Cerebrospinal fluid-contacting neuron tracing reveals structural and functional connectivity for locomotion in the mouse spinal cord.

Cerebrospinal fluid-contacting neurons (CSF-cNs) are enigmatic mechano- or chemosensory cells lying along the central canal of the spinal cord. Recent studies in zebrafish larvae and lampreys have shown that CSF-cNs control postures and movements via spinal connections. However, the structures, connectivity, and functions in mammals remain largely unknown. Here we developed a method to genetically target mouse CSF-cNs that highlighted structural connections and functions. We first found that intracerebroventricular injection of adeno-associated virus with a neuron-specific promoter and Pkd2l1-Cre mice specifically labeled CSF-cNs. Single-cell labeling of 71 CSF-cNs revealed rostral axon extensions of over 1800 µm in unmyelinated bundles in the ventral funiculus and terminated on CSF-cNs to form a recurrent circuitry, which was further determined by serial electron microscopy and electrophysiology. CSF-cNs were also found to connect with axial motor neurons and premotor interneurons around the central canal and within the axon bundles. Chemogenetic CSF-cNs inactivation reduced speed and step frequency during treadmill locomotion. Our data revealed the basic structures and connections of mouse CSF-cNs to control spinal motor circuits for proper locomotion. The versatile methods developed in this study will contribute to further understanding of CSF-cN functions in mammals.

Structural and functional properties of spinal dorsal horn neurons after peripheral nerve injury change overtime via astrocyte activation.

Chronic pain remains challenging to treat, despite numerous reports of its pathogenesis, including neuronal plasticity in the spinal dorsal horn (SDH). We hypothesized that understanding plasticity only at a specific time point after peripheral nerve injury (PNI) is insufficient to solve chronic pain. Here, we analyzed the temporal changes in synaptic transmission and astrocyte-neuron interactions in SDH after PNI. We found that synaptic transmission in the SDH after PNI changed in a time-dependent manner, which was accompanied by astrocyte proliferation and loss of inhibitory and excitatory neurons. Furthermore, neuronal loss was accompanied by necroptosis. Short-term inhibition of astrocytes after PNI suppressed these physiological and morphological changes and long-term pain-related behaviors. These results are the first to demonstrate that the inhibition of astrocyte proliferation after PNI contributes to the long-term regulation of plasticity and of necroptosis development in the SDH.

Serotonin Plays a Key Role in the Development of Opioid-Induced Hyperalgesia in Mice.

Opioid usage for pain therapy is limited by its undesirable clinical effects, including paradoxical hyperalgesia, also known as opioid-induced hyperalgesia (OIH). However, the mechanisms associated with the development and maintenance of OIH remain unclear. Here, we investigated the effect of serotonin inhibition by the 5-HT3 receptor antagonist, ondansetron (OND), as well as serotonin deprivation via its synthesis inhibitor para-chlorophenylalanine, on mouse OIH models, with particular focus on astrocyte activation. Co-administering of OND and morphine, in combination with serotonin depletion, inhibited mechanical hyperalgesia and astrocyte activation in the spinal dorsal horn of mouse OIH models. Although previous studies have suggested that activation of astrocytes in the spinal dorsal horn is essential for the development and maintenance of OIH, herein, treatment with carbenoxolone (CBX), a gap junction inhibitor that suppresses astrocyte activation, did not ameliorate mechanical hyperalgesia in mouse OIH models. These results indicate that serotonin in the spinal dorsal horn, and activation of the 5-HT3 receptor play essential roles in OIH induced by chronic morphine, while astrocyte activation in the spinal dorsal horn serves as a secondary effect of OIH. Our findings further suggest that serotonergic regulation in the spinal dorsal horn may be a therapeutic target of OIH. PERSPECTIVE: The current study revealed that the descending serotonergic pain-facilitatory system in the spinal dorsal horn is crucial in OIH, and that activation of astrocytes is a secondary phenotype of OIH. Our study offers new therapeutic targets for OIH and may help reduce inappropriate opioid use.

Congenital Tracheal Aplasia Without Prenatal Diagnosis Masked by Maternal Obesity and Gestational Diabetes: A Case Report.

This case report describes a neonate with tracheal aplasia first diagnosed after birth due to the presentation of respiratory distress, absence of crying, and unsuccessful tracheal intubation. The most common finding with tracheal aplasia is polyhydramnios. However, diagnosis remains challenging in the prenatal period. In this case, maternal obesity and gestational diabetes made diagnosis more difficult. The only lifesaving treatment available is ventilation through esophageal intubation or tracheostomy. However, in some cases, tracheostomy is not an option.

Corrigendum: Intravenous administration of lidocaine directly acts on spinal dorsal horn and produces analgesic effect: An in vivo patch-clamp analysis.

This corrects the article DOI: 10.1038/srep26253.

Intravenous administration of lidocaine directly acts on spinal dorsal horn and produces analgesic effect: An in vivo patch-clamp analysis.

Intravenous lidocaine administration produces an analgesic effect in various pain states, such as neuropathic and acute pain, although the underlying mechanisms remains unclear. Here, we hypothesized that intravenous lidocaine acts on spinal cord neurons and induces analgesia in acute pain. We therefore examined the action of intravenous lidocaine in the spinal cord using the in vivo patch-clamp technique. We first investigated the effects of intravenous lidocaine using behavioural measures in rats. We then performed in vivo patch-clamp recording from spinal substantia gelatinosa (SG) neurons. Intravenous lidocaine had a dose-dependent analgesic effect on the withdrawal response to noxious mechanical stimuli. In the electrophysiological experiments, intravenous lidocaine inhibited the excitatory postsynaptic currents (EPSCs) evoked by noxious pinch stimuli. Intravenous lidocaine also decreased the frequency, but did not change the amplitude, of both spontaneous and miniature EPSCs. However, it did not affect inhibitory postsynaptic currents. Furthermore, intravenous lidocaine induced outward currents in SG neurons. Intravenous lidocaine inhibits glutamate release from presynaptic terminals in spinal SG neurons. Concomitantly, it hyperpolarizes postsynaptic neurons by shifting the membrane potential. This decrease in the excitability of spinal dorsal horn neurons may be a possible mechanism for the analgesic action of intravenous lidocaine in acute pain.

Perforation of the superior vena cava 5 days after insertion of a central venous catheter through the left internal jugular vein.

We describe a very rare case of an indwelling central venous catheter (CVC) through the left internal jugular vein that perforated the superior vena cava (SVC) wall postoperatively, although the CVC was placed in the appropriate position preoperatively. Three days after CVC insertion, a chest radiograph showed that the CVC tip had moved from the lower SVC to the upper SVC. Five days after the insertion, computed tomography showed SVC perforation and the resulting hydrothorax. In cases of CVC insertion through the left side, the CVC tip should not be placed in the upper SVC (zone B). Considering individual clinical factors and the indwelling period for the CVC, the left innominate vein (zone C) may be a suitable site for the left-sided CVC tip to reduce the risk of SVC perforation.