Sex differences in the neurobiology of fear conditioning and extinction: a preliminary fMRI study of shared sex differences with stress-arousal circuitry

Biology of Mood & Anxiety Disorders

Kelimer Lebron-Milad¹  Brandon Abbs³  Mohammed R Milad¹  Clas Linnman²  Ansgar Rougemount-Bücking⁴  Mohammed A Zeidan¹  Daphne J Holt¹  Jill M Goldstein³ 

[1] Department of Psychiatry, Harvard Medical School & Massachusetts General Hospital, 149 13th St, Charlestown, MA, 02129, USA

[2] P.A.I.N. Group, Department of Anesthesia, Children´s Hospital, Boston, MA, USA

[3] Departments of Psychiatry and Medicine, Harvard Medical School, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02120, USA

[4] Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 7 rue Saint-Martin, 1003, Lausanne, Switzerland

关键词: Stress response circuitry;    fMRI;    Fear conditioning;    Fear extinction;    Sex differences;   

Others  :  794362
DOI  :  10.1186/2045-5380-2-7

 received in 2012-01-12, accepted in 2012-04-16,  发布年份 2012

【 摘 要 】

Background

The amygdala, hippocampus, medial prefrontal cortex (mPFC) and brain-stem subregions are implicated in fear conditioning and extinction, and are brain regions known to be sexually dimorphic. We used functional magnetic resonance imaging (fMRI) to investigate sex differences in brain activity in these regions during fear conditioning and extinction.

Methods

Subjects were 12 healthy men comparable to 12 healthy women who underwent a 2-day experiment in a 3 T MR scanner. Fear conditioning and extinction learning occurred on day 1 and extinction recall occurred on day 2. The conditioned stimuli were visual cues and the unconditioned stimulus was a mild electric shock. Skin conductance responses (SCR) were recorded throughout the experiment as an index of the conditioned response. fMRI data (blood-oxygen-level-dependent [BOLD] signal changes) were analyzed using SPM8.

Results

Findings showed no significant sex differences in SCR during any experimental phases. However, during fear conditioning, there were significantly greater BOLD-signal changes in the right amygdala, right rostral anterior cingulate (rACC) and dorsal anterior cingulate cortex (dACC) in women compared with men. In contrast, men showed significantly greater signal changes in bilateral rACC during extinction recall.

Conclusions

These results indicate sex differences in brain activation within the fear circuitry of healthy subjects despite similar peripheral autonomic responses. Furthermore, we found that regions where sex differences were previously reported in response to stress, also exhibited sex differences during fear conditioning and extinction.

