Mechanoreceptor signal convergence and transformation in the dorsal horn flexibly shape a diversity of outputs to the brain

Chirila, Anda M.; Rankin, Genelle; Tseng, Shih-Yi; Emanuel, Alan J.; Chavez‐Martinez, Carmine L.; Zhang, Dawei; Harvey, Christopher D.; Ginty, David D.

doi:10.1016/j.cell.2022.10.012

Cited by 34 publications

(38 citation statements)

References 94 publications

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“…This finding is consistent with prior results showing that ablating PV + interneurons increased punctate mechanical sensitivity 36,56 . On the other hand, disruption of either PSI or Rorβ-mediated FFI, both of which lead to a dramatic increased physiological reactivity to step indentations 15 and increased correlated activity in the DH (Figures 4G-4H and S4I), caused behavioral overreactivity to light touch but not pain-like behaviors reflected by lateral kicking and licking of the contacted paw (Figure 4I) 15,[24][25][26]59 . Taken together, these findings suggest that decorrelated activity at the population level in the DH, resulting from altered PV + interneuron activity, and not a generalized increased in evoked reactivity across the DH, underlies mechanical allodynia in a peripheral nerve injury-induced neuropathic pain state.…”

Section: Pv + Interneurons Control Temporal Activity Patterns Across ...mentioning

confidence: 99%

“…The first stage of integration of tactile signals flowing from the periphery is the spinal cord dorsal horn (DH). In the DH, axons of primary sensory neurons that innervate the skin and convey discrete streams of sensory information, including those in response to innocuous and noxious touch, synapse onto functionally diverse populations of interneurons as well as small populations of projection neurons [15][16][17][18] . The mechanosensory DH contains 10 or more interneuron subtypes, based on morphological, intrinsic physiological, molecular, and synaptic properties, at least four of which are inhibitory interneurons that collectively constitute ~30% of the DH neuronal population [19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

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Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV⁺interneurons

Rankin

Chirila

Emanuel

et al. 2023

Preprint

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How mechanical allodynia following nerve injury is encoded in patterns of neural activity in the spinal cord dorsal horn (DH) is not known. We addressed this using the spared nerve injury model of neuropathic pain andin vivoelectrophysiological recordings. Surprisingly, despite dramatic behavioral over-reactivity to mechanical stimuli following nerve injury, an overall increase in sensitivity or reactivity of DH neurons was not observed. We did, however, observe a marked decrease in correlated neural firing patterns, including the synchrony of mechanical stimulus-evoked firing, across the DH. Alterations in DH temporal firing patterns were recapitulated by silencing DH parvalbumin+ (PV+) inhibitory interneurons, previously implicated in mechanical allodynia, as were allodynic pain-like behaviors in mice. These findings reveal decorrelated DH network activity, driven by alterations in PV+ interneurons, as a prominent feature of neuropathic pain, and suggest that restoration of proper temporal activity is a potential treatment for chronic neuropathic pain.

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Section: Pv + Interneurons Control Temporal Activity Patterns Across ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV⁺interneurons

Rankin

Chirila

Emanuel

et al. 2023

Preprint

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“…The mechanosensory system similarly contains well-defined input channels that detect specific stimulus features (e.g., indentation or vibration), suggesting that these channels could potentially mediate distinct aspects of touch perception ( Abraira and Ginty, 2013 ). However, recent studies suggest that inputs from different mechanosensory types are integrated, beginning at the first synapse, to create mixed representations ( Emanuel et al, 2021 ; Chirila et al, 2022 ). Uncovering when and how sensory circuits integrate different inputs, and how this relates to perception and behavior, lies at the core of understanding how we interpret signals from the world.…”

