Fear conditioning and extinction: influence of sex and menstrual cycle in healthy humans.

Although sex differences have been demonstrated in behavioral paradigms of fear conditioning, the findings have been inconsistent, and fear extinction has been little studied. The present study investigated the influence of sex and menstrual cycle phase on the recall of fear extinction. Three groups of healthy adult participants were studied: women at 2 different phases of the menstrual cycle (early follicular [early cycle] and late follicular [midcycle]) and men. Participants underwent a 2-day fear conditioning and extinction protocol. The paradigm entailed habituation, fear conditioning, and extinction learning on Day 1 and extinction recall and fear renewal on Day 2. Skin conductance served as the dependent variable. During fear acquisition on Day 1, men showed significantly larger conditioned responses relative to women; early cycle and midcycle women did not differ. No significant group differences were found during extinction learning. On Day 2, men and early cycle women expressed greater extinction memory than midcycle women. These data confirm sex differences in conditioned fear acquisition and suggest that midcycle hormones attenuate extinction recall.

[1]  F. Scorza,et al.  Progress in neuro-psychopharmacology and biological psychiatry Re.: Omega-3 fatty acids and sudden unexpected death in epilepsy: What does the evidence tell us? , 2007, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[2]  Dirk Hermans,et al.  Extinction in Human Fear Conditioning , 2006, Biological Psychiatry.

[3]  S. Rauch,et al.  Fear extinction in rats: Implications for human brain imaging and anxiety disorders , 2006, Biological Psychology.

[4]  Lynn Nadel,et al.  Stress Differentially Modulates Fear Conditioning in Healthy Men and Women , 2006, Biological Psychiatry.

[5]  Michael Davis,et al.  Different mechanisms of fear extinction dependent on length of time since fear acquisition. , 2006, Learning & memory.

[6]  D. Pfaff,et al.  Estrogen facilitates fear conditioning and increases corticotropin-releasing hormone mRNA expression in the central amygdala in female mice , 2006, Hormones and Behavior.

[7]  David Silbersweig,et al.  Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Poldrack,et al.  Hormonal Cycle Modulates Arousal Circuitry in Women Using Functional Magnetic Resonance Imaging , 2005, The Journal of Neuroscience.

[9]  Michael Davis,et al.  Sex Differences in Hormonal Modulation of Anxiety Measured with Light-Enhanced Startle: Possible Role for Arginine Vasopressin in the Male , 2005, The Journal of Neuroscience.

[10]  Timothy J Desmond,et al.  Behavioral / Systems / Cognitive Hippocampal Inactivation Disrupts the Acquisition and Contextual Encoding of Fear Extinction , 2005 .

[11]  Bruce Fischl,et al.  Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Rauch,et al.  Context modulation of memory for fear extinction in humans. , 2005, Psychophysiology.

[13]  Kevin S LaBar,et al.  Sex, stress, and fear: Individual differences in conditioned learning , 2005, Cognitive, affective & behavioral neuroscience.

[14]  Brian J. Wiltgen,et al.  Trace fear conditioning is enhanced in mice lacking the δ subunit of the GABAA receptor , 2005 .

[15]  T. Beckers,et al.  Return of fear in a human differential conditioning paradigm caused by a return to the original acquistion context. , 2005, Behaviour research and therapy.

[16]  R. Handa,et al.  Novel Actions of Estrogen Receptor-β on Anxiety-Related Behaviors , 2005 .

[17]  J. Deakin,et al.  Characterization of a psychophysiological model of classical fear conditioning in healthy volunteers: influence of gender, instruction, personality and placebo , 2005, Psychopharmacology.

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

[19]  R. Dolan,et al.  Human orbitofrontal cortex mediates extinction learning while accessing conditioned representations of value , 2004, Nature Neuroscience.

[20]  G. Quirk,et al.  Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex. , 2004, Learning & memory.

[21]  T. Shors,et al.  High levels of estrogen enhance associative memory formation in ovariectomized females , 2004, Psychoneuroendocrinology.

[22]  G. Quirk,et al.  Consolidation of Fear Extinction Requires Protein Synthesis in the Medial Prefrontal Cortex , 2004, The Journal of Neuroscience.

[23]  G. Parker,et al.  From Diathesis to Dimorphism: The Biology of Gender Differences in Depression , 2004, The Journal of nervous and mental disease.

[24]  G. Quirk Learning not to fear, faster. , 2004, Learning & memory.

[25]  Stephen Maren,et al.  Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus. , 2004, Behavioral neuroscience.

[26]  Y. Hurd,et al.  Estrogen Receptor Gene Expression in Relation to Neuropsychiatric Disorders , 2003, Annals of the New York Academy of Sciences.

[27]  Michael Davis,et al.  Applying Learning Principles to the Treatment of Post‐Trauma Reactions , 2003, Annals of the New York Academy of Sciences.

[28]  Larry Cahill,et al.  Sex- and hemisphere-related influences on the neurobiology of emotionally influenced memory , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[29]  J. Gray,et al.  Fearfulness and sex in F2 Roman rats: males display more fear though both sexes share the same fearfulness traits , 2003, Physiology & Behavior.

