Spinal Nucleus Research Articles

Experience-dependent plasticity in early stations of sensory processing in mature brains: effects of environmental enrichment on dendrite measures in trigeminal nuclei

Nervous systems respond with structural changes to environmental changes even in adulthood. In recent years, experience-dependent structural plasticity was shown not to be restricted to the cerebral cortex, as it also occurs at subcortical and even peripheral levels. We have previously shown that two populations of trigeminal nuclei neurons, trigeminothalamic barrelette neurons of the principal nucleus (Pr5), and intersubnuclear neurons in the caudal division of the spinal trigeminal nucleus (Sp5C) that project to Pr5 underwent morphometric and topological changes in their dendritic trees after a prolonged total or partial loss of afferent input from the vibrissae. Here we examined whether and what structural alterations could be elicited in the dendritic trees of the same cell populations in young adult rats after being exposed for 2 months to an enriched environment (EE), and how these changes evolved when animals were returned to standard housing for an additional 2 months. Neurons were retrogradely labeled with BDA delivered to, respectively, the ventral posteromedial thalamic nucleus or Pr5. Fully labeled cells were digitally reconstructed with Neurolucida and analyzed with NeuroExplorer. EE gave rise to increases in dendritic length, number of trees and branching nodes, spatial expansion of the trees, and dendritic spines, which were less pronounced in Sp5C than in Pr5 and differed between sides. In Pr5, these parameters returned, but only partially, to control values after EE withdrawal. These results underscore a ubiquity of experience-dependent changes that should not be overlooked when interpreting neuroplasticity and developing plasticity-based therapeutic strategies.

Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors.

Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.

A Multidisciplinary Approach to Simultaneously Monitoring Real-Time Neuronal Activity and Pain Behaviors During Optogenetic Stimulation of Brain Neurons in Freely Moving Mice.

BackgroundHighlighted by the current opioid epidemic, identifying novel therapies to treat chronic trigeminal neuropathic pain is a critical need. To develop these treatments, it is necessary to have viable targets in the brain to act on. Historically, neural tracing studies have been extremely useful in determining connections between brain areas but do not provide information about the functionality of these connections. Combining optogenetics and behavioral observation allows researchers to determine whether a particular brain area is involved in the regulation of such behavior. The addition of multi-channel electrophysiological recording provides information on real-time neuronal activity in the specific neuronal pathway.MethodsMale C57/BL/6J mice (8-week-old) underwent either chronic constriction injury of infraorbital nerve (CCI-ION) or a sham surgery and were injected with either channelrhodopsin (ChR2) or a control virus in the hypothalamic A11 nucleus. Two weeks after CCI-ION, they were tested in real-time place preference (RTPP), while neuronal activity in the spinal trigeminal nucleus caudalis (Sp5C) was recorded.ResultsOptogenetic excitation of the A11 neurons results in more time spent in the stimulation chamber during RTPP testing. Additionally, stimulation of the A11 results in a greater number of neuronal activity increase in the Sp5C in animals with the injection of AAV carrying ChR2 compared to animals injected with a control virus or that underwent a sham surgery.ConclusionIn vivo multi-channel electrophysiological recording, optogenetic stimulation, and behavioral observation can be combined in a mouse model of chronic trigeminal neuropathic pain to validate brain areas involved in the modulation of such pain.

Olfactory stimulation Inhibits Nociceptive Signal Processing at the Input Stage of the Central Trigeminal System

The spinal trigeminal nucleus caudalis (SpVc) in the mammalian brainstem serves a pivotal function in pain processing. As the main relay center for nociceptive signals, SpVc conducts pain-related signals from various regions of the head toward higher levels of central processing such as the thalamus. SpVc also receives modulatory signals from other brain areas, which can alleviate the perception of headache. We studied the impact of olfactory co-stimulation on pain-related behavior and SpVc neural activity in mice. Using the TRPA1 agonist allyl isothiocyanate (AITC) as noxious stimulus, we quantified the aversive response and the perceived pain intensity by evaluating explorative running and the mouse grimace scale, respectively. We found that the floral odorants phenylethyl alcohol (PEA) and lavender oil mitigated the aversive response to AITC. Consistent with this finding, a newly developed, automated quantification of c-Fos expression in SpVc revealed that co-stimulation with PEA or lavender profoundly reduced network activity in the presence of AITC. These results demonstrated a substantial analgesic potential of odor stimulation in the trigeminal system and provide an explanation for the palliative effect of odors in the treatment of headache.

