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Panic results in unique molecular and network changes in the amygdala that facilitate fear responses

Molecular Psychiatry volume 25, pages 442–460 (2020)Cite this article

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Abstract

Recurrent panic attacks (PAs) are a common feature of panic disorder (PD) and post-traumatic stress disorder (PTSD). Several distinct brain regions are involved in the regulation of panic responses, such as perifornical hypothalamus (PeF), periaqueductal gray, amygdala and frontal cortex. We have previously shown that inhibition of GABA synthesis in the PeF produces panic-vulnerable rats. Here, we investigate the mechanisms by which a panic-vulnerable state could lead to persistent fear. We first show that optogenetic activation of glutamatergic terminals from the PeF to the basolateral amygdala (BLA) enhanced the acquisition, delayed the extinction and induced the persistence of fear responses 3 weeks later, confirming a functional PeF-amygdala pathway involved in fear learning. Similar to optogenetic activation of PeF, panic-prone rats also exhibited delayed extinction. Next, we demonstrate that panic-prone rats had altered inhibitory and enhanced excitatory synaptic transmission of the principal neurons, and reduced protein levels of metabotropic glutamate type 2 receptor (mGluR2) in the BLA. Application of an mGluR2-positive allosteric modulator (PAM) reduced glutamate neurotransmission in the BLA slices from panic-prone rats. Treating panic-prone rats with mGluR2 PAM blocked sodium lactate (NaLac)-induced panic responses and normalized fear extinction deficits. Finally, in a subset of patients with comorbid PD, treatment with mGluR2 PAM resulted in complete remission of panic symptoms. These data demonstrate that a panic-prone state leads to specific reduction in mGluR2 function within the amygdala network and facilitates fear, and mGluR2 PAMs could be a targeted treatment for panic symptoms in PD and PTSD patients.

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References

  1. Stein DJ, Bouwer C. A neuro-evolutionary approach to the anxiety disorders. J Anxiety Disord. 1997;11:409–29.

    CAS  PubMed  Google Scholar 

  2. DSM-V. Diagnostic and Statistical Manual—Fifth Edn. (DSM-V). Washington, DC: American Psychiatric Association; 2013.

    Google Scholar 

  3. Rasche D, Foethke D, Gliemroth J, Tronnier VM. [Deep brain stimulation in the posterior hypothalamus for chronic cluster headache. Case report and review of the literature]. Schmerz. 2006;20:439–44.

    CAS  PubMed  Google Scholar 

  4. Wilent WB, Oh MY, Buetefisch C, Bailes JE, Cantella D, Angle C, et al. Mapping of microstimulation evoked responses and unit activity patterns in the lateral hypothalamic area recorded in awake humans. Technical note. J Neurosurg. 2011;115:295–300.

    PubMed  Google Scholar 

  5. Wilent WB, Oh MY, Buetefisch CM, Bailes JE, Cantella D, Angle C, et al. Induction of panic attack by stimulation of the ventromedial hypothalamus. J Neurosurg. 2010;112:1295–8.

    PubMed  Google Scholar 

  6. Anderson JJ, DiMicco JA. Effect of local inhibition of gamma-aminobutyric acid uptake in the dorsomedial hypothalamus on extracellular levels of gamma-aminobutyric acid and on stress-induced tachycardia: a study using microdialysis. J Pharmacol Exp Ther. 1990;255:1399–407.

    CAS  PubMed  Google Scholar 

  7. Samuels BC, Zaretsky DV, DiMicco JA. Tachycardia evoked by disinhibition of the dorsomedial hypothalamus in rats is mediated through medullary raphe. J Physiol. 2002;538:941–6. Pt 3

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Shekhar A, DiMicco JA. Defense reaction elicited by injection of GABA antagonists and synthesis inhibitors into the posterior hypothalamus in rats. Neuropharmacology. 1987;26:407–17.

    CAS  PubMed  Google Scholar 

  9. Shekhar A, Hingtgen JN, DiMicco JA. GABA receptors in the posterior hypothalamus regulate experimental anxiety in rats. Brain Res. 1990;512:81–88.

    CAS  PubMed  Google Scholar 

  10. Soltis RP, DiMicco JA, Hypothalamic excitatory amino acid receptors mediate stress-induced tachycardia in rats. Am J Physiol. 1992;262(4 Pt 2):R689–R697.

