Dopaminergic regulation of fear extinction learning

• Project/Area Number: 15H04264
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Johansen Joshua 国立研究開発法人理化学研究所, 脳科学総合研究センター, チームリーダー (80625351)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2015: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: Dopamine / Extinction / Fear / Prefrontal cortex / Basal Ganglia / dopamine / fear extinction / prediction error / reward / basal ganglia / Fear extinction / Nucleus Accumbens / fear / extinction learning

Outline of Final Research Achievements

We examined the contribution of the ventral tegmental area (VTA) dopamine system to fear extinction learning. During fear conditioning, animals learn that an auditory tone stimulus predicts the occurrence of an aversive event (shock) and animals exhibit fear behaviors to the tone following learning. If the tone is presented repeatedly in the absence of the aversive event fear responses are reduced through extinction. We found that optogenetic inhibition of VTA-dopamine neurons during the shock omission period of extinction blocked extinction learning as well as biochemical signatures of neural plasticity in the extinction learning system. Furthermore, we discovered that a specific population of dopamine neurons projecting to the nucleus accumbens were responsible for this effect. These results reveal an unappreciated role for the dopamine reward system in extinguishing fear memories and suggest novel treatment avenues for fear related psychiatric disorders.

Research Products

• [Journal Article] A dopaminergic switch for fear to safety transitions (2018)
  • Author(s): Luo, R., Uematsu, A., Weitemier, A., Aquili, L., Koivumaa, J., McHugh, T.J. and Johansen, J.P.
  • Journal Title: Nature Communications Volume: In press
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Learning rules for aversive associative memory formation (2018)
  • Author(s): Ozawa, T. & Johansen, J.P.
  • Journal Title: Current Opinion in Neurobiology Volume: 49 Pages: 148-157
  • DOI: 10.1016/j.conb.2018.02.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysregulation of aversive signaling pathways: a novel circuit endophenotype for pain and anxiety disorders (2017)
  • Author(s): Yeh, L.-F., Watanabe, M., Sulkes-Cuevas, J. Johansen, J.P.
  • Journal Title: Current Opinion in Neurobiology Volume: 48 Pages: 37-44
  • DOI: 10.1016/j.conb.2017.09.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Modular organization of the brainstem noradrenaline system coordinates opposing learning states (2017)
  • Author(s): Uematsu Akira、Tan Bao Zhen、Ycu Edgar A、Cuevas Jessica Sulkes、Koivumaa Jenny、Junyent Felix、Kremer Eric J、Witten Ilana B、Deisseroth Karl、Johansen Joshua P
  • Journal Title: Nature Neuroscience Volume: 20 Issue: 11 Pages: 1602-1611
  • DOI: 10.1038/nn.4642
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A feedback neural circuit for calibrating aversive memory strength (2017)
  • Author(s): Ozawa, T., Ycu, E.A., Kumar, A., Yeh. L-F., Ahmed, T., Koivumaa, J., and Johansen, J.P.
  • Journal Title: Nature Neuroscience Volume: 20(1) Issue: 1 Pages: 90-97
  • DOI: 10.1038/nn.4439
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] β-Adrenergic Receptors Regulate the Acquisition and Consolidation Phases of Aversive Memory Formation Through Distinct, Temporally Regulated Signaling Pathways (2017)
  • Author(s): Schiff, H.C., Johansen, J.P., Hou, M., Bush, D.E., Smith, E.K., Klein, J.E., LeDoux, J.E., Sears, R.M.
  • Journal Title: Neuropsychopharmacology Volume: 42(4) Issue: 4 Pages: 895-903
  • DOI: 10.1038/npp.2016.238
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evaluation of ambiguous associations in the amygdala by learning the structure of the environment. (2016)
  • Author(s): Madarasz, T.J., Diaz-Mataix, L., Akhand, O., Ycu, E.A., LeDoux, J.E., Johansen, J.P.
  • Journal Title: Nature Neuroscience Volume: In press Issue: 7 Pages: 965-972
  • DOI: 10.1038/nn.4308
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Alterations in the rostral ventromedial medulla after the selective ablation of mu-opioid receptor expressing neurons. (2016)
  • Author(s): Harasawa, I., Johansen, J.P., Fields, H.L., Porreca, F., Meng, I.D.
  • Journal Title: Pain Volume: 157(1) Issue: 1 Pages: 166-173
  • DOI: 10.1097/j.pain.0000000000000344
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Projection specificity in heterogeneous locus coeruleus cell populations: implications for learning and memory. (2015)
  • Author(s): Uematsu, A., Tan, B.Z., Johansen, J.P.
  • Journal Title: Learning & Memory Volume: 22 Issue: 9 Pages: 444-451
  • DOI: 10.1101/lm.037283.114
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Meta-organization in the locus coeruleus noradrenaline system coordinates emotional and flexible learning states (2016)
  • Author(s): Joshua Johansen
  • Organizer: Arrowhead 10 years on: What have we learned and what is there still to learn about the neural bases of decision-making?
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2016-12-11
  • Invited
• [Presentation] Multiplexed signaling across distinct noradrenaline cell populations coordinates opposing emotional learning functions (2016)
  • Author(s): Joshua Johansen
  • Organizer: Nature Conference on Neural Circuitry of Emotion
  • Place of Presentation: Shenzhen, China
  • Year and Date: 2016-11-02
  • Invited
• [Presentation] Functional specificity based on efferent connectivity in the locus coeruleus noradrenaline system (2016)
  • Author(s): Joshua Johansen
  • Organizer: Japan Neuroscience Society Meeting Symposium (Chaired)
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-07-20
  • Int'l Joint Research / Invited
• [Presentation] Regulation of fear & extinction learning through distinct neuromodulatory circuits (2016)
  • Author(s): Joshua Johansen
  • Organizer: Federation of European Neuroscience Societies Symposium (Chaired)
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2016-07-02
  • Int'l Joint Research / Invited
• [Presentation] Neural circuit mechanisms for triggering and reversing aversive memories (2016)
  • Author(s): Joshua Johansen
  • Organizer: Neural mechanisms of decision making: achievements and new directions
  • Place of Presentation: CiNet Bldg Conference room, Osaka, Japan
  • Year and Date: 2016-02-03
  • Invited
• [Presentation] A feedback neural circuit for calibrating memory strength (2015)
  • Author(s): Joshua Johansen
  • Organizer: International Symposium on Optogenetics (Tokyo, Japan)
  • Place of Presentation: Akio Suzuki Memorial Hall, Tokyo, Japan
  • Year and Date: 2015-12-05
  • Invited
• [Presentation] Functional and anatomical specificity in locus coeruleus noradrenaline neurons (2015)
  • Author(s): Joshua Johansen
  • Organizer: Gordon Conference: Amygdala in health and disease
  • Place of Presentation: Easton, USA
  • Year and Date: 2015-08-04
  • Int'l Joint Research / Invited