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Serotonin modulates an inhibitory input to the central amygdala from the ventral periaqueductal gray

Abstract

Fear is an adaptive state that drives defensive behavioral responses to specific and imminent threats. The central nucleus of the amygdala (CeA) is a critical site of adaptations that are required for the acquisition and expression of fear, in part due to alterations in the activity of inputs to the CeA. Here, we characterize a novel GABAergic input to the CeA from the ventral periaqueductal gray (vPAG) using fiber photometry and ex vivo whole-cell slice electrophysiology combined with optogenetics and pharmacology. GABA transmission from this ascending vPAG-CeA input was enhanced by serotonin via activation of serotonin type 2 C (5HT2C) receptors. Results suggest that these receptors are presynaptic. Interestingly, we found that GABA release from the vPAG-CeA input is enhanced following fear learning via activation of 5HT2C receptors and that this pathway is dynamically engaged in response to aversive stimuli. Additionally, we characterized serotonin release in the CeA during fear learning and recall for the first time using fiber photometry coupled to a serotonin biosensor. Together, these findings describe a mechanism by which serotonin modulates GABA release from ascending vPAG GABA inputs to the CeA and characterize a role for this pathway in fear.

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Fig. 1: vPAG GABA neurons have functional projections to the CeA.
Fig. 2: 5HT is released in the CeA during fear conditioning.
Fig. 3: The vPAGVgat-CeA pathway is modulated by serotonin directly and via presynaptic 5HT2C receptors.
Fig. 4: Fear learning engages the vPAGVgat-CeA pathway.
Fig. 5: vPAGVgat-CeA pathway is dynamically engaged during fear learning and responds to shock-predicting cues.

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Acknowledgements

Schematics for this manuscript were created using Biorender.com.

Funding

This work was supported by the Bowles Center for Alcohol Studies and NIAAA/ NIH: F32-AA022549 (EGLG); T32-AA007573 (EGLG); R01-AA019454 (TLK); U01-AA020911 (TLK); P60-AA011605 (TLK); T32-NS007431 (OJH).

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OJH, EGLG and TLK: designed the experiments. OJH, EGLG, JFD, JS, DWB, MH, AK, NMM and AJL: performed the experiments. OJH, EGLG, JFD, CMM and JAH: analyzed data. OJH, EGLG and TLK: interpreted the data and wrote the manuscript.

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Correspondence to Emily G. Lowery-Gionta.

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Hon, O.J., DiBerto, J.F., Mazzone, C.M. et al. Serotonin modulates an inhibitory input to the central amygdala from the ventral periaqueductal gray. Neuropsychopharmacol. 47, 2194–2204 (2022). https://doi.org/10.1038/s41386-022-01392-4

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