{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:10:34Z","timestamp":1790961034432,"version":"4.1.0"},"reference-count":68,"publisher":"National Academy of Sciences","issue":"51","license":[{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Netherlands Organization for Scientific Research","award":["863.15.008"],"award-info":[{"award-number":["863.15.008"]}]},{"name":"Netherlands Organization for Scientific Research","award":["864.10.003"],"award-info":[{"award-number":["864.10.003"]}]},{"name":"Netherlands Organization for Scientific Research","award":["453.12.001"],"award-info":[{"award-number":["453.12.001"]}]},{"name":"European Research Council","award":["2018_772337"],"award-info":[{"award-number":["2018_772337"]}]},{"name":"European Research Council","award":["ERC-2015-CoG 682591"],"award-info":[{"award-number":["ERC-2015-CoG 682591"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,12,17]]},"abstract":"<jats:p>\n                    Susceptibility to stress-related psychopathology is associated with reduced expression of the serotonin transporter (5-HTT), particularly in combination with stress exposure. Aberrant physiological and neuronal responses to threat may underlie this increased vulnerability. Here, implementing a cross-species approach, we investigated the association between 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance and action preparation. We tested this during threat anticipation induced by a well-established fear conditioning paradigm applied in both humans and rodents. In humans, we studied the effect of the common 5-HTT-linked polymorphic region (5-HTTLPR) on bradycardia and neural responses to anticipatory threat during functional magnetic resonance imaging scanning in healthy volunteers (\n                    <jats:italic>n<\/jats:italic>\n                    = 104). Compared with homozygous long-allele carriers, the 5-HTTLPR short-allele carriers displayed an exaggerated bradycardic response to threat, overall reduced activation of the medial prefrontal cortex (mPFC), and increased threat-induced connectivity between the amygdala and periaqueductal gray (PAG), which statistically mediated the effect of the 5-HTTLPR genotype on bradycardia. In parallel, 5-HTT knockout (KO) rats also showed exaggerated threat-related bradycardia and behavioral freezing. Immunohistochemistry indicated overall reduced activity of glutamatergic neurons in the mPFC of KO rats and increased activity of central amygdala somatostatin-positive neurons, putatively projecting to the PAG, which\u2014similarly to the human population\u2014mediated the 5-HTT genotype\u2019s effect on freezing. Moreover, the ventrolateral PAG of KO rats displayed elevated overall activity and increased relative activation of CaMKII-expressing projection neurons. Our results provide a mechanistic explanation for previously reported associations between 5-HTT gene variance and a stress-sensitive phenotype.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1904843116","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T17:27:33Z","timestamp":1574789253000},"page":"25941-25947","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":45,"title":["The association between serotonin transporter availability and the neural correlates of fear bradycardia"],"prefix":"10.1073","volume":"116","author":[{"given":"Pieter","family":"Schipper","sequence":"first","affiliation":[{"name":"Donders Institute for Brain, Cognition, and Behaviour, Radboud University, 6500 HB Nijmegen, The Netherlands;"},{"name":"Department of Cognitive Neuroscience, Radboud University Medical Center, 6500 HB Nijmegen, The 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Sci."},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.neubiorev.2004.03.005","article-title":"A two-dimensional neuropsychology of defense: Fear\/anxiety and defensive distance","volume":"28","author":"McNaughton N.","year":"2004","unstructured":"N. McNaughton, P. J. Corr, A two-dimensional neuropsychology of defense: Fear\/anxiety and defensive distance. Neurosci. Biobehav. Rev. 28, 285\u2013305 (2004).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0079-6123(06)56001-7","article-title":"Emotion, motivation, and the brain: Reflex foundations in animal and human research","volume":"156","author":"Lang P. J.","year":"2006","unstructured":"P. J. Lang, M. Davis, Emotion, motivation, and the brain: Reflex foundations in animal and human research. Prog. Brain Res. 156, 3\u201329 (2006).","journal-title":"Prog. Brain Res."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1037\/0097-7403.28.1.27","article-title":"Unawareness is more than a chance event: Comment on Lovibond and Shanks (2002)","volume":"28","author":"Wiens S.","year":"2002","unstructured":"S. Wiens, A. Ohman, Unawareness is more than a chance event: Comment on Lovibond and Shanks (2002). J. Exp. Psychol. Anim. Behav. Process. 28, 27\u201331 (2002).","journal-title":"J. Exp. Psychol. Anim. Behav. Process."