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PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction

Molecular Psychiatry volume 27, pages 896–906 (2022)Cite this article

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Abstract

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

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Fig. 1: Fear extinction induces low-PV plasticity in the IL cortex.
Fig. 2: Sustained low-PV plasticity in the IL cortex is required for fear extinction.
Fig. 3: PV network plasticity is sustained through NRG1-ErbB4 signalling.
Fig. 4: NRG1-ErBb4 signalling regulates fear extinction.
Fig. 5: NRG1 signalling regulates fear extinction by modulating PV network plasticity.
Fig. 6: BMA-projecting IL neuron activation depends on PV network configuration and contributes to fear extinction.

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References

  1. Parsons RG, Ressler KJ. Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci. 2013;16:146–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci. 2005;6:119–30.

    Article  CAS  PubMed  Google Scholar 

  3. Squire LR, Bayley PJ. The neuroscience of remote memory. Curr Opin Neurobiol. 2007;17:185–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Neves G, Cooke SF, Bliss TV. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci. 2008;9:65–75.

    Article  CAS  PubMed  Google Scholar 

  5. Martin SJ, Grimwood PD, Morris RG. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci. 2000;23:649–711.

    Article  CAS  PubMed  Google Scholar 

  6. Rudy B, Fishell G, Lee S, Hjerling-Leffler J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol. 2011;71:45–61.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hu H, Gan J, Jonas P. Interneurons. Fast-spiking, parvalbumin(+) GABAergic interneurons: from cellular design to microcircuit function. Science. 2014;345:1255263.

    Article  PubMed  CAS  Google Scholar 

  8. Stark E, Eichler R, Roux L, Fujisawa S, Rotstein HG, Buzsaki G. Inhibition-induced theta resonance in cortical circuits. Neuron. 2013;80:1263–76.

    Article  CAS  PubMed  Google Scholar 

  9. Fagiolini M, Fritschy JM, Low K, Mohler H, Rudolph U, Hensch TK. Specific GABAA circuits for visual cortical plasticity. Science. 2004;303:1681–3.

    Article  CAS  PubMed  Google Scholar 

  10. Yazaki-Sugiyama Y, Kang S, Cateau H, Fukai T, Hensch TK. Bidirectional plasticity in fast-spiking GABA circuits by visual experience. Nature. 2009;462:218–21.

    Article  CAS  PubMed  Google Scholar 

  11. Levelt CN, Hubener M. Critical-period plasticity in the visual cortex. Annu Rev Neurosci. 2012;35:309–30.

    Article  CAS  PubMed  Google Scholar 

  12. Caroni P. Regulation of parvalbumin basket cell plasticity in rule learning. Biochem Biophys Res Commun. 2015;460:100–3.

    Article  CAS  PubMed  Google Scholar 

  13. Sotres-Bayon F, Cain CK, LeDoux JE. Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex. Biol Psychiatry. 2006;60:329–36.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  15. Morgan MA, Romanski LM, LeDoux JE. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci Lett. 1993;163:109–13.

    Article  CAS  PubMed  Google Scholar 

  16. Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature. 2002;420:70–4.

    Article  CAS  PubMed  Google Scholar 

  17. Do-Monte FH, Manzano-Nieves G, Quinones-Laracuente K, Ramos-Medina L, Quirk GJ. Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J Neurosci. 2015;35:3607–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Adhikari A, Lerner TN, Finkelstein J, Pak S, Jennings JH, Davidson TJ, et al. Basomedial amygdala mediates top-down control of anxiety and fear. Nature. 2015;527:179–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Induction of fear extinction with hippocampal-infralimbic BDNF. Science. 2010;328:1288–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bukalo O, Pinard CR, Silverstein S, Brehm C, Hartley ND, Whittle N, et al. Prefrontal inputs to the amygdala instruct fear extinction memory formation. Sci Adv. 2015;1:e1500251.

  21. Cho JH, Deisseroth K, Bolshakov VY. Synaptic encoding of fear extinction in mPFC-amygdala circuits. Neuron. 2013;80:1491–507.

    Article  CAS  PubMed  Google Scholar 

  22. Sananbenesi F, Fischer A, Wang X, Schrick C, Neve R, Radulovic J, et al. A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat Neurosci. 2007;10:1012–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Myers KM, Davis M. Mechanisms of fear extinction. Mol Psychiatry. 2007;12:120–50.

    Article  CAS  PubMed  Google Scholar 

  24. Karunakaran S, Chowdhury A, Donato F, Quairiaux C, Michel CM, Caroni P. PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation. Nat Neurosci. 2016;19:454–64.

