Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Bertels, Zachariah; Grewal, Harinder; Dripps, Isaac; Siegersma, Kendra; Laboy, Alycia; Witkowski, Wiktor D; Sheets, Zoie; Shah, Pal; Conway, Catherine; Petukhova, Valentina; Karumudi, Bhargava; Petukhov, Pavel A.; Baca, Serapio M.; Rasenick, Mark M.; Pradhan, Amynah

doi:10.1101/2020.04.21.053272

Cited by 3 publications

(17 citation statements)

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“…This study, and previous work, 15 showed decreased neuronal complexity within the vlPAG following chronic migraine and CSD. We determined if CRPS produced similar changes in this key pain processing region (Figure 5A).…”

Section: Resultssupporting

confidence: 87%

“…The aim of this study was to further investigate alterations that occur following chronic migraine and assess if similar alterations in cytoarchitecture are observed in a hind paw model of CRPS. We previously showed that there were neuronal cytoarchitectural differences in key migraine pain processing regions following the NTG model of chronic migraine 15 . These results revealed a novel mechanism responsible for the transition of migraine from an episodic to a chronic condition.…”

Section: Introductionmentioning

confidence: 84%

“…NTG produces delayed allodynia, photophobia, and altered meningeal blood flow in mice 48–50 and results in activation of nociceptive pathways 51,52 . We previously demonstrated that chronic NTG decreased cytoarchitectural complexity in many brain regions important for migraine processing including the TNC, SCx, and the PAG 15 …”

Section: Discussionmentioning

confidence: 99%

“…While much has been recently learned about the pathophysiology responsible for the transition of migraine from an acute to chronic state the underlying mechanisms are still being explored 14 . A chronic migraine model, which uses the human migraine trigger nitroglycerin (NTG), as well as a model of cortical spreading depression (CSD), were recently shown to result in alterations in cytoarchitecture within key migraine regulating regions 15 . This, along with human research showing alterations in gray matter volume following chronic migraine further indicates a possible causal mechanism between headache chronicity and alterations in cytoarchitectural dynamics 16,17 .…”

Section: Introductionmentioning

confidence: 99%

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Migraine and peripheral pain models show differential alterations in neuronal complexity

et al. 2022

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Objective Our laboratory has recently shown that there is a decrease in neuronal complexity in head pain processing regions in mouse models of chronic migraine‐associated pain and aura. Importantly, restoration of this neuronal complexity corresponds with anti‐migraine effects of known and experimental pharmacotherapies. The objective of the current study was to expand this work and examine other brain regions involved with pain or emotional processing. We also investigated the generalizability of our findings by analyzing neuronal cytoarchitectural changes in a model of complex regional pain syndrome (CRPS), a peripheral pain disorder. Methods We used the nitroglycerin (NTG) model of chronic migraine‐associated pain in which mice receive 10 mg/kg NTG every other day for 9 days. Cortical spreading depression (CSD), a physiological corelate of migraine aura, was evoked in anesthetized mice using KCl. CRPS was induced by tibial fracture followed by casting. Neuronal cytoarchitecture was visualized with Golgi stain and analyzed with Simple Neurite Tracer. Results In the NTG model, we previously showed decreased neuronal complexity in the trigeminal nucleus caudalis (TNC) and periaqueductal gray (PAG). In contrast, we found increased neuronal complexity in the thalamus and no change in the amygdala or caudate putamen in this study. Following CSD, we observed decreased neuronal complexity in the PAG, in line with decreases in the somatosensory cortex and TNC reported with this model previously. In the CRPS model there was decreased neuronal complexity in the hippocampus, as reported by others; increased complexity in the PAG; and no change within the somatosensory cortex. Conclusions Collectively these results demonstrate that alterations in neuronal complexity are a feature of both chronic migraine and chronic CRPS. However, each type of pain presents a unique cytoarchitectural signature, which may provide insight on how these pain states differentially transition from acute to chronic conditions.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Migraine and peripheral pain models show differential alterations in neuronal complexity

et al. 2022

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“…Stellate neurons also consist of three groups (40–42), while basket neurons are from (43) and (44). Finally, pyramidal neurons are totally taken from four groups (45–48). The number of points that make up a neuron varies from 1 × 10 3 to 6 ×10 3 .…”

Section: Methodsmentioning

confidence: 99%

MorphoGNN: Morphological Embedding for Single Neuron with Graph Neural Networks

Zhu

Yao

et al. 2022

Preprint

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With the development of optical imaging systems, neuroscientists can now obtain large datasets of morphological structure at a single neuron scale positioned across the whole mouse brain. However, the enormous amount of morphological data challenges the classic approach of neuron classification, indexing and other analysis tasks. In this paper, we propose MorphoGNN, a single neuron morphological embedding based on the graph neural networks (GNN). This method learns the spatial structure information between the nodes of reconstructed neuron fibers by its nearest neighbors on each layer and captures the lower-dimensional representation of a single neuron through an end-to-end model. This model is composed of densely connected edge convolution (EdgeConv) layers and a double pooling operator, regularized with joint cross-entropy loss and triplet loss. An increasing population of the neighbor nodes meets the need of learning more information with features expanding at the deep layer. We tested the proposed embeddings on the neuron classification and retrieval tasks. Our method achieves competitive performance both on the general point cloud dataset and the neuron morphology dataset.

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CGRP-dependent sensitization of PKC-δ positive neurons in central amygdala mediates chronic migraine

et al. 2022

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Background To investigate specific brain regions and neural circuits that are responsible for migraine chronification. Methods We established a mouse model of chronic migraine with intermittent injections of clinically-relevant dose of nitroglycerin (0.1 mg/kg for 9 days) and validated the model with cephalic and extracephalic mechanical sensitivity, calcitonin gene-related peptide (CGRP) expression in trigeminal ganglion, and responsiveness to sumatriptan or central CGRP blockade. We explored the neurons that were sensitized along with migraine chronification and investigated their roles on migraine phenotypes with chemogenetics. Results After repetitive nitroglycerin injections, mice displayed sustained supraorbital and hind paw mechanical hyperalgesia, which lasted beyond discontinuation of nitroglycerin infusion and could be transiently reversed by sumatriptan. The CGRP expression in trigeminal ganglion was also upregulated. We found the pERK positive cells were significantly increased in the central nucleus of the amygdala (CeA), and these sensitized cells in the CeA were predominantly protein kinase C-delta (PKC-δ) positive neurons co-expressing CGRP receptors. Remarkably, blockade of the parabrachial nucleus (PBN)-CeA CGRP neurotransmission by CGRP8–37 microinjection to the CeA attenuated the sustained cephalic and extracephalic mechanical hyperalgesia. Furthermore, chemogenetic silencing of the sensitized CeA PKC-δ positive neurons reversed the mechanical hyperalgesia and CGRP expression in the trigeminal ganglion. In contrast, repetitive chemogenetic activation of the CeA PKC-δ positive neurons recapitulated chronic migraine-like phenotypes in naïve mice. Conclusions Our data suggest that CeA PKC-δ positive neurons innervated by PBN CGRP positive neurons might contribute to the chronification of migraine, which may serve as future therapeutic targets for chronic migraine. Graphical Abstract

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Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Cited by 3 publications

References 84 publications

Migraine and peripheral pain models show differential alterations in neuronal complexity

Migraine and peripheral pain models show differential alterations in neuronal complexity

MorphoGNN: Morphological Embedding for Single Neuron with Graph Neural Networks

CGRP-dependent sensitization of PKC-δ positive neurons in central amygdala mediates chronic migraine

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