Journal
MOLECULAR PSYCHIATRY
Volume 27, Issue 12, Pages 4881-4892Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-022-01782-6
Keywords
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Funding
- National Key R&D Program of China [2021YFA0804900]
- National Natural Science Foundation of China [32225020, 91849206, 91649121, 91942315, 92049304, 32121002]
- 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]
- 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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This study reveals a neural projection from the dorsal raphe nucleus (DRN) to the reticulotegmental nucleus (RtTg) that mediates enhanced startle response under fear condition. The study identifies an inhibitory microcircuit within RtTg, consisting of GABAergic neurons in pericentral RtTg (RtTgP) and glutamatergic neurons in central RtTg (RtTgC). The conditioned fear-activated DRN 5-HTergic neurons send inhibitory projections to RtTgP GABAergic neurons, which upregulate neuronal activities of RtTgC glutamatergic neurons.
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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