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Role of the extended amygdala in short-duration versus sustained fear: a tribute to Dr. Lennart Heimer

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Abstract

The concept of the “extended amygdala”, developed and explored by Lennart Heimer, Jose de Olmos, George Alheid, and their collaborators, has had an enormous impact on the field of neuroscience and on our own work. Measuring fear-potentiated startle test using conditioned stimuli that vary in length we suggest that the central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNSTL) are involved in short-term versus long-term fear responses we call phasic versus sustained fear, respectively. Outputs from the basolateral amygdala (BLA) activate the medial division of the CeA (CeAM) to very rapidly elicit phasic fear responses via CeAM projections to the hypothalamus and brainstem. The BLA also projects to the BNSTL, which together with other BNSTL inputs from the lateral CeA (CeAL) initiate a slower developing, but sustained fear response, akin to anxiety. We hypothesize this occurs because the CeAL releases the peptide corticotropin releasing hormone (CRF) into the BNSTL which facilitates the release of glutamate from BLA terminals. This activates the BNSTL which projects to hypothalamic and brainstem areas similar to those innervated by the CeAM that mediate the specific signs of fear and anxiety. The generality of this idea is illustrated by selective studies looking at context conditioning, social defeat, drug withdrawal and stress induced reinstatement.

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References

  • Alheid G, De Olmos JS, Beltramino CA (1995) Amygdala and Extended Amygdala. In: Paxinos G (ed) The rat nervous system. Academic Press, New York, pp 495–578

    Google Scholar 

  • Alheid GF, Heimer L (1988) New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience 27:1–39. doi:10.1016/0306-4522(88)90217-5

    PubMed  CAS  Google Scholar 

  • Alheid GF, Beltramino CA, De Olmos JS, Forbes MS, Swanson DJ, Heimer L (1998) The neuronal organization of the supracapsular part of the stria terminalis in the rat: the dorsal component of the extended amygdala. Neuroscience 84:967–996. doi:10.1016/S0306-4522(97)00560-5

    PubMed  CAS  Google Scholar 

  • Amir S, Lamont EW, Robinson B, Stewart J (2004) A circadian rhythm in the expression of PERIOD2 protein reveals a novel SCN-controlled oscillator in the oval nucleus of the bed nucleus of the stria terminalis. J Neurosci 24:781–790. doi:10.1523/JNEUROSCI.4488-03.2004

    PubMed  CAS  Google Scholar 

  • Aston-Jones G, Delfs JM, Druhan J, Zhu Y (1999) The bed nucleus of the stria terminalis. A target site for noradrenergic actions in opiate withdrawal. Ann NY Acad Sci 877:486–498. doi:10.1111/j.1749-6632.1999.tb09284.x

    PubMed  CAS  Google Scholar 

  • Bartfai T, Iverfeldt K, Fisone G, Serfozo P (1988) Regulation of the release of coexisting neurotransmitters. Annu Rev Pharmacol Toxicol 28:285–310. doi:10.1146/annurev.pa.28.040188.001441

    PubMed  CAS  Google Scholar 

  • Beck CHM, Fibiger HC (1995) Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment. J Neurosci 15:709–720

    PubMed  CAS  Google Scholar 

  • Berendse HW, Groenewegen HJ (1991) Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat. Neuroscience 42:73–102. doi:10.1016/0306-4522(91)90151-D

    PubMed  CAS  Google Scholar 

  • Bhatnagar S, Dallman M (1998) Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress. Neuroscience 84:1025–1039. doi:10.1016/S0306-4522(97)00577-0

    PubMed  CAS  Google Scholar 

  • Bhatnagar S, Dallman MF (1999) The paraventricular nucleus of the thalamus alters rhythms in core temperature and energy balance in a state-dependent manner. Brain Res 851:66–75. doi:10.1016/S0006-8993(99)02108-3

    PubMed  CAS  Google Scholar 

  • Bourgeais L, Gauriau C, Bernard JF (2001) Projections from the nociceptive area of the central nucleus of the amygdala to the forebrain: a PHA-L study in the rat. Eur J Neurosci 14:229–255. doi:10.1046/j.0953-816x.2001.01640.x

    PubMed  CAS  Google Scholar 

  • Bourque CW (1991) Activity-dependent modulation of nerve terminal excitation in a mammalian peptidergic system. Trends Neurosci 14:28–30. doi:10.1016/0166-2236(91)90180-3

    PubMed  CAS  Google Scholar 

  • Brown MR, Gray TS (1988) Peptide injections into the amygdala of conscious rats: Effects on blood pressure, heart rate and plasma catecholamines. Regul Pept 21:95–106. doi:10.1016/0167-0115(88)90094-8

    PubMed  CAS  Google Scholar 

  • Bubser M, Deutch AY (1999) Stress induces Fos expression in neurons of the thalamic paraventricular nucleus that innervate limbic forebrain sites. Synapse 32:13–22. doi :10.1002/(SICI)1098-2396(199904)32:1<13::AID-SYN2>3.0.CO;2-R

    PubMed  CAS  Google Scholar 

  • Buchel C, Morris J, Dolan RJ, Friston KJ (1998) Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 20:947–957. doi:10.1016/S0896-6273(00)80476-6

    PubMed  CAS  Google Scholar 

  • Campeau S, Davis M (1995) Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J Neurosci 15:2301–2311