[30]  Michael Davis,et al.  Behavioral and Neural Analysis of Extinction , 2002, Neuron.

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

[32]  G. Quirk Memory for extinction of conditioned fear is long-lasting and persists following spontaneous recovery. , 2002, Learning & memory.

[33]  Michael Davis,et al.  Facilitation of Conditioned Fear Extinction by Systemic Administration or Intra-Amygdala Infusions of d-Cycloserine as Assessed with Fear-Potentiated Startle in Rats , 2002, The Journal of Neuroscience.

[34]  C. Herry,et al.  Prefrontal Cortex Long-Term Potentiation, But Not Long-Term Depression, Is Associated with the Maintenance of Extinction of Learned Fear in Mice , 2002, The Journal of Neuroscience.

[35]  B. Rothbaum,et al.  Exposure therapy for posttraumatic stress disorder. , 2002, American journal of psychotherapy.

[36]  B. McEwen Estrogen actions throughout the brain. , 2002, Recent progress in hormone research.

[37]  D. Pfaff,et al.  Effects of Estrogen on Activity and Fear-Related Behaviors in Mice , 2001, Hormones and Behavior.

[38]  R. Muller,et al.  Consolidation of Extinction Learning Involves Transfer from NMDA-Independent to NMDA-Dependent Memory , 2001, The Journal of Neuroscience.

[39]  N. Makris,et al.  Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. , 2001, Cerebral cortex.

[40]  Stephen Maren,et al.  Hippocampal Inactivation Disrupts Contextual Retrieval of Fear Memory after Extinction , 2001, The Journal of Neuroscience.

[41]  Brian J. Wiltgen,et al.  Sex differences, context preexposure, and the immediate shock deficit in Pavlovian context conditioning with mice. , 2001, Behavioral neuroscience.

[42]  Stephen Maren,et al.  Estrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats 1 1 Published on the World Wide Web on 1 December 2000. , 2001, Brain Research.

[43]  G. Quirk,et al.  The Role of Ventromedial Prefrontal Cortex in the Recovery of Extinguished Fear , 2000, The Journal of Neuroscience.

[44]  E. Gould,et al.  The modulation of Pavlovian memory , 2000, Behavioural Brain Research.

[45]  S. Orr,et al.  De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder. , 2000, Journal of abnormal psychology.

[46]  M. Bouton,et al.  The effects of neurotoxic hippocampal lesions on two effects of context after fear extinction. , 2000, Behavioral neuroscience.

[47]  J. Feldon,et al.  Effect of Sex on Fear Conditioning is Similar for Context and Discrete CS in Wistar, Lewis and Fischer Rat Strains , 1999, Pharmacology Biochemistry and Behavior.

[48]  P. Holland,et al.  Hippocampus and context in classical conditioning , 1999, Current Opinion in Neurobiology.

[49]  D. Kennedy,et al.  Images in neuroscience. Brain development, XI: sexual dimorphism. , 1999, The American journal of psychiatry.

[50]  B. McEwen Multiple ovarian hormone effects on brain structure and function. , 1998, The journal of gender-specific medicine : JGSM : the official journal of the Partnership for Women's Health at Columbia.

[51]  S. Rauch,et al.  Neuroimaging and the Neuroanatomy of Posttraumatic Stress Disorder , 1998, CNS Spectrums.

[52]  T. Shors,et al.  Stages of estrous mediate the stress‐induced impairment of associative learning in the female rat , 1998, Neuroreport.

[53]  N. Swerdlow,et al.  Changes in sensorimotor inhibition across the menstrual cycle: Implications for neuropsychiatric disorders , 1997, Biological Psychiatry.

[54]  D H Barlow,et al.  Advances in the psychosocial treatment of anxiety disorders. Implications for national health care. , 1996, Archives of general psychiatry.

[55]  J. Rapoport,et al.  Quantitative MRI of the temporal lobe, amygdala, and hippocampus in normal human development: Ages 4–18 years , 1995, The Journal of comparative neurology.

[56]  Michael S. Fanselow,et al.  Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning , 1994, Brain Research.

[57]  J. Hutchison,et al.  Developmental regulation of sex differences in the brain: Can the role of gonadal steroids be redefined? , 1994, Neuroscience.

[58]  Joseph E. LeDoux,et al.  Extinction of emotional learning: Contribution of medial prefrontal cortex , 1993, Neuroscience Letters.

[59]  S. Orr,et al.  Test of the conditioning model of neurosis: differential aversive conditioning of angry and neutral facial expressions in anxiety disorder patients. , 1986, Journal of abnormal psychology.

[60]  J. Lanzetta,et al.  Facial expressions of emotion as conditioned stimuli for human autonomic responses. , 1980, Journal of personality and social psychology.

[61]  K. Hugdahl,et al.  Electrodermal conditioning to potentially phobic stimuli in male and female subjects , 1976, Biological Psychology.