of fear. , 1992, Science.

[40]  Emilio Kropff,et al.  Place cells, grid cells, and the brain's spatial representation system. , 2008, Annual review of neuroscience.

[41]  R. Dolan,et al.  Task and Content Modulate Amygdala-Hippocampal Connectivity in Emotional Retrieval , 2006, Neuron.

[42]  Joseph E. LeDoux,et al.  Extinction resistant changes in the human auditory association cortex following threat learning , 2014, Neurobiology of Learning and Memory.

[43]  B L McNaughton,et al.  Coordinated Reactivation of Distributed Memory Traces in Primate Neocortex , 2002, Science.

[44]  Bruce S. McEwen,et al.  Stress, memory and the amygdala , 2009, Nature Reviews Neuroscience.

[45]  T. Seidenbecher,et al.  Amygdalar and Hippocampal Theta Rhythm Synchronization During Fear Memory Retrieval , 2003, Science.

[46]  A. Wagner,et al.  Sources of Method Bias in Social Science Research and Recommendations on How to Control It , 2015 .

[47]  Michael Davis,et al.  Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala , 1990, Nature.

[48]  N. Kanwisher,et al.  The Fusiform Face Area: A Module in Human Extrastriate Cortex Specialized for Face Perception , 1997, The Journal of Neuroscience.

[49]  H. Nusbaum,et al.  Task-dependent organization of brain regions active during rest , 2009, Proceedings of the National Academy of Sciences.

[50]  Andrew M. Poulos,et al.  Persistence of fear memory across time requires the basolateral amygdala complex , 2009, Proceedings of the National Academy of Sciences.

[51]  J. W. Rudy,et al.  Understanding contextual fear conditioning: insights from a two-process model , 2004, Neuroscience & Biobehavioral Reviews.

[52]  C. Büchel,et al.  The robustness of perception , 2005, The European journal of neuroscience.

[53]  Gabriele Janzen,et al.  Neural Encoding of Objects Relevant for Navigation and Resting State Correlations with Navigational Ability , 2011, Journal of Cognitive Neuroscience.

[54]  Margaret F. Carr,et al.  Hippocampal replay in the awake state: a potential substrate for memory consolidation and retrieval , 2011, Nature Neuroscience.

[55]  L. Frank,et al.  New Experiences Enhance Coordinated Neural Activity in the Hippocampus , 2008, Neuron.

[56]  R. Cabeza,et al.  Cognitive neuroscience of emotional memory , 2006, Nature Reviews Neuroscience.

[57]  Douglas H. Schultz,et al.  Resting-state connectivity of the amygdala is altered following Pavlovian fear conditioning , 2012, Front. Hum. Neurosci..

[58]  Greg J Siegle,et al.  Use of concurrent pupil dilation assessment to inform interpretation and analysis of fMRI data , 2003, NeuroImage.

[59]  Joseph E LeDoux,et al.  Human Amygdala Activation during Conditioned Fear Acquisition and Extinction: a Mixed-Trial fMRI Study , 1998, Neuron.

[60]  Merel Kindt,et al.  Neural pattern similarity predicts long-term fear memory , 2013, Nature Neuroscience.

[61]  Denis Paré,et al.  Role of the basolateral amygdala in memory consolidation , 2003, Progress in Neurobiology.

[62]  Bruce Fischl,et al.  Brain structure correlates of individual differences in the acquisition and inhibition of conditioned fear. , 2011, Cerebral cortex.

[63]  Joseph E LeDoux,et al.  Extinction Learning in Humans Role of the Amygdala and vmPFC , 2004, Neuron.

[64]  G. Quirk,et al.  Neurons in medial prefrontal cortex signal memory for fear extinction , 2002, Nature.

[65]  B. McNaughton,et al.  Memory reprocessing in corticocortical and hippocampocortical neuronal ensembles. , 1997, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[66]  Erno J. Hermans,et al.  Enhanced resting-state connectivity of amygdala in the immediate aftermath of acute psychological stress , 2010, NeuroImage.

[67]  E. Phelps Human emotion and memory: interactions of the amygdala and hippocampal complex , 2004, Current Opinion in Neurobiology.

[68]  E. Phelps,et al.  Arousal-Mediated Memory Consolidation: Role of the Medial Temporal Lobe in Humans , 1998 .

[69]  L. Frank,et al.  Awake Hippocampal Sharp-Wave Ripples Support Spatial Memory , 2012, Science.

[70]  Lila Davachi,et al.  Persistence of hippocampal multivoxel patterns into postencoding rest is related to memory , 2013, Proceedings of the National Academy of Sciences.

[71]  Sumantra Chattarji,et al.  Functional Connectivity from the Amygdala to the Hippocampus Grows Stronger after Stress , 2013, The Journal of Neuroscience.

[72]  M. Wilson,et al.  Disruption of ripple‐associated hippocampal activity during rest impairs spatial learning in the rat , 2009, Hippocampus.

[73]  M. Corbetta,et al.  Learning sculpts the spontaneous activity of the resting human brain , 2009, Proceedings of the National Academy of Sciences.

[74]  R. Adolphs,et al.  Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans , 1995, Science.

[75]  M. Fendt,et al.  The neuroanatomical and neurochemical basis of conditioned fear , 1999, Neuroscience & Biobehavioral Reviews.

[76]  Mattias P. Karlsson,et al.  Awake replay of remote experiences in the hippocampus , 2009, Nature Neuroscience.

[77]  D. Paré,et al.  Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. , 2010, Physiological reviews.

[78]  Guillén Fernández,et al.  Persistent schema-dependent hippocampal-neocortical connectivity during memory encoding and postencoding rest in humans , 2010, Proceedings of the National Academy of Sciences.

[79]  Nicholas A. Ketz,et al.  Enhanced Brain Correlations during Rest Are Related to Memory for Recent Experiences , 2010, Neuron.

[80]  M. Bouton Context, ambiguity, and unlearning: sources of relapse after behavioral extinction , 2002, Biological Psychiatry.

[81]  John Ashburner,et al.  A fast diffeomorphic image registration algorithm , 2007, NeuroImage.

[82]  Stefan Skare,et al.  How to correct susceptibility distortions in spin-echo echo-planar images: application to diffusion tensor imaging , 2003, NeuroImage.

[83]  D. Lundqvist,et al.  Karolinska Directed Emotional Faces , 2015 .

[84]  Alex Martin,et al.  Aversive learning modulates cortical representations of object categories. , 2014, Cerebral cortex.

[85]  B. McNaughton,et al.  Replay of Neuronal Firing Sequences in Rat Hippocampus During Sleep Following Spatial Experience , 1996, Science.

[86]  Mark Mayford,et al.  Localization of a Stable Neural Correlate of Associative Memory , 2007, Science.