Vagus nerve stimulation activates two distinct neuroimmune circuits converging in the spleen to protect mice from kidney injury

Acute kidney injury is highly prevalent and associated with high morbidity and mortality, and there are no approved drugs for its prevention and treatment. Vagus nerve stimulation (VNS) alleviates inflammatory diseases including kidney disease; however, neural circuits involved in VNS-induced tissue protection remain poorly understood. The vagus nerve, a heterogeneous group of neural fibers, innervates numerous organs. VNS broadly stimulates these fibers without specificity. We used optogenetics to selectively stimulate vagus efferent or afferent fibers. Anterograde efferent fiber stimulation or anterograde (centripetal) sensory afferent fiber stimulation both conferred kidney protection from ischemia–reperfusion injury. We identified the C1 neurons–sympathetic nervous system–splenic nerve–spleen–kidney axis as the downstream pathway of vagus afferent fiber stimulation. Our study provides a map of the neural circuits important for kidney protection induced by VNS, which is critical for the safe and effective clinical application of VNS for protection from acute kidney injury.

Synaptic Dynamics of the Feed-forward Inhibitory Circuitry Gating Mechanical Allodynia in Mice

Background The authors’ previous studies have found that spinal protein kinase C γ expressing neurons are involved in the feed-forward inhibitory circuit gating mechanical allodynia in the superficial dorsal horn. The authors hypothesize that nerve injury enhances the excitability of spinal protein kinase C γ expressing interneurons due to disinhibition of the feed-forward inhibitory circuit, and enables Aβ primary inputs to activate spinal protein kinase C γ expressing interneurons. Methods Prkcg-P2A-tdTomato mice were constructed using the clustered regularly interspaced short palindromic repeats and clustered regularly interspaced short palindromic repeats-associated nuclease 9 technology, and were used to analyze the electrophysiologic properties of spinal protein kinase C γ expressing neurons in both normal conditions and pathologic conditions induced by chronic constriction injury of the sciatic nerve. Patch-clamp whole cell recordings were used to identify the nature of the dynamic synaptic drive to protein kinase C γ expressing neurons. Results Aβ fiber stimulation evoked a biphasic synaptic response in 42% (31 of 73) of protein kinase C γ expressing neurons. The inhibitory components of the biphasic synaptic response were blocked by both strychnine and bicuculline in 57% (16 of 28) of neurons. Toll-like receptor 5 immunoreactive fibers made close contact with protein kinase C γ expressing neurons. After nerve injury, the percentage of neurons double-labeled for c-fos and Prkcg-P2A-tdTomato in animals walking on a rotarod was significantly higher than that in the nerve injury animals (4.1% vs. 9.9%, 22 of 539 vs. 54 of 548,P < 0.001). Aβ fiber stimulation evoked burst action potentials in 25.8% (8 of 31) of protein kinase C γ expressing neurons in control animals, while the proportion increased to 51.1% (23 of 45) in nerve injury animals (P = 0.027). Conclusions The Prkcg-P2A-tdTomato mice the authors constructed provide a useful tool for further analysis on how the spinal allodynia gate works. The current study indicated that nerve injury enhanced the excitability of spinal protein kinase C γ expressing interneurons due to disinhibition of the feed-forward inhibitory circuit, and enabled Aβ primary inputs to activate spinal protein kinase C γ expressing interneurons. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Transient effect of mossy fiber stimulation on spatial firing of CA3 neurons

Strong hippocampal mossy fiber synapses are thought to function as detonators, imposing ‘teaching’ signals onto CA3 neurons during new memory formation. For an empirical test of this long-standing view, we examined effects of stimulating mossy fibers on spatial firing of CA3 neurons in freely-moving mice. We found that optogenetic stimulation of mossy fibers can alter CA3 spatial firing, but their effects are only transient. Spatially restricted mossy fiber stimulation, either congruent or incongruent with CA3 place fields, was more likely to suppress than enhance CA3 neuronal activity. Also, changes in spatial firing induced by optogenetic stimulation reverted immediately upon stimulation termination, leaving CA3 place fields unaltered. Our results do not support the traditional view that mossy fibers impose teaching signals onto CA3 network, and show robustness of established CA3 spatial representations.

Non-synaptic signaling from cerebellar climbing fibers modulates Golgi cell activity

Golgi cells are the principal inhibitory neurons at the input stage of the cerebellum, providing feedforward and feedback inhibition through mossy fiber and parallel fiber synapses. In vivo studies have shown that Golgi cell activity is regulated by climbing fiber stimulation, yet there is little functional or anatomical evidence for synapses between climbing fibers and Golgi cells. Here, we show that glutamate released from climbing fibers activates ionotropic and metabotropic receptors on Golgi cells through spillover-mediated transmission. The interplay of excitatory and inhibitory conductances provides flexible control over Golgi cell spiking, allowing either excitation or a biphasic sequence of excitation and inhibition following single climbing fiber stimulation. Together with prior studies of spillover transmission to molecular layer interneurons, these results reveal that climbing fibers exert control over inhibition at both the input and output layers of the cerebellar cortex.

Intraoperative neuromonitoring of hypogastric plexus branches during surgery for rectal cancer – preliminary report

Aim: The aim of this study was to present our preliminary experience with intraoperative neuromonitoring during rectal resection. Materials and methods: We qualified 4 patients (2 women, 2 men; age 42 – 53 years) with rectal cancer for surgery with intraoperative neuromonitoring. In all patients, functional tests of the anorectal area were performed before surgery. Action potentials from the sphincter complex in response to nerve fiber stimulation were recorded with electrodes implanted before surgery. Moreover, we inserted a standard, 18FR Foley’s urinary catheter to which a T-tube was connected to allow urine outflow and measurement of pressure changes in the bladder induced by detrusor contractions during stimulation. Results: Setting up neuromonitoring prolonged surgery time by 30 to 40 minutes, or even by 60 to 80 minutes in the case of the first two patients. Neuromonitoring itself took additional 20 to 30 minutes during surgery. In all patients, we stimulated branches of the inferior hypogastric plexus in their anatomical position during dissection. In three patients, we evoked responses both from the bladder and the sphincter in all planes of stimulation. In one patient, there was no response from the left side of the bladder, and in the same patient, we observed symptoms of neurogenic bladder. Conclusions: Based on the available literature and our own experience, we state that monitoring of bladder pressure and electromyographic signals from rectal sphincters enables visualization and preservation of autonomic nervous system structures, both sympathetic and parasympathetic. Intraoperative signals seem to be correlated with clinical presentation and functional examinations after surgery. In order to objectify our results, it is necessary to perform functional examinations before and after surgery in a larger group of patients.