    Article  CAS  PubMed  Google Scholar 

  25. Chattopadhyaya B, Di Cristo G, Wu CZ, Knott G, Kuhlman S, Fu Y, et al. GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron. 2007;54:889–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. DeNardo LA, Liu CD, Allen WE, Adams EL, Friedmann D, Fu L, et al. Temporal evolution of cortical ensembles promoting remote memory retrieval. Nat Neurosci. 2019;22:460–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tasic B, Menon V, Nguyen TN, Kim TK, Jarsky T, Yao Z, et al. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci. 2016;19:335–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci USA. 2007;104:5163–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, Forsayeth JR, et al. Engineering GPCR signaling pathways with RASSLs. Nat Methods. 2008;5:673–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pei Y, Rogan SC, Yan F, Roth BL. Engineered GPCRs as tools to modulate signal transduction. Physiology. 2008;23:313–21.

    Article  CAS  PubMed  Google Scholar 

  31. Donato F, Chowdhury A, Lahr M, Caroni P. Early- and late-born parvalbumin basket cell subpopulations exhibiting distinct regulation and roles in learning. Neuron. 2015;85:770–86.

    Article  CAS  PubMed  Google Scholar 

  32. Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008;9:437–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen YH, Lan YJ, Zhang SR, Li WP, Luo ZY, Lin S, et al. ErbB4 signaling in the prelimbic cortex regulates fear expression. Transl Psychiatry. 2017;7:e1168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wen L, Lu YS, Zhu XH, Li XM, Woo RS, Chen YJ, et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA. 2010;107:1211–6.

    Article  CAS  PubMed  Google Scholar 

  35. Fazzari P, Paternain AV, Valiente M, Pla R, Lujan R, Lloyd K, et al. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature. 2010;464:1376–80.

    Article  CAS  PubMed  Google Scholar 

  36. Neddens J, Buonanno A. Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice. Hippocampus. 2010;20:724–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen YJ, Zhang M, Yin DM, Wen L, Ting A, Wang P, et al. ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc Natl Acad Sci USA. 2010;107:21818–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen Y-H, Wu J-L, Hu N-Y, Zhuang J-P, Li W-P, Zhang S-R, et al. Distinct projections from the infralimbic cortex exert opposing effects in modulating anxiety and fear. J Clin Invest. 2021;131:e145692.

  39. Kandel ER, Dudai Y, Mayford MR. The molecular and systems biology of memory. Cell. 2014;157:163–86.

    Article  CAS  PubMed  Google Scholar 

  40. Huang ZJ, Paul A. The diversity of GABAergic neurons and neural communication elements. Nat Rev Neurosci. 2019;20:563–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Trimble WS, Cowan DM, Scheller RH. VAMP-1: a synaptic vesicle-associated integral membrane protein. Proc Natl Acad Sci USA. 1988;85:4538–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wada Y, Kitamoto K, Kanbe T, Tanaka K, Anraku Y. The SLP1 gene of Saccharomyces cerevisiae is essential for vacuolar morphogenesis and function. Mol Cell Biol. 1990;10:2214–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Robinson JS, Klionsky DJ, Banta LM, Emr SD. Protein sorting in Saccharomyces cerevisiae: isolation of mutants defective in the delivery and processing of multiple vacuolar hydrolases. Mol Cell Biol. 1988;8:4936–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Halachmi N, Lev Z. The Sec1 family: a novel family of proteins involved in synaptic transmission and general secretion. J Neurochem. 1996;66:889–97.

    Article  CAS  PubMed  Google Scholar 

  45. Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O’Leary OF, et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science. 2008;320:385–8.

    Article  CAS  PubMed  Google Scholar 

  46. Dehorter N, Ciceri G, Bartolini G, Lim L, del Pino I, Marin O. Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch. Science. 2015;349:1216–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Donato F, Rompani SB, Caroni P. Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature. 2013;504:272–6.

    Article  CAS  PubMed  Google Scholar 

  48. Eilam R, Pinkas-Kramarski R, Ratzkin BJ, Segal M, Yarden Y. Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain. Proc Natl Acad Sci USA. 1998;95:1888–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ozaki M, Itoh K, Miyakawa Y, Kishida H, Hashikawa T. Protein processing and releases of neuregulin-1 are regulated in an activity-dependent manner. J Neurochem. 2004;91:176–88.

    Article  CAS  PubMed  Google Scholar 

  50. Tan GH, Liu YY, Hu XL, Yin DM, Mei L, Xiong ZQ. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci. 2011;15:258–66.

    Article  PubMed  CAS  Google Scholar 

  51. Liu X, Bates R, Yin DM, Shen C, Wang F, Su N, et al. Specific regulation of NRG1 isoform expression by neuronal activity. J Neurosci. 2011;31:8491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ikawa D, Makinodan M, Iwata K, Ohgidani M, Kato TA, Yamashita Y, et al. Microglia-derived neuregulin expression in psychiatric disorders. Brain Behav Immun. 2017;61:375–85.

    Article  CAS  PubMed  Google Scholar 

  53. Pankonin MS, Sohi J, Kamholz J, Loeb JA. Differential distribution of neuregulin in human brain and spinal fluid. Brain Res. 2009;1258:1–11.