    CAS  PubMed  Google Scholar 

  11. Johnson PL, Shekhar A. Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors. J Neurosci. 2006;26:7093–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Shekhar A, Keim SR. The circumventricular organs form a potential neural pathway for lactate sensitivity: implications for panic disorder. J Neurosci. 1997;17:9726–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Shekhar A, Keim SR, Simon JR, McBride WJ. Dorsomedial hypothalamic GABA dysfunction produces physiological arousal following sodium lactate infusions. Pharmacol Biochem Behav. 1996;55:249–56.

    CAS  PubMed  Google Scholar 

  14. Johnson PL, Shekhar A. An animal model of panic vulnerability with chronic disinhibition of the dorsomedial/perifornical hypothalamus. Physiol Behav. 2012;107:686–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gorman JM, Papp LA, Coplan JD, Martinez JM, Lennon S, Goetz RR, et al. Anxiogenic effects of CO2 and hyperventilation in patients with panic disorder. Am J Psychiatry. 1994;151:547–53.

    CAS  PubMed  Google Scholar 

  16. Pitts FN Jr., McClure JN Jr. Lactate metabolism in anxiety neurosis. N Engl J Med. 1967;277:1329–36.

    PubMed  Google Scholar 

  17. Woods SW, Charney DS, Goodman WK, Heninger GR. Carbon dioxide-induced anxiety. Behavioral, physiologic, and biochemical effects of carbon dioxide in patients with panic disorders and healthy subjects. Arch Gen Psychiatry. 1988;45:43–52.

    CAS  PubMed  Google Scholar 

  18. Mineka S, Zinbarg R. A contemporary learning theory perspective on the etiology of anxiety disorders: it’s not what you thought it was. Am Psychol. 2006;61:10–26.

    PubMed  Google Scholar 

  19. Asselmann E, Pane-Farre C, Isensee B, Wittchen HU, Lieb R, Hofler M, et al. Characteristics of initial fearful spells and their associations with DSM-IV panic attacks and panic disorder in adolescents and young adults from the community. J Affect Disord. 2014;165:95–102.

    PubMed  Google Scholar 

  20. Bryant RA, Brooks R, Silove D, Creamer M, O’Donnell M, McFarlane AC. Peritraumatic dissociation mediates the relationship between acute panic and chronic posttraumatic stress disorder. Behav Res Ther. 2011;49:346–51.

    PubMed  Google Scholar 

  21. Fikretoglu D, Brunet A, Best SR, Metzler TJ, Delucchi K, Weiss DS, et al. Peritraumatic fear, helplessness and horror and peritraumatic dissociation: do physical and cognitive symptoms of panic mediate the relationship between the two? Behav Res Ther. 2007;45:39–47.

    PubMed  Google Scholar 

  22. Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology. 2008;33:56–72.

    PubMed  Google Scholar 

  23. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18:9996–10015.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Johnson PL, Truitt WA, Fitz SD, Lowry CA, Shekhar A. Neural pathways underlying lactate-induced panic. Neuropsychopharmacology. 2008;33:2093–107.

    CAS  PubMed  Google Scholar 

  25. Schmitt O, Usunoff KG, Lazarov NE, Itzev DE, Eipert P, Rolfs A, et al. Orexinergic innervation of the extended amygdala and basal ganglia in the rat. Brain Struct Funct. 2012;217:233–56.

    CAS  PubMed  Google Scholar 

  26. Myers B, Mark Dolgas C, Kasckow J, Cullinan WE, Herman JP. Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. Brain Struct Funct. 2014;219:1287–303.

    CAS  PubMed  Google Scholar 

  27. Shekhar A, Johnson PL, Sajdyk TJ, Fitz SD, Keim SR, Kelley PE, et al. Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus. J Neurosci. 2006;26:9205–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Monfils MH, Cowansage KK, Klann E, LeDoux JE. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science. 2009;324:951–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Karpova NN, Pickenhagen A, Lindholm J, Tiraboschi E, Kulesskaya N, Agustsdottir A, et al. Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science. 2011;334:1731–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao S, Ting JT, Atallah HE, Qiu L, Tan J, Gloss B, et al. Cell type-specific channelrhodopsin-2 transgenic mice for optogenetic dissection of neural circuitry function. Nat Methods. 2011;8:745–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Molosh AI, Sajdyk TJ, Truitt WA, Zhu W, Oxford GS, Shekhar A. NPY Y1 receptors differentially modulate GABAA and NMDA receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons. Neuropsychopharmacology. 2013;38:1352–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Paxinos G, Watson C . The rat brain in stereotaxic coordinates.5th ed. San Diego: Elsevier Academic Press; 2005. P.

