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A midbrain-reticulotegmental circuit underlies exaggerated startle under fear emotions

Abstract

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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Fig. 1: RtTg glutamatergic neurons exhibit elevated activities during FPS.
Fig. 2: Screening of candidate RtTg upstream regulatory nucleus involved in the regulation of FPS.
Fig. 3: DRN 5-HTergic neurons specifically project to RtTgP GABAergic neurons that form inhibitory microcircuit with RtTgC glutamatergic neurons.
Fig. 4: Functional verification of a DRN-RtTgP-RtTgC disinhibitory circuit.
Fig. 5: Screening of RtTgP 5-HT receptor subtypes responsible for FPS.

Data availability

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.

Code availability

The custom codes that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

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).

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WX initiated, designed and supervised the project; WG and SF conducted most of the experiments; DX conducted FPS tests and immunostaining experiments; CH and MG analyzed data with assistance from WX; WX and WG wrote the manuscript.

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Correspondence to Wei Xiong.

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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

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