    PubMed  CAS  Google Scholar 

  • Cassell MD, Gray TS, Kiss JZ (1986) Neuronal architecture in the rat central nucleus of the amygdala: a cytological, hodological, and immunocytochemical study. J Comp Neurol 246:478–499. doi:10.1002/cne.902460406

    PubMed  CAS  Google Scholar 

  • Cecchi M, Capriles N, Watson SJ, Akil H (2007) Beta1 adrenergic receptors in the bed nucleus of stria terminalis mediate differential responses to opiate withdrawal. Neuropsychopharmacology 32:589–599. doi:10.1038/sj.npp.1301140

    PubMed  CAS  Google Scholar 

  • Chastrette N, Pfaff DW, Gibbs RB (1991) Effects of daytime and nighttime stress on Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus, the habenula, and the posterior paraventricular nucleus of the thalamus. Brain Res 563:339–344. doi:10.1016/0006-8993(91)91559-J

    PubMed  CAS  Google Scholar 

  • Chen Y, Brunson KL, Muller MB, Cariaga W, Baram TZ (2000) Immunocytochemical distribution of corticotropin-releasing hormone receptor type-1 (CRF(1))-like immunoreactivity in the mouse brain: light microscopy analysis using an antibody directed against the C-terminus. J Comp Neurol 420:305–323. doi :10.1002/(SICI)1096-9861(20000508)420:3<305::AID-CNE3>3.0.CO;2-8

    PubMed  CAS  Google Scholar 

  • Ciccocioppo R, Cippitelli A, Economidou D, Fedeli A, Massi M (2004) Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect. Physiol Behav 82:63–68. doi:10.1016/j.physbeh.2004.04.035

    PubMed  CAS  Google Scholar 

  • Ciccocioppo R, Fedeli A, Economidou D, Policani F, Weiss F, Massi M (2003) The bed nucleus is a neuroanatomical substrate for the anorectic effect of corticotropin-releasing factor and for its reversal by nociceptin/orphanin FQ. J Neurosci 23:9445–9451

    PubMed  CAS  Google Scholar 

  • Cintra A, Fuxe K, Harfstrand A, Agnati LF, Wikstrom AC, Okret S et al (1987) Presence of glucocorticoid receptor immunoreactivity in corticotrophin releasing factor and in growth hormone releasing factor immunoreactive neurons of the rat di- and telencephalon. Neurosci Lett 77:25–30. doi:10.1016/0304-3940(87)90601-X

    PubMed  CAS  Google Scholar 

  • Contarino A, Papaleo F (2005) The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal. Proc Natl Acad Sci USA 102:18649–18654. doi:10.1073/pnas.0506999102

    PubMed  CAS  Google Scholar 

  • Crawley JN (1981) Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines. Pharmacol Biochem Behav 15:695–699. doi:10.1016/0091-3057(81)90007-1

    PubMed  CAS  Google Scholar 

  • Cullinan WE, Herman JP, Watson SJ (1993) Ventral subicular interaction with the hypothalamic paraventricular nucleus: Evidence for a relay in the bed nucleus of the stria terminalis. J Comp Neurol 332:1–20. doi:10.1002/cne.903320102

    PubMed  CAS  Google Scholar 

  • Cullinan WE, Herman JP, Battaglia DF, Akil H, Watson SJ (1995) Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64:477–505. doi:10.1016/0306-4522(94)00355-9

    PubMed  CAS  Google Scholar 

  • Cummings S, Elde R, Ells J, Lindall A (1983) Corticotropin-releasing factor immunoreactivity is widely distributed within the central nervous system of the rat: an immunohistochemical study. J Neurosci 3:1355–1368

    PubMed  CAS  Google Scholar 

  • Davis M (2000) The role of the amygdala in conditioned and unconditioned fear and anxiety. In: Aggleton JP (ed) The amygdala, vol 2. Oxford University Press, Oxford, pp 213–287

    Google Scholar 

  • Davis M, Whalen P (2001) The amygdala: Vigilance and emotion. Mol Psychiatry 6:13–34. doi:10.1038/sj.mp.4000812

    PubMed  CAS  Google Scholar 

  • Davis M, Schlesinger LS, Sorenson CA (1989) Temporal specificity of fear-conditioning: effects of different conditioned stimulus-unconditioned stimulus intervals on the fear-potentiated startle effect. J Exp Psychol Anim Behav Process 15:295–310. doi:10.1037/0097-7403.15.4.295

    PubMed  CAS  Google Scholar 

  • Davis M, Walker DL, Lee Y (1997) Roles of the amygdala and bed nucleus of the stria terminalis in fear and anxiety measured with the acoustic startle reflex: Possible relevance to PTSD. Ann NY Acad Sci 821:305–331. doi:10.1111/j.1749-6632.1997.tb48289.x

    PubMed  CAS  Google Scholar 

  • Day HE, Curran EJ, Watson SJ Jr, Akil H (1999) Distinct neurochemical populations in the rat central nucleus of the amygdala and bed nucleus of the stria terminalis: evidence for their selective activation by interleukin-1Beta. J Comp Neurol 413:113–128. doi :10.1002/(SICI)1096-9861(19991011)413:1<113::AID-CNE8>3.0.CO;2-B