    Google Scholar 

  33. Truitt WA, Hauser SR, Deehan GA Jr, Toalston JE, Wilden JA, Bell RL, et al. Ethanol and nicotine interaction within the posterior ventral tegmental area in male and female alcohol-preferring rats: evidence of synergy and differential gene activation in the nucleus accumbens shell. Psychopharmacology (Berlin). 2015;232:639–49.

    CAS  Google Scholar 

  34. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034.

    PubMed  PubMed Central  Google Scholar 

  35. File SE. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods. 1980;2:219–38.

    CAS  PubMed  Google Scholar 

  36. Sanders SK, Shekhar A. Regulation of anxiety by GABAA receptors in the rat amygdala. Pharmacol Biochem Behav. 1995;52:701–6.

    CAS  PubMed  Google Scholar 

  37. Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, et al. A key role for orexin in panic anxiety. Nat Med. 2010;16:111–5.

    CAS  PubMed  Google Scholar 

  38. Lightowler S, Kennett GA, Williamson IJ, Blackburn TP, Tulloch IF. Anxiolytic-like effect of paroxetine in a rat social interaction test. Pharmacol Biochem Behav. 1994;49:281–5.

    CAS  PubMed  Google Scholar 

  39. Metcalf CS, Klein BD, Smith MD, Pruess T, Ceusters M, Lavreysen H, et al. Efficacy of mGlu2-positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures. Epilepsia. 2017;58:484–93.

    CAS  PubMed  Google Scholar 

  40. Cid JM, Tresadern G, Duvey G, Lutjens R, Finn T, Rocher JP, et al. Discovery of 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1 H)-pyridone (JNJ-40411813): a novel positive allosteric modulator of the metabotropic glutamate 2 receptor. J Med Chem. 2014;57:6495–512.

    CAS  PubMed  Google Scholar 

  41. Lavreysen H, Langlois X, Donck LV, Nunez JM, Pype S, Lutjens R, et al. Preclinical evaluation of the antipsychotic potential of the mGlu2-positive allosteric modulator JNJ-40411813. Pharmacol Res Perspect. 2015;3:e00097.

    PubMed  PubMed Central  Google Scholar 

  42. Lavreysen H, Ahnaou A, Drinkenburg W, Langlois X, Mackie C, Pype S, et al. Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor. Pharmacol Res Perspect. 2015;3:e00096.

    PubMed  Google Scholar 

  43. Cid JM, Tresadern G, Vega JA, de Lucas AI, Matesanz E, Iturrino L, et al. Discovery of 3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605): a positive allosteric modulator of the metabotropic glutamate 2 receptor. J Med Chem. 2012;55:8770–89.

    CAS  PubMed  Google Scholar 

  44. Kent JM, Daly E, Kezic I, Lane R, Lim P, De Smedt H, et al. Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression. Prog Neuropsychopharmacol Biol Psychiatry. 2016;67:66–73.

    CAS  PubMed  Google Scholar 

  45. Johnson PL, Fitz SD, Engleman EA, Svensson KA, Schkeryantz JM, Shekhar A. Group II metabotropic glutamate receptor type 2 allosteric potentiators prevent sodium lactate-induced panic-like response in panic-vulnerable rats. J Psychopharmacol. 2013;27:152–61.

    CAS  PubMed  Google Scholar 

  46. Johnson PL, Federici LM, Fitz SD, Renger JJ, Shireman B, Winrow CJ, et al. Orexin 1 and 2 receptor involvement in Co2-induced panic-associated behavior and autonomic responses. Depress Anxiety. 2015;32:671–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Washburn MS, Moises HC. Electrophysiological and morphological properties of rat basolateral amygdaloid neurons in vitro. J Neurosci. 1992;12:4066–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Abel HJ, Lee JC, Callaway JC, Foehring RC. Relationships between intracellular calcium and afterhyperpolarizations in neocortical pyramidal neurons. J Neurophysiol. 2004;91:324–35.

    CAS  PubMed  Google Scholar 

  49. Blechert J, Michael T, Vriends N, Margraf J, Wilhelm FH. Fear conditioning in posttraumatic stress disorder: evidence for delayed extinction of autonomic, experiential, and behavioural responses. Behav Res Ther. 2007;45:2019–33.

    PubMed  Google Scholar 

  50. Wessa M, Flor H. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from second-order conditioning. Am J Psychiatry. 2007;164:1684–92.

