Exaggerated startle has been recognized as a core hyperarousal symptom of multiple fear-related anxiety disorders, such as post-traumatic stress disorder (PTSD) and panic disorder. However, the mechanisms driving this symptom are poorly understood. Here we reveal a neural projection from dorsal raphe nucleus (DRN) to a startle-controlling center reticulotegmental nucleus (RtTg) that mediates enhanced startle response under fear condition. Within RtTg, we identify an inhibitory microcircuit comprising GABAergic neurons in pericentral RtTg (RtTgP) and glutamatergic neurons in central RtTg (RtTgC). Inhibition of this RtTgP-RtTgC microcircuit leads to elevated startle amplitudes. Furthermore, we demonstrate that the conditioned fear-activated DRN 5-HTergic neurons send inhibitory projections to RtTgP GABAergic neurons, which in turn upregulate neuronal activities of RtTgC glutamatergic neurons. Chemogenetic activation of the DRN-RtTgP projections mimics the increased startle response under fear emotions. Moreover, conditional deletion of 5-HT1B receptor from RtTgP GABAergic neurons largely reverses the exaggeration of startle during conditioned fear. Thus, our study establishes the disinhibitory DRN-RtTgP-RtTgC circuit as a critical mechanism underlying exaggerated startle under fear emotions, and provides 5-HT1B receptor as a potential therapeutic target for treating hyperarousal symptom in fear-associated psychiatric disorders.
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The data that support the findings of this study are provided in the manuscript and supplementary information files and are available from the corresponding author upon reasonable request.
The custom codes that support the findings of this study are available from the corresponding author upon reasonable request.
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We acknowledge support from National Key R&D Program of China (2021YFA0804900), National Natural Science Foundation of China (32225020, 91849206, 91649121, 91942315, 92049304, 32121002), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB39050000), Key Research Program of Frontier Science (CAS, ZDBS-LY-SM002), CAS Interdisciplinary Innovation Team (JCTD-2018-20), the Fundamental Research Funds for the Central Universities, USTC Research Funds of the Double First-Class Initiative (YD9100002001), CAS Project for Young Scientists in Basic Research (YSBR-013).
The authors declare no competing interests.
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Guo, W., Fan, S., Xiao, D. et al. A midbrain-reticulotegmental circuit underlies exaggerated startle under fear emotions. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01782-6