Comparative anatomy of the subscapularis, teres major and latissimus dorsi muscles from salamanders to mammals with special reference to their innervations from the brachial plexus.

It has been reported that the ramification pattern of spinal motor nerves reflected the spatial orientation of motoneuron pools in the ventral horn of spinal cord and this topography of spinal motor nuclei was very similar in different vertebrates. Therefore, the ramification pattern of spinal nerves was an important criterion for discussing the phylogenetic homology of muscles. It has been reported that the human subscapularis muscle was innervated by several branches, the proximal branch of them was from the ventral layer of the dorsal cord and the distal one from the dorsal layer of the dorsal cord of the brachial plexus. This fact suggested the human subscapularis had different phylogenetic origins. In this study, I unveil the phylogenetic origin of the mammalian subscapularis. The animals observed were a chimpanzee, a lar gibbon, a cat, a fetal pig, a koala, a possum (mammals), a lizard, an iguana (reptiles) and salamanders (amphibians). The branches to the mammalian subscapularis were divided into proximal and distal groups based on the origin from the brachial plexus, just like the human subscapularis. In salamanders and lizards, the homologous branch with the mammalian proximal branch to the subscapularis was observed and the segmentally higher branch innervating the latissimus dorsi was homologous with the distal branch to the mammalian subscapularis. Conclusively, I suppose that the dorsal-most portion of the reptilian latissimus dorsi muscle differentiates to the mammalian teres major, and the segmentally higher portion of the reptilian latissimus dorsi contributes to the formation of the mammalian subscapularis.

Peripheral and central mechanisms of migraine provide rationale for combination therapy

The purpose of this study was to determine the effects of BoNT-A/atogepant (ATO) combination treatment on activation/sensitization of high-threshold (HT) and wide-dynamic range (WDR) trigeminovascular neurons in the spinal trigeminal nucleus (STN) by CSD. ATO is a small molecule CGRP receptor antagonist. (A) Individual analysis: in the control group, CSD activated 80% of HT and 70% of WDR neurons whereas in the treatment group it activated 10% of HT (p = 0.001, c2 = 9.8) and 0% of WDR (p = 0.001, c2 = 10.7) neurons. Similarly, in the control group, CSD sensitized 80% of HT and 60% of WDR neurons whereas in the treatment group it sensitized 0% of HT and 5% of WDR neurons. (B) Group analysis: statistical analyses of all neurons revealed that in the control group, spontaneous activity increased significantly in both HT (c2 = 6.4, p = 0.039) and WDR (c2 = 7.8, p = 0.004) neurons, whereas in the treatment group it remained unchanged in the HT (c2 = 1.4, p = 0.35) and decreased, rather than increased, significantly (c2 = 8.6, p = 0.003) in the WDR neurons. A similar pattern was seen in responses to mechanical stimulation of the dura and skin. Given BoNT-A preferential inhibitory effects on unmyelinated C- but not thinly myelinated Ad-fibers, and fremanezumab preferential inhibitory effects on Ad- but not C-fibers, it is reasonable to propose that the robust inhibition of activation and sensitization of the HT and WDR trigeminovascular neurons by the BoNT-A/ATO combination treatment was achieved through a dual blockade of both classes of meningeal nociceptors.

Exacerbation of syringomyelia/syringobulbia symptoms after COVID-19: Case report

In syringomyelia there is a known Substance P (SP) overexpression, predominantly in the external laminae of the dorsal horn. It has been hypothesized that several infections, particularly COVID-19, may increase the expression of the TRPV1 gene in lung, producing an increment of SP and IL-6, which would involve an alteration of the spinal trigeminal nuclei responsible for its secretion. The aim is to report the first case of exacerbation of syringomyelia/syringobulbia symptoms after a COVID-19 infection.

