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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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.).
Extended data figures
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.
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.