Sensory innervation of the calvarial bones of the mouse

Abstract

Migraine sufferers frequently testify that their headache feels as if the calvarial bones are deformed, crushed, or broken (Jakubowski et al., 2006). This has lead us to postulate that nociceptive fibers supply the calvarial bones. We studied sensory innervation of the calvaria in coronal and horizontal sections of whole-head preparations of postnatal and adult mice, using immunostaining of peripherin – a marker of thinly-myelinated and unmyelinated fibers – and calcitonin gene-related peptide (CGRP) – a marker more typical of unmyelinated nerve fibers. In pups, we observed nerve bundles coursing between the galea aponeurotica and the periosteum; between the periosteum and the bone; between the bone and the meninges; as well as fibers that run inside the diploë in different orientations. Some dural fibers issued collateral branches to the pia at the frontal part of the brain. In the adult calvaria, the highest concentration of peripherin- and CGRP-labeled fibers were found in sutures where they appeared to emerge from the dura. Labeled fibers were also observed in emissary canals, bone marrow and periosteum. In contrast to pups, no labeled fibers were found in the diploë of the adult calvaria. Meningeal nerves that infiltrate the periosteum through the calvarial sutures may be positioned to mediate migraine headache triggered by pathophysiology of extracranial tissues, such as muscle tenderness and mild trauma to the skull. In view of the concentration of sensory fibers in the sutures, it may be useful to avoid drilling the sutures in patients undergoing craniotomies for a variety of neurosurgical procedures.

Axonal projections of mechanoreceptive dorsal root ganglion neurons depend on Ret

“…3G). By contrast, fibers that are positive for peripherin, a marker for prospective unmyelinated axons (Kosaras et al, 2009;Lariviere et al, 2002), were unaffected in Ret GFP/GFP mice (Fig. 3I), consistent with the idea that Ret + neurons are myelinated mechanoreceptive neurons, although the staining specificity of NF-200 and peripherin is somewhat controversial (Jackman and Fitzgerald, 2000).…”

Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache

“…Because the PVS is considered essential for clearance of brain solutes (Abbott, 2004;Carare et al, 2008;Iliff et al, 2012Iliff et al, , 2014Jessen et al, 2015), we sought to determine the effects of CSD on interstitial/glymphatic flow. Accordingly, we injected dye (3 kDa FITC-dextran) into the frontal cortex (3.5 mm anterior to the imaging window) of ubiquitously labeled tdTomato red fluorescent mice, and observed how quickly the dye filled the posterior PVS in CSD-induced and non-CSDinduced mice (Fig.…”

“…This closure is not likely to be simply a result of the CSD-induced changes in vessel diameter, because it was maximal throughout both the initial dilation and constriction exhibited by the arteries, and because the closure of the paravenous space (i.e., PVS near pial veins) occurred in the absence of any detectable change in the diameter of the pial vein. Based on reports of neuronal (Takano et al, 2007) and astrocytic endfeet (Tomita et al, 2011) swelling after CSD, it may be more likely that the closure of the PVS is secondary to such swelling-especially considering that astrocytic endfeet form the outer wall of the PVS (Jessen et al, 2015). Also, we observed that the PVS around penetrating arteries may close seconds before it closes around the surface arteries, which raises the possibility that the CSD-induced parenchymal swelling spreads from deep layer I up to the pia.…”

“…To date, the focus of much research has been on CSD's vascular effects, which include mild oligemia (Fabricius and Lauritzen, 1993;, impairment of neurovascular coupling (Østergaard et al, 2015), and creation of an O 2 supply-demand mismatch (von Bornstädt et al, 2015) that can lead to anoxic levels in metabolically compromised brain. At the cellular and molecular level, repetitive CSDs were also found to induce an inflammatory cascade resulting in the production of inducible nitric oxide synthase and COX-2 in the brain parenchyma (Karatas et al, 2013), as well activation of microglia (Gehrmann et al, 1993) and hypertrophy, proliferation, and activation of astrocytic cells (Kraig et al, 1991;Xue et al, 2009;Sukhotinsky et al, 2011). The clearance of intraparenchymal extracellular macromolecules, like those produced during the inflammatory cascade described above, is thought to be mediated mainly via the glymphatic system.…”

“…The clearance of intraparenchymal extracellular macromolecules, like those produced during the inflammatory cascade described above, is thought to be mediated mainly via the glymphatic system. The glymphatic system is a newly characterized series of extracellular compartments that clears waste from the brain parenchyma (Carare et al, 2008;Jessen et al, 2015) into paravascular spaces (PVSs) and then through the dural lymphatics to cervical lymph nodes (Aspelund et al, 2015;Louveau et al, 2015). Impairment of glymphatic pathway function in the aging brain (Kress et al, 2014), during prolonged wakefulness (Xie et al, 2013), after traumatic brain injury (Iliff et al, 2014), or in aquaporin 4 (AQP4) knock-out mice (Iliff et al, 2012) suggests that proper clearance of interstitial fluid and solutes, such as amyloid-␤ and hyperphosphorylated tau, through this paravascular drainage system is critical for maintaining a healthy brain.…”