    PubMed  CAS  Google Scholar 

  • de Jongh R, Groenink L, van der Gugten J, Olivier B (2002) Pharmacological validation of the light-enhanced startle paradigm as a putative animal model of anxiety. Psychopharmacology (Berl) 159:176–180. doi:10.1007/s002130100914

    Google Scholar 

  • de Jongh R, Groenink L, van der Gugten J, Olivier B (2003) Light-enhanced and fear-potentiated startle: temporal characteristics and effects of alpha-helical corticotropin-releasing hormone. Biol Psychiatry 54:1041–1048. doi:10.1016/S0006-3223(03)00468-2

    PubMed  Google Scholar 

  • Deak T, Nguyen KT, Ehrlich AL, Watkins LR, Spencer RL, Maier SF et al (1999) The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress. Endocrinology 140:79–86. doi:10.1210/en.140.1.79

    PubMed  CAS  Google Scholar 

  • DeFries JC, Hegmann JP, Weir MW (1966) Open-field behavior in mice: evidence for a major gene effect mediated by the visual system. Science 154:1577. doi:10.1126/science.154.3756.1577

    PubMed  CAS  Google Scholar 

  • Delfs JM, Zhu Y, Druhan JP, Aston-Jones G (2000) Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature 403:430–434. doi:10.1038/35000212

    PubMed  CAS  Google Scholar 

  • DeSouza EB, Insel TR, Perrin MH, Rivier J, Vale WW, Kuhar MJ (1985) Corticotropin-releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study. J Neurosci 5:3189–3203

    CAS  Google Scholar 

  • Deyama S, Nakagawa T, Kaneko S, Uehara T, Minami M (2007) Involvement of the bed nucleus of the stria terminalis in the negative affective component of visceral and somatic pain in rats. Behav Brain Res 176:367–371. doi:10.1016/j.bbr.2006.10.021

    PubMed  Google Scholar 

  • Dobolyi A, Irwin S, Makara G, Usdin TB, Palkovits M (2005) Calcitonin gene-related peptide-containing pathways in the rat forebrain. J Comp Neurol 489:92–119. doi:10.1002/cne.20618

    PubMed  CAS  Google Scholar 

  • Dong HW, Petrovich GD, Swanson LW (2001) Topography of projections from amygdala to bed nuclei of the stria terminalis. Brain Res Brain Res Rev 38:192–246. doi:10.1016/S0165-0173(01)00079-0

    PubMed  CAS  Google Scholar 

  • Duncan GE, Knapp DJ, Breese GR (1996) Neuroanatomical characterization of Fos induction in rat behavioral models of anxiety. Brain Res 713:79–91. doi:10.1016/0006-8993(95)01486-1

    PubMed  CAS  Google Scholar 

  • Erb S, Salmaso N, Rodaros D, Stewart J (2001) A role for the CRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 158:360–365. doi:10.1007/s002130000642

    CAS  Google Scholar 

  • Fendt M, Koch M, Schnitzler H-U (1994) Lesions of the central grey block the sensitization of the acoustic startle response in rats. Brain Res 661:163–173. doi:10.1016/0006-8993(94)91193-2

    PubMed  CAS  Google Scholar 

  • Fendt M, Endres T, Apfelbach R (2003) Temporary inactivation of the bed nucleus of the stria terminalis but not of the amygdala blocks freezing induced by trimethylthiazoline, a component of fox feces. J Neurosci 23:23–28

    PubMed  CAS  Google Scholar 

  • File SE, Hyde JRG (1978) Can social interaction be used to measure anxiety. Br J Pharmacol 62:19–24

    PubMed  CAS  Google Scholar 

  • Forray MI, Gysling K (2004) Role of noradrenergic projections to the bed nucleus of the stria terminalis in the regulation of the hypothalamic-pituitary-adrenal axis. Brain Res Brain Res Rev 47:145–160. doi:10.1016/j.brainresrev.2004.07.011

    PubMed  CAS  Google Scholar 

  • Forray MI, Gonzales M, Hadwed N, Gonzalez MP (2005) Chronic immobilization stress increases glutamatergic transmission in the rat bed nucleus of the stria terminalis. in vivo microdialysis studies. Soc Neuosci Abstr Program No. 187.3

  • Frenois F, Cador M, Caille S, Stinus L, Le Moine C (2002) Neural correlates of the motivational and somatic components of naloxone-precipitated morphine withdrawal. Eur J Neurosci 16:1377–1389. doi:10.1046/j.1460-9568.2002.02187.x

    PubMed  Google Scholar 

  • Frenois F, Stinus L, Di Blasi F, Cador M, Le Moine C (2005) A specific limbic circuit underlies opiate withdrawal memories. J Neurosci 25:1366–1374. doi:10.1523/JNEUROSCI.3090-04.2005

    PubMed  CAS  Google Scholar 

  • Funk CK, O’Dell LE, Crawford EF, Koob GF (2006) Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J Neurosci 26:11324–11332. doi:10.1523/JNEUROSCI.3096-06.2006

    PubMed  CAS  Google Scholar 

  • Gracy KN, Dankiewicz LA, Koob GF (2001) Opiate withdrawal-induced fos immunoreactivity in the rat extended amygdala parallels the development of conditioned place aversion. Neuropsychopharmacology 24:152–160. doi:10.1016/S0893-133X(00)00186-X

