A high-performance GRAB sensor reveals differences in the dynamics and molecular regulation between neuropeptide and neurotransmitter release

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 18, 2025

The co-existence and co-transmission of neuropeptides small molecule neurotransmitters within individual neuron represent a fundamental characteristic observed across various species. However, the differences regarding their in vivo spatiotemporal dynamics underlying molecular regulation remain poorly understood. Here, we develop GPCR-activation-based (GRAB) sensor for detecting short neuropeptide F (sNPF) with high sensitivity resolution. Furthermore, investigate between sNPF acetylcholine (ACh) from same neurons. Interestingly, our findings reveal distinct release ACh. Notably, results indicate that synaptotagmins (Syt) are involved these two processes, as Syt7 Sytα release, while Syt1 ACh release. Thus, this high-performance GRAB provides robust tool studying shedding insights into unique distinguish neurotransmitters.

Language: Английский

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Comparative perspectives on neuropeptide function and social isolation

Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Pain persists in mice lacking both Substance P and CGRPα signaling

eLife, Journal Year: 2025, Volume and Issue: 13

Published: March 18, 2025

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides their receptors are expressed at high levels in pain-responsive neurons from the periphery to brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve clinical trials. Since extensively co-expressed, we hypothesized that simultaneous inhibition would be required effective analgesia. We therefore generated Tac1 Calca double knockout (DKO) mice assessed behavior using a wide range of pain-relevant assays. As expected, were undetectable throughout nervous system DKO mice. To our surprise, animals displayed largely intact responses mechanical, thermal, chemical, visceral stimuli, as well itch. Moreover, chronic inflammatory neurogenic inflammation unaffected by loss two peptides. Finally, neuropathic evoked nerve injury or chemotherapy treatment was also preserved peptide-deficient Thus, results demonstrate even combination, transmission acute pain.

Language: Английский

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Neuropeptide signaling network of Caenorhabditis elegans: from structure to behavior

Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 30, 2024

Abstract Neuropeptides are abundant signaling molecules that control neuronal activity and behavior in all animals. Owing part to its well-defined compact nervous system, Caenorhabditis elegans has been one of the primary model organisms used investigate how neuropeptide networks organized these neurochemicals regulate behavior. We here review recent work expanded our understanding neuropeptidergic network C. by mapping evolutionary conservation, molecular expression, receptor–ligand interactions, system-wide organization pathways system. also describe general insights into circuit motifs spatiotemporal range peptidergic transmission have emerged from vivo studies on signaling. With efforts ongoing chart peptide other organisms, connectome can serve as a prototype further understand dynamics at organismal level.

Language: Английский

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Xenon gas as a potential treatment for opioid use disorder, alcohol use disorder, and related disorders

Medical Gas Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Xenon gas is considered to be a safe anesthetic and imaging agent. Research on its other potentially beneficial effects suggests that xenon may have broad efficacy for treating health disorders. A number of reviews applications been published, but none focused substance use Accordingly, we review targets relevant the treatment disorders, with focus opioid disorder alcohol disorder. We report inhaled at subsedative concentrations inhibits conditioned memory reconsolidation withdrawal symptoms. work by others reporting antidepressant, anxiolytic, analgesic properties xenon, which could diminish negative affective states pain. discuss research supporting possibility prevent analgesic- or stress-induced tolerance and, so doing reduce risk developing The rapid kinetics, favorable safety side effect profiles, multitargeting capability suggest it used as an ambulatory on-demand rapidly attenuate maladaptive memory, physical symptoms, pain drivers disorders when they occur. also human immunodeficiency virus oncology because exploited target reservoirs, protein-induced abnormalities, cancers. Although expensive, low exert effects, separation, recovery, recycling advancements will lower costs, increasing economic feasibility therapeutic use. More needed better understand remarkable repertoire potential applications.