Blockade of kappa opioid receptors reduces mechanical hyperalgesia and anxiety-like behavior in a rat model of trigeminal neuropathic pain

It has been shown that kappa opioid receptor (KOR) antagonists, such as nor-binaltorphimine (nor-BNI), have antinociceptive effects in some pain models that affect the trigeminal system. Also, its anxiolytic-like effect has been extensively demonstrated in the literature. The present study aimed to investigate the systemic, local, and central effect of nor-BNI on trigeminal neuropathic pain using the infraorbital nerve constriction model (CCI-ION), as well as to evaluate its effect on anxiety-like behavior associated with this model. Animals received nor-BNI systemically; in the trigeminal ganglion (TG); in the subarachnoid space to target the spinal trigeminal nucleus caudalis (Sp5C) or in the central amygdala (CeA) 14 days after CCI-ION surgery. Systemic administration of nor-BNI caused a significant reduction of facial mechanical hyperalgesia and promoted an anxiolytic-like effect, which was detected in the elevated plus-maze and the light-dark transition tests. When administered in the TG or CeA, the KOR antagonist was able to reduce facial mechanical hyperalgesia induced by CCI-ION, but without changing the anxiety-like behavior. Moreover, no change was observed on nociception and anxiety-like behavior after nor-BNI injection into the Sp5C. The present study demonstrated antinociceptive and anxiolytic-like effects of nor-BNI in a model of trigeminal neuropathic pain. The antinociceptive effect seems to be dissociated from the anxiolytic-like effect, at both the sites involved and at the dose need to achieve the effect. In conclusion, the kappa opioid system may represent a promising target to be explored for the control of trigeminal pain and associated anxiety. However, further studies are necessary to better elucidate its functioning and modulatory role in chronic trigeminal pain states.

Involvement of P2Y12 receptors in a nitroglycerin-induced model of migraine in male mice.

P2Y12 receptors regulate different forms of pain and inflammation. In this study, we investigated the participation of P2Y12 receptors in an animal model of migraine. We tested the effect of the centrally administered selective P2Y12 antagonist PSB-0739 and P2Y12 receptor gene (P2ry12-/- ) deficiency in acute nitroglycerin-treated mice. Additionally, platelet depletion was used to investigate the role of platelet P2Y12 receptors during migraine-like pain. Nitroglycerin induced sensory hypersensitivity of C57BL/6 wild-type (P2ry12+/+ ) mice accompanied by an increase in c-fos and CGRP expression in the upper cervical spinal cord (C1-C2) and trigeminal nucleus caudalis. Similar changes were also observed in P2Y12 gene-deficient (P2ry12-/- ) mice. Prophylactic intrathecal application of PSB-0739 reversed thermal hyperalgesia and head grooming time in wild-type mice but had no effect in P2ry12-/- mice. Furthermore, PSB-0739 was also effective when applied as a post-treatment. PSB-0739 administration suppressed the expression of c-fos in C1-C2 and trigeminal nucleus caudalis, and decreased the levels of dopamine and 5-hydroxytryptamine in C1-C2 in wild-type mice. Nitroglycerin treatment itself did not change adenosine diphosphate (ADP)-induced platelet activation measured by CD62P up-regulation in wild-type mice. Platelet depletion by anti-mouse CD41 antibody and clopidogrel attenuated nitroglycerin-induced thermal hypersensitivity and head grooming time in mice. Our findings show that acute inhibition of P2Y12 receptors alleviates migraine-like pain in mice by modulating the expression of c-fos and that platelet P2Y12 receptors might contribute to this effect. Thus the blockade of P2Y12 receptors may have therapeutic potential against migraine.

Intracranial nociception.