    PubMed  CAS  Google Scholar 

  • Gray TS, Magnusson DJ (1987) Neuropeptide neuronal efferents from the bed nucleus of the stria terminalis and central amygdaloid nucleus to the dorsal vagal complex in the rat. J Comp Neurol 262:365–374. doi:10.1002/cne.902620304

    PubMed  CAS  Google Scholar 

  • Gray TS, Magnuson DJ (1992) Peptide immunoreactive neurons in the amygdala and the bed nucleus of the stria terminalis project to the midbrain central gray in the rat. Peptides 13:451–460. doi:10.1016/0196-9781(92)90074-D

    PubMed  CAS  Google Scholar 

  • Hamlin AS, Buller KM, Day TA, Osborne PB (2004) Effect of naloxone-precipitated morphine withdrawal on c-fos expression in rat corticotropin-releasing hormone neurons in the paraventricular hypothalamus and extended amygdala. Neurosci Lett 362:39–43. doi:10.1016/j.neulet.2004.02.033

    PubMed  CAS  Google Scholar 

  • Hammack SE, Richey KJ, Watkins LR, Maier SF (2004) Chemical lesion of the bed nucleus of the stria terminalis blocks the behavioral consequences of uncontrollable stress. Behav Neurosci 118:443–448. doi:10.1037/0735-7044.118.2.443

    PubMed  Google Scholar 

  • Haring C, Humpel C, Skofitsch G, Krobath J, Javorsky F, Saria A (1991) Calcitonin gene-related peptide in the amygdaloid complex of the rat: immunohistochemical and quantitative distribution, and drug effects on calcium dependent, potassium-evoked in vitro release. Synapse 8:261–269. doi:10.1002/syn.890080404

    PubMed  CAS  Google Scholar 

  • Harrigan EA, Magnuson DJ, Thunstedt GM, Gray TS (1994) Corticotropin releasing factor neurons are innervated by calcitonin gene-related peptide terminals in the rat central amygdaloid nucleus. Brain Res Bull 33:529–534. doi:10.1016/0361-9230(94)90079-5

    PubMed  CAS  Google Scholar 

  • Heinrichs SC, Menzaghi F, Schulteis G, Koob GF, Stinus L (1995) Suppression of corticotropin-releasing factor in the amygdala attenuates aversive consequences of morphine withdrawal. Behav Pharmacol 6:74–80. doi:10.1097/00008877-199501000-00011

    PubMed  CAS  Google Scholar 

  • Hitchcock JM, Davis M (1986) Lesions of the amygdala, but not of the cerebellum or red nucleus, block conditioned fear as measured with the potentiated startle paradigm. Behav Neurosci 100:11–22. doi:10.1037/0735-7044.100.1.11

    PubMed  CAS  Google Scholar 

  • Hitchcock JM, Davis M (1987) Fear-potentiated startle using an auditory conditioned stimulus: effect of lesions of the amygdala. Physiol Behav 39:403–408. doi:10.1016/0031-9384(87)90242-3

    PubMed  CAS  Google Scholar 

  • Hitchcock JM, Davis M (1991) The efferent pathway of the amygdala involved in conditioned fear as measured with the fear-potentiated startle paradigm. Behav Neurosci 105:826–842. doi:10.1037/0735-7044.105.6.826

    PubMed  CAS  Google Scholar 

  • Honkaniemi J, Pelto-Huikko M, Rechardt L, Isola J, Lammi A, Fuxe K et al (1992) Colocalization of peptide and glucocorticoid receptor immunoreactivities in rat central amygdaloid nucleus. Neuroendocrinology 55:451–459. doi:10.1159/000126156

    PubMed  CAS  Google Scholar 

  • Ip NY (1994) Pattern of presynaptic nerve activity can determine the type of neurotransmitter regulating a postsynaptic event. Nature 311:472–474. doi:10.1038/311472a0

    Google Scholar 

  • Iredale PA, Alvaro JD, Lee Y, Terwilliger R, Chen YL, Duman RS (2000) Role of corticotropin-releasing factor receptor–1 in opiate withdrawal. J Neurochem 74:199–208. doi:10.1046/j.1471-4159.2000.0740199.x

    PubMed  CAS  Google Scholar 

  • Iwata J, LeDoux JE, Meeley MP, Arneric S, Reis DJ (1986) Intrinsic neurons in the amygdala field projected to by the medial geniculate body mediate emotional responses conditioned to acoustic stimuli. Brain Res 383:195–214. doi:10.1016/0006-8993(86)90020-X

    PubMed  CAS  Google Scholar 

  • Jasnow AM, Davis M, Huhman KL (2004) Involvement of central amygdalar and bed nucleus of the stria terminalis corticotropin-releasing factor in behavioral responses to social defeat. Behav Neurosci 118:1052–1061. doi:10.1037/0735-7044.118.5.1052

    PubMed  CAS  Google Scholar 

  • Jin C, Araki H, Nagata M, Suemaru K, Shibata K, Kawasaki H et al (2004) Withdrawal-induced c-Fos expression in the rat centromedial amygdala 24 h following a single morphine exposure. Psychopharmacology (Berl) 175:428–435

    CAS  Google Scholar 

  • Johnston JB (1923) Further contribution to the study of the evolution of the forebrain. J Comp Neurol 35:337–481. doi:10.1002/cne.900350502