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.neubiorev.2014.07.021","article-title":"Updating freeze: Aligning animal and human research","volume":"47","author":"Hagenaars M. A.","year":"2014","unstructured":"M. A. Hagenaars, M. Oitzl, K. Roelofs, Updating freeze: Aligning animal and human research. Neurosci. Biobehav. Rev. 47, 165\u2013176 (2014).","journal-title":"Neurosci. Biobehav. 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Gen."},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1177\/0956797610384746","article-title":"Facing freeze: Social threat induces bodily freeze in humans","volume":"21","author":"Roelofs K.","year":"2010","unstructured":"K. Roelofs, M. A. Hagenaars, J. Stins, Facing freeze: Social threat induces bodily freeze in humans. Psychol. Sci. 21, 1575\u20131581 (2010).","journal-title":"Psychol. Sci."},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10253890802046281","article-title":"Stress, depression and cardiovascular dysregulation: A review of neurobiological mechanisms and the integration of research from preclinical disease models","volume":"12","author":"Grippo A. J.","year":"2009","unstructured":"A. J. Grippo, A. K. Johnson, Stress, depression and cardiovascular dysregulation: A review of neurobiological mechanisms and the integration of research from preclinical disease models. 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Neurol."},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1523\/JNEUROSCI.08-07-02517.1988","article-title":"Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear","volume":"8","author":"LeDoux J. E.","year":"1988","unstructured":"J. E. LeDoux, J. Iwata, P. Cicchetti, D. J. Reis, Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517\u20132529 (1988).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/0166-2236(94)90047-7","article-title":"Columnar organization in the midbrain periaqueductal gray: Modules for emotional expression?","volume":"17","author":"Bandler R.","year":"1994","unstructured":"R. Bandler, M. T. Shipley, Columnar organization in the midbrain periaqueductal gray: Modules for emotional expression? Trends Neurosci. 17, 379\u2013389 (1994).","journal-title":"Trends Neurosci."},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrn3301","article-title":"The many paths to fear","volume":"13","author":"Gross C. T.","year":"2012","unstructured":"C. T. Gross, N. S. Canteras, The many paths to fear. Nat. Rev. Neurosci. 13, 651\u2013658 (2012).","journal-title":"Nat. Rev. Neurosci."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1177\/026988119100500414","article-title":"5-HT and mechanisms of defence","volume":"5","author":"Deakin J. F.","year":"1991","unstructured":"J. F. Deakin, F. G. Graeff, 5-HT and mechanisms of defence. J. Psychopharmacol. 5, 305\u2013315 (1991).","journal-title":"J. Psychopharmacol."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0165-1838(86)90066-4","article-title":"The hypothalamic and brainstem areas from which the cardiovascular and behavioural components of the defence reaction are elicited in the rat","volume":"15","author":"Yardley C. P.","year":"1986","unstructured":"C. P. Yardley, S. M. Hilton, The hypothalamic and brainstem areas from which the cardiovascular and behavioural components of the defence reaction are elicited in the rat. J. Auton. Nerv. Syst. 15, 227\u2013244 (1986).","journal-title":"J. Auton. Nerv. Syst."},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0304-3959(85)90088-0","article-title":"Ventrolateral medullary lesions block the antinociceptive and cardiovascular responses elicited by stimulating the dorsal periaqueductal grey matter in rats","volume":"21","author":"Lovick T. A.","year":"1985","unstructured":"T. A. 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Rep."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1002\/cne.901220310","article-title":"The role of central midbrain structures in conditioned responding to aversive noise in the rat","volume":"122","author":"Lyon M.","year":"1964","unstructured":"M. Lyon, The role of central midbrain structures in conditioned responding to aversive noise in the rat. J. Comp. Neurol. 122, 407\u2013429 (1964).","journal-title":"J. Comp. Neurol."},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nature17996","article-title":"Midbrain circuits for defensive behaviour","volume":"534","author":"Tovote P.","year":"2016","unstructured":"P. Tovote ., Midbrain circuits for defensive behaviour. Nature 534, 206\u2013212 (2016).","journal-title":"Nature"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"12707","DOI":"10.1523\/JNEUROSCI.1100-16.2016","article-title":"Neural correlates of fear in the periaqueductal gray","volume":"36","author":"Watson T. C.","year":"2016","unstructured":"T. C. Watson, N. L. Cerminara, B. M. Lumb, R. Apps, Neural correlates of fear in the periaqueductal gray. J. Neurosci. 36, 12707\u201312719 (2016).