Understanding intracranial nociceptive innervation is essential to understand the pathophysiology of headaches. Our knowledge about human intracranial nociception comes from sparse observations during neurosurgical procedures performed in awake patients, from human anatomical studies and from experimental studies in animals. In this article we review the anatomical and functional organization underlying nociceptive innervation. Intracranial nociception is mainly mediated by the trigeminal system, except in the posterior cranial fossa that is innervated by the first cervical roots. For decades, the dura mater, its vessels and major cerebral blood vessels were considered as the only intracranial pain-sensitive structures. Recent animal and human studies have suggested that smaller brain arteries and potentially pia mater might also be pain sensitive. Nociceptive neurons innervating intracranial blood vessels project via the ophthalmic division (V1) to the trigeminal ganglion and store several neurotransmitters including glutamate, substance P and calcitonin gene-related peptide (CGRP). The trigeminal ganglion, root and brainstem nuclei have a specific topographic and functional somatotopy. Progressive transition between the trigeminal spinal nucleus and the dorsal horn of the cervical spinal cord, and convergence of nociceptive inputs from the face, intracranial structures and the occipital area on the so-called "trigemino-cervical complex" may explain some headache features, relations between facial and occipital pain, and efficacy of occipital nerve stimulation in headache. The specific anatomic organization of the trigeminal system, from the primary-order neuron in the trigeminal ganglion, to the second-order neuron is the trigeminal nuclei, may explain a part of the various characteristics of headaches.

Percutaneous trigeminal tractotomy for trigeminal neuralgia: Postoperative MRI findings.

Percutaneous trigeminal tractotomy is an ablative procedure that can be used to treat trigeminal neuralgia in patients who have failed prior pharmacologic and surgical treatments. Using perioperative computed tomography (CT) guidance, ablation of the descending spinal trigeminal nucleus and trigeminal tract can be performed precisely to mitigate damage to surrounding structures. These patients are subsequently followed with postoperative imaging and clinical visits to assess long-term pain relief. In this report, we present a series of four patients with trigeminal neuralgia who were had refractory disease after prior medical and surgical interventions. These patients underwent CT-guided percutaneous trigeminal tractotomy for pain relief. The patients underwent postoperative MRI and were followed for up to 6 months for long-term clinical outcomes. For intraoperative CT, we find that preprocedure lumbar contrast injection enables better visualization of the cord during placement of the ablation probe. On postoperative imaging, we find that all four patients have hyperintense lesions on T2-weighted MRI that correspond with the location of the trigeminal nucleus and tract. Three patients had short-term pain relief, one of which continued to have long-term relief. Intraoperative CT and postoperative MRI serve as useful modalities for confirming localization, evaluating complications, and can be used as a metric for quality control.

Netrin1 and reelin signaling are required for the migration of anterolateral system neurons in the embryonic spinal cord.

Projection neurons of the spinal cord dorsal horn which transmit pain, itch, and temperature information to the brain comprise the anterolateral system (AS). A recent molecular and genetic study showed that many developing AS neurons express the transcription factor Phox2a and provided insights into the mechanisms of their ontogeny and wiring of nociceptive neuronal circuits. Here, we show that the loss of the axonal guidance and neuronal migration signal netrin1 results in impaired migration of mouse Phox2a+ AS neurons into the spinal lamina I. Furthermore, we show that in the absence of Dab1, an intracellular transducer of the neuronal migration signal reelin, the migration of spinal lamina V and lateral spinal nucleus Phox2a+ AS neurons is impaired, in line with deficits in nociception seen in mice with a loss of reelin signaling. Together, these results provide evidence that netrin1 and reelin control the development of spinal nociceptive projection neurons, suggesting a mechanistic explanation for studies that link sequence variations in human genes encoding these neurodevelopmental signals and abnormal pain sensation.

The art of facilitation: a delicate hormonal balance!

The art of facilitation: a delicate hormonal balance!