    Google Scholar 

  • Jolkkonen E, Pitkanen A (1998) Intrinsic connections of the rat amygdaloid complex: projections originating in the central nucleus. J Comp Neurol 395:53–72. doi :10.1002/(SICI)1096-9861(19980525)395:1<53::AID-CNE5>3.0.CO;2-G

    PubMed  CAS  Google Scholar 

  • Kalin NH (2005) Brain regions associated with the expression and contextual regulation of anxiety in primates. Biol Psychiatry 58:796–804. doi:10.1016/j.biopsych.2005.05.021

    PubMed  Google Scholar 

  • Kalin NH, Takahashi LK (1990) Fear-motivated behavior induced by prior shock experience is mediated by corticotropin-releasing hormone systems. Brain Res 509:80–84. doi:10.1016/0006-8993(90)90311-X

    PubMed  CAS  Google Scholar 

  • Kapp BS, Frysinger RC, Gallagher M, Haselton JR (1979) Amygdala central nucleus lesions: effect on heart rate conditioning in the rabbit. Physiol Behav 23:1109–1117. doi:10.1016/0031-9384(79)90304-4

    PubMed  CAS  Google Scholar 

  • Kocorowski LH, Helmstetter FJ (2001) Calcitonin gene-related peptide released within the amygdala is involved in Pavlovian auditory fear conditioning. Neurobiol Learn Mem 75:149–163. doi:10.1006/nlme.2000.3963

    PubMed  CAS  Google Scholar 

  • Kruger L, Mantyh PW, Sternini C, Brecha NC, Mantyh CR (1988) Calcitonin gene-related peptide (CGRP) in the rat central nervous system: patterns of immunoreactivity and receptor binding sites. Brain Res 463:223–244. doi:10.1016/0006-8993(88)90395-2

    PubMed  CAS  Google Scholar 

  • Lechner SM, Valentino RJ (1999) Glucocorticoid receptor-immunoreactivity in corticotrophin-releasing factor afferents to the locus coeruleus. Brain Res 816:17–28. doi:10.1016/S0006-8993(98)00900-7

    PubMed  CAS  Google Scholar 

  • LeDoux JE, Iwata J, Cicchetti P, Reis DJ (1988) Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J Neurosci 8:2517–2529

    PubMed  CAS  Google Scholar 

  • Lee Y, Davis M (1997) Role of the hippocampus, bed nucleus of the stria terminalis and amygdala in the excitatory effect of corticotropin releasing hormone on the acoustic startle reflex. J Neurosci 17:6434–6446

    PubMed  CAS  Google Scholar 

  • Lee Y, Schulkin J, Davis M (1994) Effect of corticosterone on the enhancement of the acoustic startle reflex by corticotropin releasing factor (CRF). Brain Res 666:93–98. doi:10.1016/0006-8993(94)90286-0

    PubMed  CAS  Google Scholar 

  • Lee Y, Fitz S, Johnson PL, Shekhar A (2008) Repeated Stimulation of CRF Receptors in the BNST of Rats Selectively Induces Social but not Panic-Like Anxiety. Neuropsychopharmacology (Advance online publication)

  • Li S, Kirouac GJ (2008) Projections from the paraventricular nucleus of the thalamus to the forebrain, with special emphasis on the extended amygdala. J Comp Neurol 506:263–287. doi:10.1002/cne.21502

    PubMed  Google Scholar 

  • Liang KC, Melia KR, Campeau S, Falls WA, Miserendino MJD, Davis M (1992) Lesions of the central nucleus of the amygdala, but not of the paraventricular nucleus of the hypothalamus, block the excitatory effects of corticotropin releasing factor on the acoustic startle reflex. J Neurosci 12:2313–2320

    PubMed  CAS  Google Scholar 

  • Liu IY, Lyons WE, Mamounas LA, Thompson RF (2004) Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning. J Neurosci 24:7958–7963. doi:10.1523/JNEUROSCI.1948-04.2004

    PubMed  CAS  Google Scholar 

  • Lu L, Liu D, Ceng X, Ma L (2000) Differential roles of corticotropin-releasing factor receptor subtypes 1 and 2 in opiate withdrawal and in relapse to opiate dependence. Eur J Neurosci 12:4398–4404. doi:10.1046/j.1460-9568.2000.01310.x

    PubMed  CAS  Google Scholar 

  • Lundberg JM, Rudehill A, Sollevi A (1986) Frequency- and reserpine-dependent chemical coding of sympathetic transmission: differential release of noradrenaline and neuropeptide Y from pig spleen. Neurosci Lett 63:96–100. doi:10.1016/0304-3940(86)90020-0

    PubMed  CAS  Google Scholar 

  • Maier SF, Grahn RE, Kalman BA, Sutton LC, Wiertelak EP, Watkins LR (1993) The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock. Behav Neurosci 107:377–388. doi:10.1037/0735-7044.107.2.377

    PubMed  CAS  Google Scholar 

  • Makino S, Gold PW, Schulkin J (1994)a Corticosterone effects on corticotropin-releasing hormone mRNA in the central nucleus of the amygdala and the parvocellular region of the paraventricular nucleus of the hypothalamus. Brain Res 640:105–112. doi:10.1016/0006-8993(94)91862-7

    PubMed  CAS  Google Scholar 

  • Makino S, Gold PW, Schulkin J (1994)b Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus. Brain Res 657:141–149. doi:10.1016/0006-8993(94)90961-X

    PubMed  CAS  Google Scholar 

  • McDonald AJ, Shamman-Lagnado SJ, Shi CJ, Davis M (1999) Cortical afferents to the extended amygdala. In: McGinty JF (ed) Annals of the New York Academy of Sciences. Annals of the New York Academy of Sciences, New York, pp 309–338

    Google Scholar 

  • McDonald J (1991) Topographical organization of amygdaloid projections to the caudatoputamen, nucleus accumbens, and related striatal-like areas of the rat brain. Neuroscience 44:15–33. doi:10.1016/0306-4522(91)90248-M

    PubMed  CAS  Google Scholar 

  • McDonald RJ, Murphy RA, Guarraci FA, Gortler JR, White NM, Baker AG (1997) Systematic comparison of the effects of hippocampal and fornix-fimbria lesions on acquisition of three configural discriminations. Hippocampus 7:371–388. doi :10.1002/(SICI)1098-1063(1997)7:4<371::AID-HIPO3>3.0.CO;2-M

    PubMed  CAS  Google Scholar 

  • McNally GP, Akil H (2002) Role of corticotropin-releasing hormone in the amygdala and bed nucleus of the stria terminalis in the behavioral, pain modulatory, and endocrine consequences of opiate withdrawal. Neuroscience 112:605–617. doi:10.1016/S0306-4522(02)00105-7

    PubMed  CAS  Google Scholar 

  • Meloni EG, Davis M (1999) Muscimol in the deep layers of the superior colliculus/mesencephalic reticular formation blocks expression but not acquisition of fear-potentiated startle in rats. Behav Neurosci 113:1152–1160. doi:10.1037/0735-7044.113.6.1152

    PubMed  CAS  Google Scholar 

  • Meloni EG, Jackson A, Gerety LP, Cohen BM, Carlezon WA Jr (2006) Role of the bed nucleus of the stria terminalis (BST) in the expression of conditioned fear. Ann N Y Acad Sci 1071:538–541. doi:10.1196/annals.1364.059

    PubMed  Google Scholar 

  • Moga MM, Gray TS (1985) Evidence for corticotropin-releasing factor, neurotensin, and somatostatin in the neural pathway from the central nucleus of the amygdala to the parabrachial nucleus. J Comp Neurol 241:275–284. doi:10.1002/cne.902410304

    PubMed  CAS  Google Scholar 

  • Moga MM, Weis RP, Moore RY (1995) Efferent projections of the paraventricular thalamic nucleus in the rat. J Comp Neurol 359:221–238. doi:10.1002/cne.903590204

    PubMed  CAS  Google Scholar 

  • Morilak DA, Cecchi M, Khoshbouei H (2003) Interactions of norepinephrine and galanin in the central amygdala and lateral bed nucleus of the stria terminalis modulate the behavioral response to acute stress. Life Sci 73:715–726. doi:10.1016/S0024-3205(03)00392-8

    PubMed  CAS  Google Scholar 

  • Nakagawa T, Yamamoto R, Fujio M, Suzuki Y, Minami M, Satoh M et al (2005) Involvement of the bed nucleus of the stria terminalis activated by the central nucleus of the amygdala in the negative affective component of morphine withdrawal in rats. Neuroscience 134:9–19. doi:10.1016/j.neuroscience.2005.03.029

    PubMed  CAS  Google Scholar 

  • Nguyen KQ, Sills MA, Jacobowitz DM (1986) Cardiovascular effects produced by microinjection of calcitonin gene-related peptide into the rat central amygdaloid nucleus. Peptides 7:337–339. doi:10.1016/0196-9781(86)90233-0

    PubMed  CAS  Google Scholar 

  • Olive MF, Koenig HN, Nannini MA, Hodge CW (2002) Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction by subsequent ethanol intake. Pharmacol Biochem Behav 72:213–220. doi:10.1016/S0091-3057(01)00748-1

    PubMed  CAS  Google Scholar 

  • Otake K, Ruggiero DA, Nakamura Y (1995) Adrenergic innervation of forebrain neurons that project to the paraventricular thalamic nucleus in the rat. Brain Res 697:17–26. doi:10.1016/0006-8993(95)00749-G

    PubMed  CAS  Google Scholar 

  • Petrovich GD, Swanson LW (1997) Projections from the lateral part of the central amygdalar nucleus to the postulated fear conditioning circuit. Brain Res 763:247–254. doi:10.1016/S0006-8993(96)01361-3

    PubMed  CAS  Google Scholar 

  • Phelix CF, Paul WK (1990) Demonstration of distinct corticotropin releasing factor—containing neuron populatins in the bed nucleus of the stria terminalis. A light and electron microscoic immunocytochemical study in the rat. Histochemistry 94:345–364. doi:10.1007/BF00266441

    PubMed  CAS  Google Scholar 

  • Phelps EA, O’Connor KJ, Gatenby JC, Gore JC, Grillon C, Davis M (2001) Activation of the left amygdala to a cognitive representation of fear. Nat Neurosci 4:437–441. doi:10.1038/86110

    PubMed  CAS  Google Scholar 

  • Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM et al (1999) Dissociating pain from its anticipation in the human brain. Science 284:1979–1981. doi:10.1126/science.284.5422.1979

    PubMed  CAS  Google Scholar 

  • Rainnie DG, Bergeron R, Sajdyk TJ, Patil M, Gehlert DR, Shekhar A (2004) Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. J Neurosci 24:3471–3479. doi:10.1523/JNEUROSCI.5740-03.2004

    PubMed  CAS  Google Scholar 

  • Rosen JB, Hitchcock JM, Sananes CB, Miserendino MJD, Davis M (1991) A direct projection from the central nucleus of the amygdala to the acoustic startle pathway: anterograde and retrograde tracing studies. Behav Neurosci 105:817–825. doi:10.1037/0735-7044.105.6.817

    PubMed  CAS  Google Scholar 

  • Sajdyk TJ, Gehlert DR (2000) Astressin, a corticotropin releasing factor antagonist, reverses the anxiogenic effects of urocortin when administered into the basolateral amygdala. Brain Res 877:226–234. doi:10.1016/S0006-8993(00)02638-X

    PubMed  CAS  Google Scholar 

  • Sajdyk TJ, Schober DA, Gehlert DR, Shekhar A (1999) Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses. Behav Brain Res 100:207–215. doi:10.1016/S0166-4328(98)00132-6

    PubMed  CAS  Google Scholar 

  • Sakanaka M, Shibasaki T, Lederis K (1986) Distribution and efferent projections of corticotropin-releasing factor-like immunoreactivity in the rat amygdaloid complex. Brain Res 382:213–238. doi:10.1016/0006-8993(86)91332-6

    PubMed  CAS  Google Scholar 

  • Schwaber JS, Kapp BS, Higgins GA, Rapp PR (1982) Amygdaloid and basal forebrain direct connections with the nucleus of the solitary tract and the dorsal motor nucleus. J Neurosci 2:1424–1438

    PubMed  CAS  Google Scholar 

  • Shammah-Lagnado SJ, Negrao N, Silva BA, Ricardo JA (1987) Afferent connections of the nuclei reticularis pontis oralis and caudalis: A horseradish peroxidase study in the rat. Neuroscience 20:961–989. doi:10.1016/0306-4522(87)90256-9

    PubMed  CAS  Google Scholar 

  • Shaw-Lutchman TZ, Barrot M, Wallace T, Gilden L, Zachariou V, Impey S et al (2002) Regional and cellular mapping of cAMP response element-mediated transcription during naltrexone-precipitated morphine withdrawal. J Neurosci 22:3663–3672

    PubMed  CAS  Google Scholar 

  • Shepard JD, Barron KW, Myers DA (2000) Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior. Brain Res 861:288–295. doi:10.1016/S0006-8993(00)02019-9

    PubMed  CAS  Google Scholar 

  • Shi C-J, Zhou X-L, Davis M (2002) A GABAergic projection from the central extended amygdala to the deep mesencephalic nucleus in rats. Society for Neuroscience Abstract 28:Abstract 284.214

  • Shimada S, Inagaki S, Kubota Y, Ogawa N, Shibasaki T, Takagi H (1989) Coexistence of peptides (corticotropin releasing factor/neurotensin and substance P/somatostatin) in the bed nucleus of the stria terminalis and central amygdaloid nucleus of the rat. Neuroscience 30:377–383. doi:10.1016/0306-4522(89)90259-5

    PubMed  CAS  Google Scholar 

  • Stinus L, Cador M, Zorrilla EP, Koob GF (2005) Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats. Neuropsychopharmacology 30:90–98. doi:10.1038/sj.npp.1300487

    PubMed  CAS  Google Scholar 

  • Straube T, Mentzel HJ, Miltner WH (2007) Waiting for spiders: brain activation during anticipatory anxiety in spider phobics. Neuroimage 37:1427–1436. doi:10.1016/j.neuroimage.2007.06.023

    PubMed  Google Scholar 

  • Sullivan GM, Apergis J, Bush DE, Johnson LR, Hou M, Ledoux JE (2004) Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus. Neuroscience 128:7–14. doi:10.1016/j.neuroscience.2004.06.015

    PubMed  CAS  Google Scholar 

  • Sun N, Roberts L, Cassell D (1991) Rat central amygdaloid nucleus projections to the bed nucleus of the stria terminalis. Brain Res Bull 27:651–662. doi:10.1016/0361-9230(91)90041-H

    PubMed  CAS  Google Scholar 

  • Sun N, Yi H, Cassell MD (1994) Evidence for a GABAergic interface between cortical afferents and brainstem projection neurons in the rat central extended amygdala. J Comp Neurol 340:43–64. doi:10.1002/cne.903400105

    PubMed  CAS  Google Scholar 

  • Swanson LW, Simmons DM (1989) Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat. J Comp Neurol 285:413–435. doi:10.1002/cne.902850402

    PubMed  CAS  Google Scholar 

  • Turner BH, Herkenham M (1991) Thalamoamygdaloid projections in the rat: a test of the amygdala’s role in sensory processing. J Comp Neurol 313:295–325. doi:10.1002/cne.903130208

