Novel genetically encoded tools for imaging or silencing neuropeptide release from presynaptic terminalsin vivo

Abstract

Neurons produce and release neuropeptides to communicate with one another. Despite their profound impact on critical brain functions, circuit-based mechanisms of peptidergic transmission are poorly understood, primarily due to the lack of tools for monitoring and manipulating neuropeptide release in vivo. Here, we report the development of two genetically encoded tools for investigating peptidergic transmission in behaving mice: a genetically encoded large dense core vesicle (LDCV) sensor that detects the neuropeptides release presynaptically, and a genetically encoded silencer that specifically degrades neuropeptides inside the LDCV. Monitoring and silencing peptidergic and glutamatergic transmissions from presynaptic terminals using our newly developed tools and existing genetic tools, respectively, reveal that neuropeptides, not glutamate, are the primary transmitter in encoding unconditioned stimulus during Pavlovian threat learning. These results show that our sensor and silencer for peptidergic transmission are reliable tools to investigate neuropeptidergic systems in awake behaving animals.

Gustatory Thalamic Neurons Mediate Aversive Behaviors

“…The glutamate signaling from the CGRP PBN neurons is likely to be the most relevant transmitter, because the receptors for some of neuropeptides (CGRP, NTS, PACAP and Substance P) made by CGRP PBN neurons were not detected in the VPMpc. In contrast, neuropeptide signaling from CGRP PBN neurons to the central nucleus of the amygdala is critical for fear learning and memory 42 .…”

Pain persists in mice lacking both Substance P and CGRPα signaling

“…For example, the development of effective migraine therapeutics targeting CGRPα or its receptor confirm the important role this peptide plays in headache (De Matteis et al, 2020 ;Tso and Goadsby, 2017 ) Beyond Substance P and CGRPα, pain-responsive neurons express a rich repertoire of potential signaling molecules, including other neuropeptides. Emerging approaches to image and manipulate these molecules (Girven et al, 2022 ;Kim et al, 2023 ), as well as advances in quantitating pain behaviors (Bohic et al, 2023 ;MacDonald and Chesler, 2023 ), may ultimately reveal the fundamental roles of neuropeptides in generating our experience of pain.…”

Pain persists in mice lacking both Substance P and CGRPα signaling

“…Beyond Substance P and CGRPα, pain-responsive neurons express a rich repertoire of potential signaling molecules, including other neuropeptides. Emerging approaches to image and manipulate these molecules (Girven et al, 2022; Kim et al, 2023), as well as advances in quantitating pain behaviors (Bohic et al, 2023; MacDonald and Chesler, 2023), may ultimately reveal the fundamental roles of neuropeptides in generating our experience of pain.…”