【 授权许可】

   
2012 Lebron-Milad et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Shin LM, Whalen PJ, Pitman RK, Bush G, Macklin ML, Lasko NB, Orr SP, McInerney SC, Rauch SL: An fMRI study of anterior cingulate function in posttraumatic stress disorder. BiolPsychiatry 2001, 50:932-942.
• [2]Graham BM, Milad MR: The Study of Fear Extinction: Implications for Anxiety Disorders. Am J Psychiatry 2011, 168:1255-1265.
• [3]Hettema JM, Kettenmann B, Ahluwalia V, McCarthy C, Kates WR, Schmitt JE, Silberg JL, Neale MC, Kendler KS, Fatouros P: Pilot multimodal twin imaging study of generalized anxiety disorder. Depress Anxiety 2011. (Epub ahead of print)
• [4]Goldstein JM, Jerram M, Abbs B, Whitfield-Gabrieli S, Makris N: Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci 2010, 30:431-438.
• [5]Goldstein JM, Seidman LJ, Horton NJ, Makris N, Kennedy DN, Caviness VS: Faraone SV, Tsuang MT: Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. CerebCortex 2001, 11:490-497.
• [6]Mong JA, Glaser E, McCarthy MM: Gonadal steroids promote glial differentiation and alter neuronal morphology in the developing hypothalamus in a regionally specific manner. J Neurosci 1999, 19:1464-1472.
• [7]Arnold AP, Gorski RA: Gonadal steroid induction of structural sex differences in the central nervous system. Annu Rev Neurosci 1984, 7:413-442.
• [8]Cahill L, Uncapher M, Kilpatrick L, Alkire MT, Turner J: Sex-related hemispheric lateralization of amygdala function in emotionally influenced memory: an FMRI investigation. LearnMem 2004, 11:261-266.
• [9]Canli T, Gabrieli JD: Imaging gender differences in sexual arousal. NatNeurosci 2004, 7:325-326.
• [10]Goldstein JM, Jerram M, Poldrack R, Anagnoson R, Breiter HC, Makris N, Goodman JM, Tsuang MT, Seidman LJ: Sex differences in prefrontal cortical brain activity during fMRI of auditory verbal working memory. Neuropsychology 2005, 19:509-519.
• [11]Baran SE, Armstrong CE, Niren DC, Hanna JJ, Conrad CD: Chronic stress and sex differences on the recall of fear conditioning and extinction. NeurobiolLearnMem 2009, 91:323-332.
• [12]Milad MR, Igoe SA, Lebron-Milad K, Novales JE: Estrous cycle phase and gonadal hormones influence conditioned fear extinction. Neuroscience 2009, 164:887-895.
• [13]Gupta RR, Sen S, Diepenhorst LL, Rudick CN, Maren S: Estrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats(1). Brain Res 2001, 888:356-365.
• [14]Dalla C, Shors TJ: Sex differences in learning processes of classical and operant conditioning. Physiol Behav 2009, 97:229-238.
• [15]Ribeiro AM, Barbosa FF, Godinho MR, Fernandes VS, Munguba H, Melo TG, Barbosa MT, Eufrasio RA, Cabral A, Izidio GS, Silva RH: Sex differences in aversive memory in rats: possible role of extinction and reactive emotional factors. Brain Cogn 2010, 74:145-151.
• [16]Merz CJ, Tabbert K, Schweckendiek J, Klucken T, Vaitl D, Stark R, Wolf OT: Investigating the impact of sex and cortisol on implicit fear conditioning with fMRI. Psychoneuroendocrinology 2010, 35:33-46.
• [17]Milad MR, Goldstein JM, Orr SP, Wedig MM, Klibanski A, Pitman RK, Rauch SL: Fear conditioning and extinction: influence of sex and menstrual cycle in healthy humans. BehavNeurosci 2006, 120:1196-1203.
• [18]Felmingham K, Williams LM, Kemp AH, Liddell B, Falconer E, Peduto A, Bryant R: Neural responses to masked fear faces: sex differences and trauma exposure in posttraumatic stress disorder. J Abnorm Psychol 2010, 119:241-247.
• [19]Wiltgen BJ, Sanders MJ, Ferguson C, Homanics GE, Fanselow MS: Trace fear conditioning is enhanced in mice lacking the delta subunit of the GABAA receptor. LearnMem 2005, 12:327-333.
• [20]Zorawski M, Cook CA, Kuhn CM, LaBar KS: Sex, stress, and fear: individual differences in conditioned learning. Cogn Affect Behav Neurosci 2005, 5:191-201.
• [21]Maren S, De Oca B, Fanselow MS: Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning. Brain Res 1994, 661:25-34.
• [22]Aguilar R, Gil L, Gray JA, Driscoll P, Flint J, Dawson GR, Gimenez-Llort L, Escorihuela RM, Fernandez-Teruel A, Tobena A: Fearfulness and sex in F2 Roman rats: males display more fear though both sexes share the same fearfulness traits. Physiol Behav 2003, 78:723-732.
• [23]Milad MR, Zeidan MA, Contero A, Pitman RK, Klibanski A, Rauch SL, Goldstein JM: The influence of gonadal hormones on conditioned fear extinction in healthy humans. Neuroscience 2010, 168:652-658.
• [24]Milad MR, Igoe SA, Lebron-Milad K, Novales JE: Estrous cycle phase and gonadal hormones influence conditioned fear extinction. Neuroscience 2009, 164:887-895.
• [25]Rosenbaum JF, Biederman J, Hirshfeld DR, Bolduc EA, Faraone SV, Kagan J, Snidman N, Reznick JS: Further evidence of an association between behavioral inhibition and anxiety disorders: results from a family study of children from a non-clinical sample. JPsychiatrRes 1991, 25:49-65.