Trigeminal neuropathy causes hypomyelination in the anterior cingulate cortex, disrupts the synchrony of neural circuitry, and impairs decision‐making in male rats

Infraorbital nerve‐chronic constriction injury (ION‐CCI) has become the most popular chronic trigeminal neuropathic pain (TNP) injury animal model which causes prolonged mechanical allodynia. Accumulative evidence suggests that TNP interferes with cognitive functions, however the underlying mechanisms are not known. The aim of this study was to investigate decision‐making performance as well as synaptic and large‐scale neural synchronized alterations in the spinal trigeminal nucleus (SpV) circuitry and anterior cingulate cortex (ACC) neural circuitry in male rats with TNP. Rat gambling task showed that ION‐CCI led to decrease the proportion of good decision makers and increase the proportion of poor decision makers. Electrophysiological recordings showed long‐lasting synaptic potentiation of local field potential in the trigeminal ganglia‐SpV caudalis (SpVc) synapses in TNP rats. In this study, TNP led to disruption of ACC spike timing and basolateral amygdala (BLA) theta oscillation associated with suppressed synchronization of theta oscillation between the BLA and ACC, indicating reduced neuronal communications. Myelination is critical for information flow between brain regions, and myelin plasticity is an important feature for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. We characterized newly formed oligodendrocyte progenitor cells, and mature OLs are reduced in TNP and are associated with reduced myelin strength in the ACC region. The functional disturbances in the BLA‐ACC neural circuitry is pathologically associated with the myelin defects in the ACC region which may be relevant causes for the deficits in decision‐making in chronic TNP state.

Trigeminal Contributions to the Dorsal Cochlear Nucleus in Mouse.

The dorsal cochlear nucleus (DCN) is the first site of multisensory integration in the auditory pathway of mammals. The DCN circuit integrates non-auditory information, such as head and ear position, with auditory signals, and this convergence may contribute to the ability to localize sound sources or to suppress perceptions of self-generated sounds. Several extrinsic sources of these non-auditory signals have been described in various species, and among these are first- and second-order trigeminal axonal projections. Trigeminal sensory signals from the face and ears could provide the non-auditory information that the DCN requires for its role in sound source localization and cancelation of self-generated sounds, for example, head and ear position or mouth movements that could predict the production of chewing or licking sounds. There is evidence for these axonal projections in guinea pigs and rats, although the size of the pathway is smaller than might be expected for a function essential for a prey animals’ survival. However, evidence for these projections in mice, an increasingly important species in auditory neuroscience, is lacking, raising questions about the universality of such proposed functions. We therefore investigated the presence of trigeminal projections to the DCN in mice, using viral and transgenic approaches. We found that the spinal trigeminal nucleus indeed projects to DCN, targeting granule cells and unipolar brush cells. However, direct axonal projections from the trigeminal ganglion itself were undetectable. Thus, secondary brainstem sources carry non-auditory signals to the DCN in mice that could provide a processed trigeminal signal to the DCN, but primary trigeminal afferents are not integrated directly by DCN.

White matter changes in the trigeminal spinal tract in chronic migraineurs: an ex vivo study combining ultra-high-field diffusion tensor imaging and polarized light imaging microscopy.

Chronic migraine (CM) is a disabling neurologic disorder that affects approximately 2% of the general population. Neuroimaging studies show functional involvement of trigeminal structures, such as the trigeminal spinal nucleus (Sp5) in migraine. However, structural changes in the Sp5 and the afferent trigeminal spinal tract (sp5) have never been found. The aim of this study was to test the hypothesis that white matter changes in the sp5 are a key feature of brain alterations in patients with CM. We used diffusion magnetic resonance imaging and polarized light imaging of postmortem brainstem specimens from healthy controls (n = 5) and patients with CM (n = 5) to study white matter alterations in the sp5. Within the sp5, diffusion magnetic resonance imaging metrics included fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity values. Polarized light imaging was used to assess myelin density by a measure of the retardance values in the sp5. This study provides histological evidence that structural alterations occur in the sp5 in patients with CM as compared with healthy controls. Myelin density, as assessed by retardance values, showed to be higher, and a corresponding increase in fractional anisotropy values was observed. In addition, accompanying decreases in mean diffusivity, axial diffusivity, and radial diffusivity values were observed. This study shows that the sp5 undergoes neuroplastic changes, a feature which substantiates evidence for the hyperactivity of the Sp5 in patients with migraine. More insights are needed to observe whether these changes only occur in patients with CM.