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1007\/s00429-019-01852-6","article-title":"The rostrodorsal periaqueductal gray influences both innate fear responses and acquisition of fear memory in animals exposed to a live predator","volume":"224","author":"de Andrade Rufino R.","year":"2019","unstructured":"R. de Andrade Rufino, S. R. Mota-Ortiz, M. A. X. De Lima, M. V. C. Baldo, N. S. Canteras, The rostrodorsal periaqueductal gray influences both innate fear responses and acquisition of fear memory in animals exposed to a live predator. Brain Struct. Funct. 224, 1537\u20131551 (2019).","journal-title":"Brain Struct. Funct."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbr.2007.10.018","article-title":"Different patterns of freezing behavior organized in the periaqueductal gray of rats: Association with different types of anxiety","volume":"188","author":"Brand\u00e3o M. L.","year":"2008","unstructured":"M. L. Brand\u00e3o, J. M. Zanoveli, R. C. Ruiz-Martinez, L. C. Oliveira, J. Landeira-Fernandez, Different patterns of freezing behavior organized in the periaqueductal gray of rats: Association with different types of anxiety. Behav. Brain Res. 188, 1\u201313 (2008).","journal-title":"Behav. Brain Res."},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0031-9384(83)90201-9","article-title":"Autonomic and somatomotor effects of amygdala central N. stimulation in awake rabbits","volume":"31","author":"Applegate C. D.","year":"1983","unstructured":"C. D. Applegate, B. S. Kapp, M. D. Underwood, C. L. McNall, Autonomic and somatomotor effects of amygdala central N. stimulation in awake rabbits. Physiol. Behav. 31, 353\u2013360 (1983).","journal-title":"Physiol. Behav."},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S0149-7634(99)00016-0","article-title":"The neuroanatomical and neurochemical basis of conditioned fear","volume":"23","author":"Fendt M.","year":"1999","unstructured":"M. Fendt, M. S. Fanselow, The neuroanatomical and neurochemical basis of conditioned fear. Neurosci. Biobehav. Rev. 23, 743\u2013760 (1999).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nature21047","article-title":"A competitive inhibitory circuit for selection of active and passive fear responses","volume":"542","author":"Fadok J. P.","year":"2017","unstructured":"J. P. Fadok ., A competitive inhibitory circuit for selection of active and passive fear responses. Nature 542, 96\u2013100 (2017).","journal-title":"Nature"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1523\/JNEUROSCI.4166-13.2014","article-title":"Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala","volume":"34","author":"Penzo M. A.","year":"2014","unstructured":"M. A. Penzo, V. Robert, B. Li, Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala. J. Neurosci. 34, 2432\u20132437 (2014).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nn.3322","article-title":"Experience-dependent modification of a central amygdala fear circuit","volume":"16","author":"Li H.","year":"2013","unstructured":"H. Li ., Experience-dependent modification of a central amygdala fear circuit. Nat. Neurosci. 16, 332\u2013339 (2013).","journal-title":"Nat. Neurosci."},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"6488","DOI":"10.1523\/JNEUROSCI.4419-15.2016","article-title":"Central amygdala somatostatin neurons gate passive and active defensive behaviors","volume":"36","author":"Yu K.","year":"2016","unstructured":"K. Yu, P. Garcia da Silva, D. F. Albeanu, B. Li, Central amygdala somatostatin neurons gate passive and active defensive behaviors. J. Neurosci. 36, 6488\u20136496 (2016).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.neuroimage.2012.10.063","article-title":"Fear bradycardia and activation of the human periaqueductal grey","volume":"66","author":"Hermans E. J.","year":"2013","unstructured":"E. J. Hermans, M. J. Henckens, K. Roelofs, G. Fern\u00e1ndez, Fear bradycardia and activation of the human periaqueductal grey. Neuroimage 66, 278\u2013287 (2013).","journal-title":"Neuroimage"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.neuroimage.2018.06.013","article-title":"Visuocortical changes during a freezing-like state in humans","volume":"179","author":"Lojowska M.","year":"2018","unstructured":"M. Lojowska, S. Ling, K. Roelofs, E. J. Hermans, Visuocortical changes during a freezing-like state in humans. Neuroimage 179, 313\u2013325 (2018).","journal-title":"Neuroimage"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1126\/science.1144298","article-title":"When fear is near: Threat imminence elicits prefrontal-periaqueductal gray shifts in humans","volume":"317","author":"Mobbs D.","year":"2007","unstructured":"D. Mobbs ., When fear is near: Threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science 317, 1079\u20131083 (2007).","journal-title":"Science"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1038\/sj.npp.1300552","article-title":"Effects of serotonin transporter promoter polymorphisms on serotonin function","volume":"29","author":"Smith G. S.","year":"2004","unstructured":"G. S. Smith ., Effects of serotonin transporter promoter polymorphisms on serotonin function. 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