    PubMed  CAS  Google Scholar 

  • Veening JG, Swanson LW, Sawchenko PE (1984) The organization of projections from the central nucleus of the amygdala to brain stem sites involved in central autonomic regulation: a combined retrograde transport-immunohistochemical study. Brain Res 303:337–357. doi:10.1016/0006-8993(84)91220-4

    PubMed  CAS  Google Scholar 

  • Veinante P, Stoeckel ME, Freund-Mercier MJ (1997) GABA- and peptide-immunoreactivities co-localize in the rat central extended amygdala. Neuroreport 8:2985–2989. doi:10.1097/00001756-199709080-00035

    PubMed  CAS  Google Scholar 

  • Veinante P, Stoeckel ME, Lasbennes F, Freund-Mercier MJ (2003) c-Fos and peptide immunoreactivities in the central extended amygdala of morphine-dependent rats after naloxone-precipitated withdrawal. Eur J Neurosci 18:1295–1305. doi:10.1046/j.1460-9568.2003.02837.x

    PubMed  Google Scholar 

  • Vertes RP, Hoover WB (2008) Projections of the paraventricular and paratenial nuclei of the dorsal midline thalamus in the rat. J Comp Neurol 508:212–237. doi:10.1002/cne.21679

    PubMed  Google Scholar 

  • Vyas A, Bernal S, Chattarji S (2003) Effects of chronic stress on dendritic arborization in the central and extended amygdala. Brain Res 965:290–294. doi:10.1016/S0006-8993(02)04162-8

    PubMed  CAS  Google Scholar 

  • Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6818

    PubMed  CAS  Google Scholar 

  • Waddell J, Morris RW, Bouton ME (2006)a Effects of bed nucleus of the stria terminalis lesions on conditioned anxiety: aversive conditioning with long-duration conditional stimuli and reinstatement of extinguished fear. Behav Neurosci 120:324–336. doi:10.1037/0735-7044.120.2.324

    PubMed  Google Scholar 

  • Waddell J, Morris RW, Bouton ME (2006)b Effects of bed nucleus of the stria terminalis lesions on conditioned anxiety: aversive conditioning with long-duration conditional stimuli and reinstatement of extinguished fear. Behav Neurosci 120:324–336. doi:10.1037/0735-7044.120.2.324

    PubMed  Google Scholar 

  • Walker DL, Davis M (1997)a Anxiogenic effects of high illumination levels assessed with the acoustic startle paradigm. Biol Psychiatry 42:461–471. doi:10.1016/S0006-3223(96)00441-6

    PubMed  CAS  Google Scholar 

  • Walker DL, Davis M (1997)b Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in light-enhanced versus fear-potentiated startle. J Neurosci 17:9375–9383

    PubMed  CAS  Google Scholar 

  • Walker DL, Davis M (2002) Light enhanced startle: Further pharmacological and behavioral evaluation. Psychopharmacology (Berl) 159:304–310. doi:10.1007/s002130100913

    CAS  Google Scholar 

  • Walker DL, Toufexis DJ, Davis M (2003) Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 463:199–216. doi:10.1016/S0014-2999(03)01282-2

    PubMed  CAS  Google Scholar 

  • Watts AG, Sanchez-Watts G (1995) Region-specific regulation of neuropeptide mRNAs in rat limbic forebrain neurones by aldosterone and corticosterone. J Physiol 484(Pt 3):721–736

    PubMed  CAS  Google Scholar 

  • Weller KL, Smith DA (1982) Afferent connections to the bed nucleus of the stria terminalis. Brain Res 232:255–270. doi:10.1016/0006-8993(82)90272-4

    PubMed  CAS  Google Scholar 

  • Whim MD (1989) Frequency-dependent release of peptide cotransmitters from identified cholinergic motor neurons in Aplysia. Proc Natl Acad Sci USA 86:9034–9038. doi:10.1073/pnas.86.22.9034

    PubMed  CAS  Google Scholar 

  • Wray S, Hoffman GE (1983) Organization and interrelationship of neuropeptides in the central amygdaloid nucleus of the rat. Peptides 4:525–541. doi:10.1016/0196-9781(83)90059-1

    PubMed  CAS  Google Scholar 

  • Xu W, Lundeberg T, Wang YT, Li Y, Yu LC (2003) Antinociceptive effect of calcitonin gene-related peptide in the central nucleus of amygdala: activating opioid receptors through amygdala-periaqueductal gray pathway. Neuroscience 118:1015–1022. doi:10.1016/S0306-4522(03)00069-1

    PubMed  CAS  Google Scholar 

  • Yasui Y, Saper C, Cechetto D (1991) Calcitonin gene-related peptide (CGRP) immunoreactive projections from the thalamus to the striatum and amygdala in the rat. J Comp Neurol 308:293–310. doi:10.1002/cne.903080212

    PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by National Institute of Mental Health grants MH069056, MH47840, MH57250 and MH59906, and the Science and Technology Center (The Center for Behavioral Neuroscience of the National Science Foundation under Agreement No. IBN–9876754) and the Yerkes Base Grant. “Principles of laboratory animal care (NIH publication No. 86–23, revised 1985) were followed and all procedures were approved by the Emory IACUC.

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Walker, D.L., Davis, M. Role of the extended amygdala in short-duration versus sustained fear: a tribute to Dr. Lennart Heimer. Brain Struct Funct 213, 29–42 (2008). https://doi.org/10.1007/s00429-008-0183-3

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