Expression of nischarin, an imidazoline 1 receptor candidate protein, in the ventrolateral medulla of newborn rats

The activation of imidazoline 1 (I1) receptors is suggested to stimulate the respiratory drive in newborn rats. Here, we immunohistochemically examined whether nischarin, an I1 receptor candidate protein, is expressed in the ventrolateral medulla, where cardiorespiratory centers are located. Newborn rats (age, 3–5 days) were deeply anesthetized with isoflurane; the brainstem was dissected, sectioned sagittally, and labeled with nischarin. Nischarin-associated signals were observed broadly throughout the newborn rat brainstem, including at motor nuclei (motor trigeminal nucleus and facial nucleus), sensory nuclei (lateral superior olive, medial and spinal vestibular nuclei, cuneate nucleus, spinal trigeminal nucleus, and solitary nucleus), and the rostral and caudal ventrolateral medullar regions. In particular, the rostral ventrolateral medulla included a layer of aggregated nischarin expression along the ventral surface, and the layer was in close contact with GFAP-positive processes. In addition, some Phox2b-positive neurons were positive for nischarin in the region. Our results reveal nischarin expression in the newborn rat brainstem and suggest that I1 receptor activation at the level of the ventrolateral medulla contributes to central chemoreception and respiratory control in newborn rats.

Distribution of nitric oxide in the rock cavy (Kerodon rupestris) brain II: The brainstem

In a recent paper, we described the distribution of Nitric oxide (NO) in the diencephalon of the rock cavy (Kerodon rupestris). This present paper follows this work, showing the distribution of NO synthesizing neurons in the rock cavy's brainstem. For this, we used immunohistochemistry against the neuronal form of nitric oxide synthase (NOS) and NADPH diaphorase histochemistry. In contrast to the diencephalon in the rock cavy, where the NOS neurons were seen to be limited to some nuclei in the thalamus and hypothalamus, the distribution of NOS in the brainstem is widespread. Neurons immunoreactive to NOS (NOS-ir) were seen as rostral as the precommissural nuclei and as caudal as the caudal and gelatinous parts of the spinal trigeminal nucleus. Places such as the raphe nuclei, trigeminal complex, superior and inferior colliculus, oculomotor complex, periaqueductal grey matter, solitary tract nucleus, laterodorsal tegmental nucleus, pedunculopontine tegmental, and other nuclei of the reticular formation are among the locations with the most NOS-ir neurons. This distribution is similar, but with some differences, to those described for other rodents, indicating that NO also has an important role in rock cavy's physiology.

Neurodegenerative disorders affecting the autonomic nervous system: Pure autonomic failure and multiple system atrophy

AbstractPure autonomic failure (PAF) and multiple system atrophy (MSA) are representative neurodegerative diseases present with a severe autonomic dysfunction in the urinary, cardiovascular, and pupillary systems, as well as the gastrointestinal tract and skin/sweat glands. Clinically PAF is characterized by chronic progressive pure autonomic dysfunction occasionally associated with parkinsonism or cognitive dysfunction (Lewy body disease), whereas MSA is associated with cerebellar manifestation and/or parkinsonism. Pathology of both PAF and MSA is characterized by α‐synuclein deposition, but in PAF major involvement exists in the sympathetic ganglion and postganglionic autonomic nerve fibers, whereas MSA mainly affects the central autonomic system, such as the vagal nerve lateral nucleus, locus coeruleus, spinal cord medial lateral nucleus, and sacral Onuf's nucleus. Therefore, it is necessary to evaluate whether peripheral or central autonomic function is predominantly affected by the differential diagnosis of PAF and MSA. Autonomic dysfunction is also frequently present in patients with Parkinson's disease, but usually not so severe as in PAF or MSA. This review summarizes features of autonomic dysfunction in PAF and MSA.

Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity.

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury.