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[Display omitted] Extracranial waste transport from the brain interstitial fluid to the deep cervical lymph node (dCLN) is not extensively understood. The present study aims to show the cranial nerves that have a role in the transport of brain lymphatics vessels (LVs), their localization, diameter, and number using podoplanin (PDPN) and CD31 immunohistochemistry (IHC) and Western blotting. Cranial nerve samples from 6 human cases (3 cadavers, and 3 autopsies) were evaluated for IHC and 3 autopsies for Western blotting. The IHC staining showed LVs along the optic, olfactory, oculomotor, trigeminal, facial, glossopharyngeal, accessory, and vagus nerves. However, no LVs present along the trochlear, abducens, vestibulocochlear, and hypoglossal nerves. The LVs were predominantly localized at the endoneurium of the cranial nerve that has motor components, and LVs in the cranial nerves that had sensory components were present in all 3 layers. The number of LVs accompanying the olfactory, optic, and trigeminal nerves was classified as numerous; oculomotor, glossopharyngeal, vagus, and accessory was moderate; and facial nerves was few. The largest diameter of LVs was in the epineurium and the smallest one was in the endoneurium. The majority of Western blotting results correlated with the IHC. The present findings suggest that specific cranial nerves with variable quantities provide a pathway for the transport of wastes from the brain to dCLN. Thus, the knowledge of the transport of brain lymphatics along cranial nerves may help understand the pathophysiology of various neurological diseases. [ABSTRACT FROM AUTHOR]

• Tinnitus affects the quality of life of millions of people, but it is still incurable in most cases. • The transcutaneous vagus nerve stimulation (tVNS) alone can control the tinnitus-associated mood and behavioral disturbances, so it has an important role in tinnitus relief. • The combination of tVNS and tones can reduce the perception and severity of salicylate-induced tinnitus. Tinnitus is the most common symptom of auditory system disorders. It affects the quality of life of millions of people, but it is still incurable in most cases. Vagus nerve stimulation (VNS) therapy is a potential new treatment for subjective tinnitus. In this study, transcutaneous vagus nerve stimulation (tVNS) combined with tones was utilized to treat salicylate-induced tinnitus since salicylate is a reliable and convenient approach for rapidly inducing tinnitus. Wistar rats were divided into acoustic stimulation alone (AS, n = 6), tVNS alone (n = 6), and tVNS with AS (n = 6) groups for behavioral and electrophysiological tests. They were assessed by auditory brainstem response (ABR), prepulse inhibition (PPI), gap prepulse inhibition of the acoustic startle (GPIAS), social interactions, and aggressive behavior tests at baseline and seven days' post-salicylate (175 mg/kg, twice a day) injection. The inhibition percentage of the GPIAS test was significantly reduced post-salicylate injection in the tVNS and AS alone groups, while it was not significant in the tVNS with AS group. There was no significant difference in the mean percentage of the GPIAS test between the tVNS groups (with or without AS) after salicylate injections. Social interactions were significantly different in the AS alone group pre- and post-salicylate injections, but they were not significant in other groups. Moreover, the results of aggressive behavior tests showed significantly increased post-salicylate injections in the AS alone group, while they were not significant in the tVNS groups (with or without AS). The current study revealed that the application of tVNS alone produced improved social interaction and mood and alleviated salicylate-induced tinnitus severity. Moreover, combining tVNS with acoustic stimulation can prevent salicylate-induced tinnitus. [ABSTRACT FROM AUTHOR]

• Surgery-induced cognitive impairment in aged rats is relieved noninvasively by aVNS. • Treatment with aVNS attenuates surgery-related neuroinflammation in aged rats. • Treatment with aVNS reduces the apoptosis induced by surgery in aged rats. • aVNS also diminishes the surgery-induced Aβ production and tau phosphorylation. Postoperative cognitive dysfunction (POCD) has been increasingly recognized as a significant complication after surgery, especially in senior patients. Vagus nerve stimulation (VNS) reportedly provides beneficial effects against various brain disorders, supporting a hypothesis of its protective role in POCD. However, direct stimulation of the vagus nerve is invasive, as it requires a surgical incision in the neck. Thus, we employed a non-invasive VNS method by stimulating the dermatome in the external ear, which is innervated by the vagus nerve (auricular vagus nerve stimulation; aVNS) and sought to investigate the efficacy of this method in treating surgery-induced cognitive dysfunction in an aged rat model of POCD. We observed that the treatment of aVNS alleviated postoperative memory impairment after exploratory laparotomy surgery, as demonstrated by the shorter swimming latency and distance in Morris water maze tests. Moreover, aVNS also reduced postoperative apoptosis in the hippocampus of the aged rats. Concomitant with these beneficial effects, we found that treatment with aVNS attenuated postoperative neuroinflammation (i.e., the protein level of interleukin-1β and tumor necrosis factor-α, along with the nuclear protein expression of NF-κB) and Alzheimer's-related pathology (tau phosphorylation at AT-8 and Ser396, as well as the levels of Aβ40 and Aβ42) in the hippocampus of the aged rats. In conclusion, our study is the first to reveal the neuroprotective effect of aVNS against POCD. This effect might be attributed to the inhibition of neuroinflammation and Alzheimer's-related pathology. This study suggests non-invasive aVNS may serve as a promising method for clinical treatment of POCD. [ABSTRACT FROM AUTHOR]

Highlights • Some vagal afferents are thermosensitive and may mediate visceral thermal reflexes. • The Vagus nerve is critical for the neuro-immune axis but may not contribute to infection and inflammation induced fever. • The vagus nerve is involved in metabolism and energy expenditure, but its role in temperature control is unclear. • Cell-type specific genetic analysis would help reveal the precise role of the vagus nerve in thermoregulation. Abstract While thermosensation from external environment has been extensively studied, physiological responses to temperature changes inside the body and the underlying regulatory mechanisms are less understood. As a critical link between body and brain that relays visceral organ information and regulates numerous physiological functions, the vagus nerve has been proposed to mediate diverse visceral thermal reflexes and indirectly regulate body temperature. However, the precise role of the vagus nerve in body thermal responses or visceral organ-related thermoregulation is still under debate due to extensive contradictory results. This data discrepancy is likely due to the high cell heterogeneity in the vagus nerve, as diverse vagal neuron types mediate numerous and sometimes opposite physiological functions. Here, we will review evidences that support and against the role of the vagus nerve in body thermosensation and thermoregulation and discuss potential future approaches for better understanding of this critical issue. [ABSTRACT FROM AUTHOR]

• Infantile epileptic spasms (IESS) are a devastating and refractory seizure syndrome. • Prenatal betamethasone/postnatal NMDA rat model of IESS was ported to mice. • Interspecies developmental differences required multiple adjustments to the model. • Prenatal betamethasone may not be necessary to render mice susceptible to ACTH. • Expansion to other mouse strains may include additional modifications of the model. Epileptic spasms during infancy represent a devastating and refractory epilepsy syndrome. To advance studies on mechanisms and treatment using available mouse mutant models, we transferred our validated rat model of epileptic spasms to mice. Initially, we determined sensitivity of C57BL/6J mice to various doses (12–20 mg/kg) of NMDA on postnatal day 11 (P11) and P15. We primed mice with different doses of betamethasone (0.4–2.0 mg/kg) prenatally on gestational day (G)14 or G12 and tested spasms on P11. We also tested 2 different ACTH treatment paradigms (0.3 or 1.0 mg/kg) in prenatally primed as well as naïve mice. Data show that spasms in P11 mice, can be induced with the highest yield after 12 mg/kg dose of NMDA. Prenatal priming on G14 did not modify response to NMDA or sensitize spasms to ACTH. The betamethasone priming on G12 resulted in an increase in the number of NMDA-triggered spasms. Data indicate that the model transfer from rats to mice is non-linear and differences in prenatal brain development, metabolic rates, as well as sensitivity to convulsant drugs have to be considered. [ABSTRACT FROM AUTHOR]

Objective The pathogenesis of sepsis associated encephalopathy (SAE) remains poorly understood. Vagus nerve plays an important role in gut-microbiota-brain axis. This study aimed to investigate whether vague nerve is a key mediator of the impact of intestinal microbiota on SAE. Methods Male rats were randomly divided into four groups (n = 20): SHAM (SH) group, lipopolysaccharide (LPS) group, fecal microbiota transplantation (FMT) +LPS group, and vagotomy (VGX) + LPS + FMT group. The left cervical vagotomy was performed 30 min before LPS administration in LPS + FMT + VGX group. LPS+ FMT and LPS + FMT + VGX groups received nasogastric infusion of feces from healthy donor three times a day. Fecal samples were collected every two days to monitor changes in microbiota composition by 16S rDNA analysis. Brain function was evaluated by behavioral tests and EEG. The levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, IL-10 in brain cortex were detected by ELISA. The expression of Iba-1 in brain cortex was assessed by immunohistochemistry and Western blot analysis. Results Significant modification of microbiota composition, characterized by a profound increase of commensals in the Firmicutes phylum and depletion of opportunistic organisms in the Proteobacteria phylum, was observed in FMT groups compared to LPS group. Furthermore, we identified a reconstituted bacterial community enriched in Firmicutes and depleted of Proteobacteria. In both FMT groups the diversity of the fecal microbiota and the microbiota composition were similar to SH group. LPS mice treated with FMT demonstrated a better spatial memory and less EEG abnormalities, significantly attenuated levels of IL-1β, IL-6, TNF-α, and decreased number of Iba-1 positive microglia in the cortex, but these beneficial effects of FMT were reversed by VGX. Conclusions FMT can change intestinal microbiota in sepsis patients, and vagus nerve is a key mediator between intestinal microbiota and SAE. These findings suggest that FMT and vagus nerve are potential therapy targets for treating SAE. [ABSTRACT FROM AUTHOR]

Transient Receptor Potential Melastatin 8 (TRPM8) is a cold receptor activated by mild cold temperature (<28 °C). TRPM8 expressed in cutaneous sensory nerves is involved in cold sensation and thermoregulation. TRPM8 mRNA is detected in various tissues, including the gastrointestinal mucosa, and in the vagal afferent nerve. The relationship between vagal afferent nerve-specific expression of TRPM8 and thermoregulation remains unclear. In this study, we aimed to investigate whether TRPM8 expression in the vagal afferent nerve is involved in autonomic thermoregulation. We found that intragastric administration of 1,8-cineole, a TRPM8 agonist, increased intrascapular brown adipose tissue and colonic temperatures, and M8-B-treatment (TRPM8 antagonist) inhibited these responses. Intravenous administration of 1,8-cineole also showed similar effects. In vagotomized mice, the responses induced by intragastric administration of 1,8-cineole were attenuated. These results suggest that TRPM8 expressed in tissues apart from cutaneous sensory nerves are involved in autonomic thermoregulation response. [ABSTRACT FROM AUTHOR]

While the parasympathetic nervous system appears to be involved in the regulation of tumor progression, its exact role is still unclear. Therefore, using a rat BP6-TU2 fibrosarcoma tumor model, we investigated the effect of (1) reduction of vagal activity produced by subdiaphragmatic vagotomy; and (2) enhancement of vagal activity produced by continuous delivery of electric impulses to the cervical part of the vagus nerve on tumor development and survival of tumor-bearing rats. We also evaluated the expression of cholinergic receptors within in vitro cultivated BP6-TU2 cells. Interestingly, we found that both, vagal stimulation and subdiaphragmatic vagotomy slightly reduced tumor incidence. However, survival of tumor-bearing rats was not affected by any of the experimental approaches. Additionally, we detected mRNA expression of the α1, α2, α5, α7, and α10 subunits of nicotinic receptors and the M1, M3, M4, and M5 subtypes of muscarinic receptors within in vitro cultivated BP6-TU2 cells. Our data indicate that the role of the vagus nerve in modulation of fibrosarcoma development is ambiguous and uncertain and requires further investigation. [ABSTRACT FROM AUTHOR]

• ZDF rats are a useful rodent model for MDD co-occurring with T2D. • taVNS has antidiabetic and antidepressant-like effects in ZDF rats. • taVNS inhibits ZDF rats' limbic-regional P2X7R expression, which may be one of the taVNS antidepressant-like mechanisms. Zucker diabetic fatty (ZDF) rats develop type 2 diabetes (T2D) along with depressive-like behaviors. Transcutaneous auricular vagal nerve stimulation (taVNS) has antidiabetic and antidepressant-like effects in ZDF rats; however, the underlying antidepressant-like mechanisms are unclear. The purinergic receptor P2X7R, which is related to inflammation and depression, is upregulated in the limbic brain regions of depressed patients and rodents and is considered as a potential therapeutic target. Thus, this study aimed to provide preliminary evidence at the molecular level of taVNS antidepressant-like effect in ZDF rats through testing their limbic-regional P2X7R expression. ZDF rats were subjected to taVNS and transcutaneous non-vagal nerve stimulation (tnVNS). Body weight and blood glucose levels were monitored weekly. Depressive-like behaviors were evaluated with the open-field test (OFT) and forced swimming test (FST). Limbic-regional P2X7R expression was examined by western blotting (WB). P2X7R expressing cells were detected by immunohistochemistry (IHC). Compared to their lean littermates (ZL rats), ZDF rats developed obesity, hyperglycemia, and depressive-like behaviors with elevated limbic-regional P2X7R expression. taVNS but not tnVNS lowered body weight, reduced and stabilized blood glucose levels, suppressed limbic-regional P2X7R expression, and reversed the depressive-like behaviors. P2X7R was found primarily expressed in ZDF rats' limbic-regional astrocytes. In conclusion, taVNS inhibits ZDF rats' limbic-regional P2X7R expression, which may be one of the taVNS antidepressant-like mechanisms. [ABSTRACT FROM AUTHOR]