    Article  CAS  PubMed  Google Scholar 

  54. Woo RS, Li XM, Tao Y, Carpenter-Hyland E, Huang YZ, Weber J, et al. Neuregulin-1 enhances depolarization-induced GABA release. Neuron. 2007;54:599–610.

    Article  CAS  PubMed  Google Scholar 

  55. Chen MS, Bermingham-McDonogh O, Danehy FT Jr, Nolan C, Scherer SS, Lucas J, et al. Expression of multiple neuregulin transcripts in postnatal rat brains. J Comp Neurol. 1994;349:389–400.

    Article  CAS  PubMed  Google Scholar 

  56. Law AJ, Shannon Weickert C, Hyde TM, Kleinman JE, Harrison PJ. Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. Neuroscience. 2004;127:125–36.

    Article  CAS  PubMed  Google Scholar 

  57. Ahrlund-Richter S, Xuan Y, van Lunteren JA, Kim H, Ortiz C, Pollak Dorocic I, et al. A whole-brain atlas of monosynaptic input targeting four different cell types in the medial prefrontal cortex of the mouse. Nat Neurosci. 2019;22:657–68.

    Article  PubMed  CAS  Google Scholar 

  58. Sun Q, Li X, Ren M, Zhao M, Zhong Q, Ren Y, et al. A whole-brain map of long-range inputs to GABAergic interneurons in the mouse medial prefrontal cortex. Nat Neurosci. 2019;22:1357–70.

    Article  CAS  PubMed  Google Scholar 

  59. Burgos-Robles A, Kimchi EY, Izadmehr EM, Porzenheim MJ, Ramos-Guasp WA, Nieh EH, et al. Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment. Nat Neurosci. 2017;20:824–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Marek R, Jin J, Goode TD, Giustino TF, Wang Q, Acca GM, et al. Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. Nat Neurosci. 2018;21:384–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Klavir O, Prigge M, Sarel A, Paz R, Yizhar O. Manipulating fear associations via optogenetic modulation of amygdala inputs to prefrontal cortex. Nat Neurosci. 2017;20:836–44.

    Article  CAS  PubMed  Google Scholar 

  62. Lu Y, Sun XD, Hou FQ, Bi LL, Yin DM, Liu F, et al. Maintenance of GABAergic activity by neuregulin 1-ErbB4 in amygdala for fear memory. Neuron. 2014;84:835–46.

    Article  CAS  PubMed  Google Scholar 

  63. Dejean C, Courtin J, Rozeske RR, Bonnet MC, Dousset V, Michelet T, et al. Neuronal circuits for fear expression and recovery: recent advances and potential therapeutic strategies. Biol Psychiatry. 2015;78:298–306.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Shuji Li, Yingying Fang and Ting Guo (Southern Medical University) for technological support. This work was supported by grants from the National Natural Science Foundation of China (grant numbers 82090032 and 31830033 to T.-M.G. and grant numbers 31801007 and 81881240049 to Y-HC), the Program for Changjiang Scholars and Innovative Research Team in University (grant number IRT_16R37 to T-MG), the Key-Area Research and Development Program of Guangdong Province (grant number 2018B030334001 to T-MG), the Guangdong Basic and Applied Basic Research Foundation (grant number 2020A1515011310 to Y-HC), the Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence Fund (grant number 2019019 to Y-HC), the Science and Technology Program of Guangzhou (grant number 202007030013, to T-MG) and the China Postdoctoral Science Foundation Grant (grant number 2020m682786 to N-YH).

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  1. These authors contributed equally: Yi-Hua Chen, Neng-Yuan Hu.

Authors and Affiliations

  1. State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Yi-Hua Chen, Neng-Yuan Hu, Ding-Yu Wu, Lin-Lin Bi, Zheng-Yi Luo, Lang Huang, Jian-Lin Wu, Meng-Ling Wang, Jing-Ting Li, Yun-Long Song, Sheng-Rong Zhang, Wei Jie, Xiao-Wen Li, Jian-Ming Yang & Tian-Ming Gao

  2. Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510515, China

    Yi-Hua Chen & Shi-Zhong Zhang

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Contributions

T-MG and Y-HC designed the study. Y-HC and N-YH performed all experiments, except electrophysiological recordings with the help of D-YW, J-LW, L-LB, M-LW, J-TL, S-RZ and Y-LS. Z-YL and LH performed all electrophysiological recordings and analysed the electrophysiological data. Y-HC analysed all other data and generated the figures. X-WL provided technical support. T-MG and Y-HC interpreted the results with critical input from J-MY and S-ZZ. T-MG and Y-HC wrote the manuscript.

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Correspondence to Tian-Ming Gao.

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Chen, YH., Hu, NY., Wu, DY. et al. PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction. Mol Psychiatry 27, 896–906 (2022). https://doi.org/10.1038/s41380-021-01355-z

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