Language: Английский

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Multi-scale Neural Homeostasis Mechanisms: Insights into Neurodegenerative Diseases and Therapeutic Approaches, Including Exercise

Advanced Exercise and Health Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Mapping and decoding neuropeptide signaling networks in nervous system function

Current Opinion in Neurobiology, Journal Year: 2025, Volume and Issue: 92, P. 103027 - 103027

Published: April 21, 2025

Neuropeptides are widespread signaling molecules that central to brain function in all animals. Recent advances profiling their expression across neural circuits, conjunction with detailed biochemical characterization of interactions receptors, have made it feasible build brain-wide maps neuropeptide signaling. Here, we discuss how recent reconstructions networks, from mammalian regions nervous system-wide C. elegans, reveal conserved organizational features neuropeptidergic networks. Furthermore, review technical breakthroughs vivo sensors for peptide release, receptor binding, and intracellular bring a mechanistic understanding networks within experimental reach. Finally, describe the architecture can change throughout evolution or even lifetime individuals, which highlights complexities must be considered understand these modulate circuit activity behavior different contexts.

Language: Английский

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Encoding opposing valences through frequency-dependent transmitter switching in single peptidergic neurons

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 9, 2024

Abstract Peptidergic neurons often co-express fast transmitters and neuropeptides in separate vesicles with distinct release properties. However, the dynamics of each transmitter various contexts have not been fully understood behaving animals. Here, we demonstrate that calcitonin gene-related peptide (CGRP) external lateral subdivision parabrachial nucleus (CGRP PBel ) encode opposing valence via differential release, rather than corelease, glutamate neuropeptides, according to firing rate. Glutamate is released preferentially at lower rates minimal higher rates, whereas are resulting frequency-dependent switching transmitters. Aversive stimuli evoke high frequency responses accompanying neuropeptide negative valence, appetitive low positive valence. Our study reveals a previously unknown capability single CGRP bidirectionally vivo .

Language: Английский

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Pain persists in mice lacking both Substance P and CGRPα signaling

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 17, 2023

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides their receptors are expressed at high levels in pain-responsive neurons from the periphery to brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve clinical trials. Since extensively co-expressed we hypothesized that simultaneous inhibition would be required effective analgesia. We therefore generated Tac1 Calca double knockout (DKO) mice assessed behavior using a wide range of pain-relevant assays. As expected, were undetectable throughout nervous system DKO mice. To our surprise, animals displayed largely intact responses mechanical, thermal, chemical, visceral stimuli, as well itch. Moreover, chronic inflammatory neurogenic inflammation unaffected by loss two peptides. Finally, neuropathic evoked nerve injury or chemotherapy treatment was also preserved peptide-deficient Thus, results demonstrate even combination, transmission acute pain.

Language: Английский

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Sex differences in central amygdala glutamate responses to calcitonin gene-related peptide

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 9, 2024

Abstract Women are disproportionately affected by chronic pain compared to men. While societal and environmental factors contribute this disparity, sex-based biological differences in the processing of also believed play significant roles. The central lateral nucleus amygdala (CeLC) is a key region for emotional-affective dimension pain, prime target exploring sex since recent study demonstrated CGRP actions region. Inputs CeLC from parabrachial (PB) causal role aversive processing, release both glutamate calcitonin gene-related peptide (CGRP). thought crucial potentiating glutamatergic signaling CeLC. However, it not known if CGRP-mediated synaptic plasticity occurs similarly males females. Here, we tested hypothesis that female neurons experience greater potentiation than following endogenous exposure. Using trains optical stimuli evoke transient PB terminals CeLC, find subsequent responses preferentially potentiated mice. This was CGRP-dependent involved postsynaptic mechanism. difference sensitivity may explain affective processing. Significance statement receives dense projection corelease (CGRP) stimuli. →CeLC plays pain. We show potentiates female, but male, neurons. In context previous work male suggests females more sensitive even events. Understanding how arises could enhance strategies treating women

Language: Английский

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