Dataset Information

A direct spino-cortical circuit bypassing the thalamus modulates nociception.

ABSTRACT: Nociceptive signals are usually transmitted to layer 4 neurons in somatosensory cortex via the spinothalamic-thalamocortical pathway. The layer 5 corticospinal neurons in sensorimotor cortex are reported to receive the output of neurons in superficial layers; and their descending axons innervate the spinal cord to regulate basic sensorimotor functions. Here, we show that a subset of layer 5 neurons receives spinal inputs through a direct spino-cortical circuit bypassing the thalamus, and thus define these neurons as spino-cortical recipient neurons (SCRNs). Morphological studies revealed that the branches from spinal ascending axons formed a kind of disciform structure with the descending axons from SCRNs in the basilar pontine nucleus (BPN). Electron microscopy and calcium imaging further confirmed that the axon terminals from spinal ascending neurons and SCRNs made functional synaptic contacts in the BPN, linking the ascending sensory pathway to the descending motor control pathway. Furthermore, behavioral tests indicated that the spino-cortical connection in the BPN was involved in nociceptive responses. In vivo calcium imaging showed that SCRNs responded to peripheral noxious stimuli faster than neighboring layer 4 cortical neurons in awake mice. Manipulating activities of SCRNs could modulate nociceptive behaviors. Therefore, this direct spino-cortical circuit represents a noncanonical pathway, allowing a fast sensory-motor transition of the brain in response to noxious stimuli.

SUBMITTER: Cai B

PROVIDER: S-EPMC10542357 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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A direct spino-cortical circuit bypassing the thalamus modulates nociception.

Cai Bing B Wu Dan D Xie Hong H Chen Yan Y Wang Huadong H Jin Sen S Song Yuran Y Li Anan A Huang Shiqi S Wang Sashuang S Lu Yingjin Y Bao Lan L Xu Fuqiang F Gong Hui H Li Changlin C Zhang Xu X

Cell research 20230613 10

Nociceptive signals are usually transmitted to layer 4 neurons in somatosensory cortex via the spinothalamic-thalamocortical pathway. The layer 5 corticospinal neurons in sensorimotor cortex are reported to receive the output of neurons in superficial layers; and their descending axons innervate the spinal cord to regulate basic sensorimotor functions. Here, we show that a subset of layer 5 neurons receives spinal inputs through a direct spino-cortical circuit bypassing the thalamus, and thus de ...[more]

PMID: 37311832

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Project description:Migraine attacks are believed to originate in the brain, but the exact mechanisms by which the brain generates peripheral nociceptive signals that drive migraine pain remain unclear. Sensory cortex hyperexcitability has been observed consistently across different migraine subtypes. Astrocytes detect aberrant increases in cortical activity via their Gq-coupled receptors and respond by releasing gliotransmitters and other factors with proinflammatory and nociceptive properties. In the present study, we used a rat model to investigate whether heightened cortical astrocyte Gq-coupled signaling is sufficient to drive peripheral trigeminal meningeal nociceptive responses linked to the generation of migraine headaches. We used an AAV-based chemogenetic approach that allows selective activation of cortical astrocyte Gq-GPCR signaling. We targeted astrocytes in the visual cortex as hyperexcitability in this region has been implicated in migraine. Furthermore, the meninges overlying the visual cortex are densely innervated by nociceptive fibers. We combined this chemogenetic approach with in vivo single-unit recording of meningeal nociceptors to assess changes in their ongoing activity and mechanosensitivity, along with testing of migraine-like behaviors. We further targeted calcitonin gene-related peptide (CGRP), using a monoclonal antibody (anti-CGRP mAb), to assess the relevance of cortical astrocyte activation to migraine. We discovered that heightened activation of Gq-coupled signaling in visual cortex astrocytes drives persistent discharge and increased mechanosensitivity of meningeal nociceptors. Cortical astrocytic activation also generated cephalic mechanical pain hypersensitivity, reduced exploratory behavior, and anxiety-like behaviors linked to migraine headaches. Blocking calcitonin gene-related peptide signaling suppressed astrocyte-mediated increases in meningeal nociceptor discharge and alleviated associated migraine-related behaviors. Our findings reveal a previously unappreciated role for augmented visual cortex astrocyte signaling as a triggering factor sufficient to generate meningeal nociception and migraine pain and greatly expand our understanding of migraine pathophysiology.

Dataset Information

A direct spino-cortical circuit bypassing the thalamus modulates nociception.

Publications

A direct spino-cortical circuit bypassing the thalamus modulates nociception.

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