    PubMed  Google Scholar 

  51. Garfinkel SN, Abelson JL, King AP, Sripada RK, Wang X, Gaines LM, et al. Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal. J Neurosci. 2014;34:13435–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Michael T, Blechert J, Vriends N, Margraf J, Wilhelm FH. Fear conditioning in panic disorder: enhanced resistance to extinction. J Abnorm Psychol. 2007;116:612–7.

    PubMed  Google Scholar 

  53. Jovanovic T, Kazama A, Bachevalier J, Davis M. Impaired safety signal learning may be a biomarker of PTSD. Neuropharmacology. 2012;62:695–704.

    CAS  PubMed  Google Scholar 

  54. Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ. LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress (Amst, Neth). 2003;6:189–97.

    CAS  Google Scholar 

  55. Molosh AI, Johnson PL, Fitz SD, Dimicco JA, Herman JP, Shekhar A. Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder. Neuropsychopharmacology. 2010;35:1333–47.

    PubMed  PubMed Central  Google Scholar 

  56. Flores A, Valls-Comamala V, Costa G, Saravia R, Maldonado R, Berrendero F. The hypocretin/orexin system mediates the extinction of fear memories. Neuropsychopharmacology. 2014;39:2732–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sears RM, Fink AE, Wigestrand MB, Farb CR, de Lecea L, Ledoux JE. Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc Natl Acad Sci USA. 2013;110:20260–5.

    CAS  PubMed  Google Scholar 

  58. Liu M, Fitzgibbon M, Wang Y, Reilly J, Qian X, O’Brien T, et al. Ulk4 regulates GABAergic signaling and anxiety-related behavior. Transl Psychiatry. 2018;8:43.

    PubMed  PubMed Central  Google Scholar 

  59. Prager EM, Pidoplichko VI, Aroniadou-Anderjaska V, Apland JP, Braga MF. Pathophysiological mechanisms underlying increased anxiety after soman exposure: reduced GABAergic inhibition in the basolateral amygdala. Neurotoxicology. 2014;44:335–43.

    CAS  PubMed  Google Scholar 

  60. Almeida-Suhett CP, Prager EM, Pidoplichko V, Figueiredo TH, Marini AM, Li Z, et al. Reduced GABAergic inhibition in the basolateral amygdala and the development of anxiety-like behaviors after mild traumatic brain injury. PLoS ONE. 2014;9:e102627.

    PubMed  PubMed Central  Google Scholar 

  61. Prager EM, Bergstrom HC, Wynn GH, Braga MF. The basolateral amygdala gamma-aminobutyric acidergic system in health and disease. J Neurosci Res. 2016;94:548–67.

    CAS  PubMed  Google Scholar 

  62. Liu ZP, Song C, Wang M, He Y, Xu XB, Pan HQ, et al. Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents. Mol Brain. 2014;7:32.

    PubMed  PubMed Central  Google Scholar 

  63. Gu G, Lorrain DS, Wei H, Cole RL, Zhang X, Daggett LP, et al. Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: implication in emotional responses and central disinhibition. Brain Res. 2008;1197:47–62.

    CAS  PubMed  Google Scholar 

  64. Felix-Ortiz AC, Burgos-Robles A, Bhagat ND, Leppla CA, Tye KM. Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex. Neuroscience. 2016;321:197–209.

    CAS  PubMed  Google Scholar 

  65. Neugebauer V, Zinebi F, Russell R, Gallagher JP, Shinnick-Gallagher P. Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala. J Neurophysiol. 2000;84:759–70.

    CAS  PubMed  Google Scholar 

  66. Hetzel A, Rosenkranz JA. Distinct effects of repeated restraint stress on basolateral amygdala neuronal membrane properties in resilient adolescent and adult rats. Neuropsychopharmacology. 2014;39:2114–30.

    PubMed  PubMed Central  Google Scholar 

  67. Rosenkranz JA, Venheim ER, Padival M. Chronic stress causes amygdala hyperexcitability in rodents. Biol Psychiatry. 2010;67:1128–36.

    PubMed  PubMed Central  Google Scholar 

  68. Rau AR, Chappell AM, Butler TR, Ariwodola OJ, Weiner JL. Increased basolateral amygdala pyramidal cell excitability may contribute to the anxiogenic phenotype induced by chronic early-life stress. J Neurosci. 2015;35:9730–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Park K, Lee S, Kang SJ, Choi S, Shin KS. Hyperpolarization-activated currents control the excitability of principal neurons in the basolateral amygdala. Biochem Biophys Res Commun. 2007;361:718–24.

