Calcitonin gene related peptide α is dispensable for many danger-related motivational responses

Zajdel, Joanna; Sköld, Johan; Jaarola, Maarit; Singh, Anand Kumar; Engblom, David

doi:10.1038/s41598-021-95670-8

Cited by 13 publications

(9 citation statements)

References 31 publications

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“…Both the Calca and Calcb genes encode calcitonin gene-related peptide (CGRP), but Calcb is only weakly expressed based on scRNA-Seq, which is consistent with the observation that Calca -null mice express negligible CGRP immunofluorescence in the PBN ( Allen et al, 2022 ; Chen et al, 2018 ; Zajdel et al, 2021 ). The AMBA shows robust expression of Calcb perhaps because their probe hybridized to both genes.…”

Section: Resultssupporting

confidence: 79%

Molecular and anatomical characterization of parabrachial neurons and their axonal projections

Pauli

Chen

Basiri

et al. 2022

eLife

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The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are involved in behaviors including food and water intake, nociceptive responses, breathing regulation, as well as learning and responding appropriately to threatening stimuli. However, it is unclear how many PBN neuron populations exist and how different behaviors may be encoded by unique signaling molecules or receptors. Here we provide a repository of data on the molecular identity, spatial location, and projection patterns of dozens of PBN neuron subclusters. Using single-cell RNA sequencing, we identified 21 subclusters of neurons in the PBN and neighboring regions. Multiplexed in situ hybridization showed many of these subclusters are enriched within specific PBN subregions with scattered cells in several other regions. We also provide detailed visualization of the axonal projections from 21 Cre-driver lines of mice. These results are all publicly available for download and provide a foundation for further interrogation of PBN functions and connections.

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Section: Resultssupporting

confidence: 79%

Molecular and anatomical characterization of parabrachial neurons and their axonal projections

Pauli

Chen

Basiri

et al. 2022

eLife

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“…2H). In line with previous findings demonstrating that the Calca gene is dispensable for acute pain sensation (Zajdel et al, 2021), these data indicate that, while activation of PBN Calca neurons is sufficient to drive nociplasticity, the Calca gene product, CGRP, does not play a role in this assay. However, it is worth noting that CGRP is important in arthritis-, formalin-, and bladder-pain models (Allen et al, 2023; Shinohara et al, 2017; Han et al, 2015).…”

Section: Resultssupporting

confidence: 91%

ParabrachialCalcaneurons drive nociplasticity

Condon,

Yu,

Park

et al. 2023

Preprint

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Pain that persists beyond the time required for tissue healing and pain that arises in the absence of tissue injury are poorly understood phenomena mediated by plasticity within the central nervous system. The parabrachial nucleus (PBN) is a hub that relays aversive sensory information and appears to play a role in nociplasticity. Here, by preventing PBNCalcaneurons from releasing neurotransmitter or directly stimulating them we demonstrate that activation ofCalcaneurons is both necessary for the manifestation of chronic pain after nerve ligation and is sufficient to drive nociplasticity in wild-type mice. Aversive stimuli such as exposure to nitroglycerin, cisplatin, or LiCl can drive nociplasticity in aCalca-neuron-dependent manner. Calcium fluorescence imaging reveals that nitroglycerin activates PBNCalcaneurons and potentiates their responses to mechanical stimulation. The activity and excitability ofCalcaneurons increased for several days after aversive events, but prolonged nociplasticity likely occurs in downstream circuitry.

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“…Previous studies have shown that CeA-projecting PbN neurons do not receive direct nociceptive inputs from the spinal cord (7, 36, 37). Separate studies have demonstrated that the PbN is activated in response to peripheral noxious stimulation (12, 13, 38, 39) and that injury potentiates the PbN→CeA pathway in several mouse models of persistent pain. Whether CeA-projecting PbN neurons are activated by peripheral noxious stimulation remains unknown.…”

Section: Resultsmentioning

confidence: 99%

The parabrachial to central amygdala circuit is a key mediator of injury-induced pain sensitization

Torres-Rodriguez

Wilson

Singh

et al. 2023

Preprint

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The spino-ponto-amygdaloid pathway is a major ascending circuit relaying nociceptive information from the spinal cord to the brain. Potentiation of excitatory synaptic transmission in the parabrachial nucleus (PbN) to central amygdala (CeA) pathway has been reported in rodent models of persistent pain. At the behavioral level, the PbN→CeA pathway has been proposed to serve as a general alarm system to potential threats that modulates pain-related escape behaviors, affective-motivational (but not somatosensory) responses to painful stimuli, aversion, and threat memory. Increased sensitivity to previously innocuous somatosensory stimulation is a hallmark of chronic pain. Whether the PbN→CeA circuit contributes to heightened sensitivity to somatosensory stimulation following an injury, however, remains unknown. Here, we demonstrate that activation of CeA-projecting PbN neurons contributes to injury-induced behavioral hypersensitivity but not baseline nociception in male and female mice. Using optogenetic assisted circuit mapping, we confirmed a functional excitatory projection from PbN→CeA that is independent of the genetic or firing identity of CeA cells. We then showed that peripheral noxious stimulation increases the expression of the neuronal activity marker c-Fos in CeA-projecting PbN neurons and chemogenetic inactivation of these cells reduces behavioral hypersensitivity in models of neuropathic and inflammatory pain without affecting baseline nociception. Lastly, we show that chemogenetic activation of CeA-projecting PbN neurons is sufficient to induce bilateral hypersensitivity without injury. Together, our results demonstrate that the PbN→CeA pathway is a key modulator pain-related behaviors that can amplify responses to somatosensory stimulation in pathological states without affecting nociception under normal physiological conditions.

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Calcitonin gene related peptide α is dispensable for many danger-related motivational responses

Cited by 13 publications

References 31 publications

Molecular and anatomical characterization of parabrachial neurons and their axonal projections

Molecular and anatomical characterization of parabrachial neurons and their axonal projections

ParabrachialCalcaneurons drive nociplasticity

The parabrachial to central amygdala circuit is a key mediator of injury-induced pain sensitization

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