• [26]Goldstein JM, Jerram M, Poldrack R, Ahern T, Kennedy DN, Seidman LJ, Makris N: Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. JNeurosci 2005, 25:9309-9316.
• [27]Protopopescu X, Pan H, Altemus M, Tuescher O, Polanecsky M, McEwen B, Silbersweig D, Stern E: Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle. Proc Natl Acad Sci USA 2005, 102:16060-16065.
• [28]Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL: Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. BiolPsychiatry 2007, 62:446-454.
• [29]Uejima A, Amano T, Nomura N, Noro M, Yasue T, Shiroishi T, Ohta K, Yokoyama H, Tamura K: Anterior shift in gene expression precedes anteriormost digit formation in amniote limbs. Dev Growth Differ 2010, 52:223-234.
• [30]Foa EB, Rothbaum BO, Riggs DS, Murdock TB: Treatment of posttraumatic stress disorder in rape victims: a comparison between cognitive-behavioral procedures and counseling. JConsult ClinPsychol 1991, 59:715-723.
• [31]Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P: Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 2010, 167:748-751.
• [32]Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan MA, Handwerger K, Orr SP, Rauch SL: Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. BiolPsychiatry 2009, 66:1075-1082.
• [33]Zeidan MA, Igoe SA, Linnman C, Vitalo A, Levine JB, Klibanski A, Goldstein JM, Milad MR: Estradiol Modulates Medial Prefrontal Cortex and Amygdala Activity During Fear Extinction in Women and Female Rats. Biol Psychiatry 2011, 70:920-927.
• [34]First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. Biometrics Research, New York State Psychiatric Institute, New York; 2002.
• [35]Milad MR, Pitman RK, Ellis CB, Gold AB, Shin LM, Lasko NB, Handwerger K, Orr SP, Rauch SL: Neurobiological basis for failure to recall extinction memory in Posttraumatic Stress Disorder. BiolPsychiatry 2009, 66:1075-1082.
• [36]Milad MR, Orr SP, Pitman RK, Rauch SL: Context modulation of memory for fear extinction in humans. Psychophysiology 2005, 42:456-464.
• [37]Orr SP, Metzger LJ, Lasko NB, Macklin ML, Peri T, Pitman RK: De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder. JAbnormPsychol 2000, 109:290-298.
• [38]Esclassan F, Coutureau E, Di Scala G, Marchand AR: A cholinergic-dependent role for the entorhinal cortex in trace fear conditioning. J Neurosci 2009, 29:8087-8093.
• [39]Stefanova N, Ovtscharoff W: Sexual dimorphism of the bed nucleus of the stria terminalis and the amygdala. Adv Anat Embryol Cell Biol 2000, 158(III-X):1-78.
• [40]Rougemont-Bucking A, Linnman C, Zeffiro TA, Zeidan MA, Lebron-Milad K, Rodriguez-Romaguera J, Rauch SL, Pitman RK, Milad MR: Altered processing of contextual information during fear extinction in PTSD: an fMRI study. CNS Neurosci Ther 2011, 17:227-236.
• [41]Linnman C, Rougemont-Bucking A, Beucke JC, Zeffiro TA, Milad MR: Unconditioned responses and functional fear networks in human classical conditioning. Behav Brain Res 2011, 221:237-245.
• [42]Milad MR, Quirk GJ: Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 2002, 420:70-74.
• [43]Curley JP, Jordan ER, Swaney WT, Izraelit A, Kammel S, Champagne FA: The meaning of weaning: influence of the weaning period on behavioral development in mice. Dev Neurosci 2009, 31:318-331.
• [44]Nielsen SE, Ertman N, Lakhani YS, Cahill L: Hormonal contraception usage is associated with altered memory for an emotional story. Neurobiol Learn Mem 2011, 96:378-384.
• [45]Chang YJ, Yang CH, Liang YC, Yeh CM, Huang CC, Hsu KS: Estrogen modulates sexually dimorphic contextual fear extinction in rats through estrogen receptor beta. Hippocampus 2009, 19:1142-1150.
• [46]Milad MR, Quirk GJ, Pitman RK, Orr SP, Fischl B, Rauch SL: A role for the human dorsal anterior cingulate cortex in fear expression. Biol Psychiatry 2007, 62:1191-1194.
• [47]Linnman C, Zeidan MA, Furtak SC, Pitman RK, Quirk GJ, Milad MR: Resting Amygdala and Medial Prefrontal Metabolism Predicts Functional Activation of the Fear Extinction Circuit. Am J Psychiatry 2012,  : . (Epub ahead of print)
• [48]Etkin A, Egner T, Kalisch R: Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 2011, 15:85-93.
• [49]Milad MR, Quirk GJ, Pitman RK, Orr SP, Fischl B, Rauch SL: A role for the human dorsal anterior cingulate cortex in fear expression. BiolPsychiatry 2007, 62:1191-1194.
• [50]Mobbs D, Marchant JL, Hassabis D, Seymour B, Tan G, Gray M, Petrovic P, Dolan RJ, Frith CD: From threat to fear: the neural organization of defensive fear systems in humans. J Neurosci 2009, 29:12236-12243.
• [51]Davis M, Whalen PJ: The amygdala: vigilance and emotion. MolPsychiatry 2001, 6:13-34.
• [52]Quirk GJ, Mueller D: Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 2008, 33:56-72.