    CAS  PubMed  Google Scholar 

  70. Park K, Yi JH, Kim H, Choi K, Kang SJ, Shin KS. HCN channel activity-dependent modulation of inhibitory synaptic transmission in the rat basolateral amygdala. Biochem Biophys Res Commun. 2011;404:952–7.

    CAS  PubMed  Google Scholar 

  71. Zhang S, You Z, Wang S, Yang J, Yang L, Sun Y, et al. Neuropeptide S modulates the amygdaloidal HCN activities (Ih) in rats: Implication in chronic pain. Neuropharmacology. 2016;105:420–33.

    CAS  PubMed  Google Scholar 

  72. Duvarci S, Pare D. Glucocorticoids enhance the excitability of principal basolateral amygdala neurons. J Neurosci. 2007;27:4482–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Noyes R Jr., Crowe RR, Harris EL, Hamra BJ, McChesney CM, Chaudhry DR. Relationship between panic disorder and agoraphobia. A family study. Arch Gen Psychiatry. 1986;4:227–32.

    Google Scholar 

  74. Yates WR. Phenomenology and epidemiology of panic disorder. Ann Clin Psychiatry. 2009;21:95–102.

    PubMed  Google Scholar 

  75. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters EE. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2006;63:415–24.

    PubMed  PubMed Central  Google Scholar 

  76. Rauch SL, Shin LM, Wright CI. Neuroimaging studies of amygdala function in anxiety disorders. Ann NY Acad Sci. 2003;985:389–410.

    PubMed  Google Scholar 

  77. Gorman JM, New molecular targets for antianxiety interventions. J Clin Psychiatry. 2003;64(Supple 3):28–35.

    CAS  PubMed  Google Scholar 

  78. Shekhar A, Keim SR. LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats. Neuropharmacology. 2000;39:1139–46.

    CAS  PubMed  Google Scholar 

  79. Ahnaou A, de Boer P, Lavreysen H, Huysmans H, Sinha V, Raeymaekers L, et al. Translational neurophysiological markers for activity of the metabotropic glutamate receptor (mGluR2) modulator JNJ-40411813: sleep EEG correlates in rodents and healthy men. Neuropharmacology. 2016;103:290–305.

    CAS  PubMed  Google Scholar 

  80. Salih H, Anghelescu I, Kezic I, Sinha V, Hoeben E, Van Nueten L, et al. Pharmacokinetic and pharmacodynamic characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomised, double-blind phase-I studies. J Psychopharmacol. 2015;29:414–25.

    CAS  PubMed  Google Scholar 

  81. Shear MK, Rucci P, Williams J, Frank E, Grochocinski V, Vander Bilt J, et al. Reliability and validity of the Panic Disorder Severity Scale: replication and extension. J Psychiatr Res. 2001;35:293–6.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIMH R01s MH052619, MH065702, and NCATS UL1 TR001108 to AS. The study was also supported by Janssen Pharmaceuticals Inc. and PLJ was supported by K01 AG044466. The authors would like to thank ADDEX Therapeutics for their involvement in the development of JNJ-40411813.

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  1. These authors contributed equally to the study conception: P. L. Johnson, A. Shekhar

Authors and Affiliations

  1. Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    A. I. Molosh, E. T. Dustrude, J. L. Lukkes, S. D. Fitz, A. R. R. Abreu & A . Shekhar

  2. Paul and Carol Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

    A. I. Molosh, W. A. Truitt, P. L. Johnson & A . Shekhar

  3. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    I. F. Caliman, A. D. Dietrich, W. A. Truitt & P. L. Johnson

  4. Janssen Research & Development, Beerse, Belgium

    L. Ver Donck & M. Ceusters

  5. Janssen Research & Development, LLC, Titusville, NJ, USA

    J. M. Kent

  6. Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, IN, USA

    A . Shekhar

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Drs. L Ver Donck, M Ceusters, and JM Kent are employees of Janssen. This work was supported by research grants to Indiana University with (Drs. Shekhar, Molosh and Johnson as PIs) from Janssen, but these authors have no other commercial conflicts.

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Molosh, A.I., Dustrude, E.T., Lukkes, J.L. et al. Panic results in unique molecular and network changes in the amygdala that facilitate fear responses. Mol Psychiatry 25, 442–460 (2020). https://doi.org/10.1038/s41380-018-0119-0

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