Section: Discussionmentioning

confidence: 99%

Selective integration of diverse taste inputs within a single taste modality

Deere

Sarkissian

Yang

et al. 2023

eLife

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A fundamental question in sensory processing is how different channels of sensory input are processed to regulate behavior. Different input channels may converge onto common downstream pathways to drive the same behaviors, or they may activate separate pathways to regulate distinct behaviors. We investigated this question in the Drosophila bitter taste system, which contains diverse bitter-sensing cells residing in different taste organs. First, we optogenetically activated subsets of bitter neurons within each organ. These subsets elicited broad and highly overlapping behavioral effects, suggesting that they converge onto common downstream pathways, but we also observed behavioral differences that argue for biased convergence. Consistent with these results, transsynaptic tracing revealed that bitter neurons in different organs connect to overlapping downstream pathways with biased connectivity. We investigated taste processing in one type of downstream bitter neuron that projects to the higher brain. These neurons integrate input from multiple organs and regulate specific taste-related behaviors. We then traced downstream circuits, providing the first glimpse into taste processing in the higher brain. Together, these results reveal that different bitter inputs are selectively integrated early in the circuit, enabling the pooling of information, while the circuit then diverges into multiple pathways that may have different roles.

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“…Whether these cells serve as passive modulators of mechanical forces impinging on the sensory axon or play an active role in initiating mechanical responses is an area of active investigation [26][27][28] . Deleting Piezo2 in both somatosensory neurons and non-neuronal cells leads to complete loss of light touch responses measured in the dorsal root ganglia (DRG), spinal cord, and brainstem, emphasizing the critical role of Piezo2 in light touch 10,11 . However, definitively answering whether Piezo2 is expressed and functions within end organ non-neuronal cells requires a high-resolution Piezo2 localization approach and physiological analyses of mice lacking Piezo2 only in non-neuronal cells.…”

Section: Piezo2 Localization Across Three Aβ Ra-ltmr End Organ Struct...mentioning

confidence: 99%

Three-dimensional reconstructions of mechanosensory end organs suggest a unifying mechanism underlying dynamic, light touch

Handler

Zhang

Pang

et al. 2023

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Specialized mechanosensory end organs within mammalian skin -- hair follicle-associated lanceolate complexes, Meissner corpuscles, and Pacinian corpuscles -- enable our perception of light, dynamic touch. In each of these end organs, fast-conducting mechanically sensitive neurons, called Aβ low-threshold mechanoreceptors (Aβ LTMRs), associate with resident glial cells, known as terminal Schwann cells (TSCs) or lamellar cells, to form complex axon ending structures. Lanceolate-forming and corpuscle-innervating Aβ LTMRs share a low threshold for mechanical activation, a rapidly adapting (RA) response to force indentation, and high sensitivity to dynamic stimuli. How mechanical stimuli lead to activation of the requisite mechanotransduction channel Piezo2 and Aβ RA-LTMR excitation across the morphologically dissimilar mechanosensory end organ structures is not understood. Here, we report the precise subcellular distribution of Piezo2 and high-resolution, isotropic 3D reconstructions of all three end organs formed by Aβ RA-LTMRs determined by large volume enhanced Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) imaging. We found that within each end organ, Piezo2 is enriched along the sensory axon membrane and is minimally or not expressed in TSCs and lamellar cells. We also observed a large number of small cytoplasmic protrusions enriched along the Aβ RA-LTMR axon terminals associated with hair follicles, Meissner corpuscles, and Pacinian corpuscles. These axon protrusions reside within close proximity to axonal Piezo2, occasionally contain the channel, and often form adherens junctions with nearby non-neuronal cells. Our findings support a unified model for Aβ RA-LTMR activation in which axon protrusions anchor Aβ RA-LTMR axon terminals to specialized end organ cells, enabling mechanical stimuli to stretch the axon in hundreds to thousands of sites across an individual end organ and leading to activation of proximal Piezo2 channels and excitation of the neuron.

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Mechanoreceptor signal convergence and transformation in the dorsal horn flexibly shape a diversity of outputs to the brain

Cited by 34 publications

References 94 publications

Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV⁺interneurons

Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV⁺interneurons

Selective integration of diverse taste inputs within a single taste modality

Three-dimensional reconstructions of mechanosensory end organs suggest a unifying mechanism underlying dynamic, light touch

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Mechanoreceptor signal convergence and transformation in the dorsal horn flexibly shape a diversity of outputs to the brain

Cited by 34 publications

References 94 publications

Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV+interneurons

Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV+interneurons

Selective integration of diverse taste inputs within a single taste modality

Three-dimensional reconstructions of mechanosensory end organs suggest a unifying mechanism underlying dynamic, light touch

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Product

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Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV⁺interneurons

Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV⁺interneurons