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The paraventricular thalamus controls a central amygdala fear circuit

Nature volume 519, pages 455459 (26 March 2015) | Download Citation


Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors1,2,3. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression4,5. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM+) CeL neurons, which has previously been shown to store fear memory6. Consistently, we found that PVT neurons preferentially innervate SOM+ neurons in the CeL, and stimulation of PVT afferents facilitated SOM+ neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression5,6. Notably, PVT modulation of SOM+ CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM+ CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT–CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.

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  1. 1.

    , & Thalamic paraventricular nucleus lesions facilitate central amygdala neuronal responses to acute psychological stress. Brain Res. 997, 234–237 (2004)

  2. 2.

    , & 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 (1991)

  3. 3.

    , , , & Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64, 477–505 (1995)

  4. 4.

    , , & Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. J. Neurosci. 26, 12387–12396 (2006)

  5. 5.

    et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468, 277–282 (2010)

  6. 6.

    et al. Experience-dependent modification of a central amygdala fear circuit. Nature Neurosci. 16, 332–339 (2013)

  7. 7.

    & Parabrachial nucleus projections to midline and intralaminar thalamic nuclei of the rat. J. Comp. Neurol. 428, 475–494 (2000)

  8. 8.

    et al. A cholecystokinin-mediated pathway to the paraventricular thalamus is recruited in chronically stressed rats and regulates hypothalamic-pituitary-adrenal function. J. Neurosci. 20, 5564–5573 (2000)

  9. 9.

    & Projections from the paraventricular nucleus of the thalamus to the forebrain, with special emphasis on the extended amygdala. J. Comp. Neurol. 506, 263–287 (2008)

  10. 10.

    & Projections of the paraventricular and paratenial nuclei of the dorsal midline thalamus in the rat. J. Comp. Neurol. 508, 212–237 (2008)

  11. 11.

    , , , & 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 104, 5163–5168 (2007)

  12. 12.

    & Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors. Proc. Natl Acad. Sci. USA 106, 14664–14669 (2009)

  13. 13.

    , & A temporal shift in the circuits mediating retrieval of fear memory. Nature (this issue)

  14. 14.

    et al. Cell-type-based analysis of microRNA profiles in the mouse brain. Neuron 73, 35–48 (2012)

  15. 15.

    et al. Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468, 270–276 (2010)

  16. 16.

    et al. Cortical representations of olfactory input by trans-synaptic tracing. Nature 472, 191–196 (2011)

  17. 17.

    et al. Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins. Nature Methods 9, 159–172 (2011)

  18. 18.

    & Neurotrophin regulation of neural circuit development and function. Nature Rev. Neurosci. 14, 7–23 (2013)

  19. 19.

    , , , & Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J. Neurosci. 17, 2295–2313 (1997)

  20. 20.

    et al. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron 43, 31–42 (2004)

  21. 21.

    et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nature Methods 11, 763–772 (2014)

  22. 22.

    et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15, 1748–1757 (2001)

  23. 23.

    , , , & Orexin, stress, and anxiety/panic states. Prog. Brain Res. 198, 133–161 (2012)

  24. 24.

    et al. Changes in emotional behavior produced by orexin microinjections in the paraventricular nucleus of the thalamus. Pharmacol. Biochem. Behav. 95, 121–128 (2010)

  25. 25.

    et al. PTSD risk is associated with BDNF Val66Met and BDNF overexpression. Mol. Psychiatry 19, 8–10 (2014)

  26. 26.

    & Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci. 35, 24–35 (2012)

  27. 27.

    et al. Visualizing the distribution of synapses from individual neurons in the mouse brain. PLoS ONE 5, e11503 (2010)

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We thank E. Nestler for providing us with the Trkblox/lox mice generated by L.F.P., K. Deisseroth for the AAV-Ef1a-fDIO backbone, E. Valjent for supporting D.D.B.’s work, and members of the Li laboratory for discussions. This work was supported by grants from the National Institutes of Health (NIH) (B.L., L.V.A. and Z.J.H.), the Dana Foundation (B.L.), NARSAD (B.L. and Z.J.H.), Louis Feil Trust (B.L.), the Stanley Family Foundation (B.L. and Z.J.H.), and a Harvey L. Karp Discovery Award (M.A.P.).

Author information

Author notes

    • Dimitri De Bundel

    Present address: Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.


  1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA

    • Mario A. Penzo
    • , Vincent Robert
    • , Jason Tucciarone
    • , Minghui Wang
    • , Linda Van Aelst
    • , Z. Josh Huang
    •  & Bo Li
  2. Ecole Normale Supérieure de Cachan, 94230 Cachan, France

    • Vincent Robert
  3. Medical Scientist Training Program & Program in Neuroscience, Stony Brook University, Stony Brook, New York 11790, USA

    • Jason Tucciarone
  4. CNRS, UMR-5203, INSERM U661, Institut de Génomique Fonctionnelle, 34090 Montpellier, France

    • Dimitri De Bundel
  5. Department of Pathology, University of Washington, Seattle, Washington 98104, USA

    • Martin Darvas
  6. Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Luis F. Parada
  7. Howard Hughes Medical Institute; Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA

    • Richard D. Palmiter
  8. Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China

    • Miao He


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M.A.P. and B.L. designed the study. M.A.P. and V.R. conducted experiments. M.A.P. analysed data. J.T. assisted with the rabies viral tracing experiments. D.D.B. assisted with the BDNF infusion experiments. M.W. made the AAV-fDIO-Cre-GFP virus. M.D. made the CAV2-Cre virus. L.F.P. generated the Trkblox/lox mouse line. M.H. generated the Som-Flp mouse line. L.V.A., R.D.P. and Z.J.H. provided critical reagents and suggestions. M.A.P. and B.L. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mario A. Penzo or Bo Li.

Extended data

Supplementary information


  1. 1.

    Saline infusion into CeL

    This video (sped up 4 times) shows a naïve mouse exploring the conditioning box immediately after bilateral infusion of saline vehicle into CeL on Day 1.

  2. 2.

    BDNF infusion into CeL

    This video (sped up 4 times) shows the same mouse as that in Supplementary Video 1 immediately after bilateral infusion of BDNF into CeL on Day 2. Robust freezing-like behavior can be observed.

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