• Lamotrigine and retigabine increase the motor threshold in rats using TMS. • Lamotrigine and retigabine inhibit maximal electroshock-induced seizures in rats. • Effective doses in the TMS study are equivalent to those for antiepileptic effects. • TMS study may be a useful translational approach for predicting antiepileptic effects. Transcranial magnetic stimulation (TMS) is a neurophysiological technique that enables noninvasive evaluation of neuronal excitability in the brain. In the past, a large number of antiepileptic drugs were shown to increase the motor threshold (MT) in clinical TMS studies, suggesting the inhibition of excessive neuronal excitability. To facilitate drug development, the confirmation of similar changes in neurophysiological biomarkers in both preclinical and clinical studies is crucial; however, until now, there have been no data showing the drug efficacies on neuronal excitabilities as measured using TMS in rodents. In this study, we found that the antiepileptic drugs, lamotrigine (10 mg/kg) and retigabine (5 mg/kg), significantly increased the MT in rats using TMS, which is similar to clinical study findings. In addition, we demonstrated that these drugs could inhibit maximal electroshock (MES)-induced seizures in rats when given at the same dose required to be effective in the TMS experiment. These findings suggest that the effects of antiepileptic drugs in our rat TMS system have a similar sensitivity to that of the antiepileptic effects in rats with MES-induced seizures. The measurement of MT in a TMS study may be a noninvasive translational approach for predicting antiepileptic efficacy in drug development. [ABSTRACT FROM AUTHOR]

Abstract: The multiple-site optical recording technique with a voltage-sensitive dye, NK2761, was used to survey the functional organization of neuronal networks related to the vagus nerve (N.X) in the E16-stage rat brainstem. When we stimulated N.X, in addition to the responses in the vagal sensory nucleus (nucleus of the tractus solitarius (NTS)) on the stimulated side, other response areas were bilaterally detected. Characteristics of the optical signals in these areas suggested that they correspond to neural activity in the second/higher-ordered nucleus of the vagal pathway. The first area was located at the level of the pons. Based upon morphological information, we suggest that this area corresponds to the parabrachial nucleus (PBN), which receives inputs from the NTS. The second area was located between the NTS and the PBN. We suggest that this area is the A5 noradrenergic group. These results suggest that the N.X-related neural networks are established similarly to the adult pattern from an early developmental stage. [Copyright &y& Elsevier]

Abstract: Damage to peripheral nerve branches triggers activation of microglia in CNS areas containing motor neuron soma and primary afferent terminals of the damaged fibers. Furthermore, microglial activation occurs in areas containing the soma and terminals of spared nerve branches of a damaged nerve. Because the abdominal viscera are innervated by spinal afferents as well as vagal afferents and efferents, we speculated that spinal nerves might respond like spared nerve branches following damage to vagal fibers. Therefore, we tested the hypothesis that damage to the abdominal vagus would result in microglial activation in vagal structures—the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve (DMV), and nodose ganglia (NG)—as well as spinal cord (SC) segments that innervate the abdominal viscera. To test this hypothesis, rats underwent subdiaphragmatic vagotomy or sham surgery and were treated with saline or the microglial inhibitor, minocycline. Microglial activation was determined by quantifying changes in the intensity of fluorescent staining with a primary antibody against ionizing calcium adapter binding molecule 1 (Iba1). We found that subdiaphragmatic vagotomy significantly activated microglia in the NTS, DMV, and NG two weeks post-vagotomy. Microglial activation remained significantly increased in the NG and DMV for at least 42 days. Surprisingly, vagotomy significantly decreased microglial activation in the SC. Minocycline treatment attenuated microglial activation in all studied areas. Our results indicate that microglial activation in vagal structures following abdominal vagal damage is accompanied by suppression of microglial activation in associated areas of the spinal cord. [Copyright &y& Elsevier]

Abstract: We examined in infant rats whether cardiac afferent neurons in the nodose ganglia (NG) express transient receptor potential vanilloid 1 (TRPV1) receptors. Anesthetized rats (9–11 days old) were injected with 2μl of a fluorescent retrograde tracer (Fluoro-Gold, FG) into the ventricular wall through the anterior epicardial surface. After 2 days, the NG were excised under anesthesia for identification of FG-labeled neurons and immunohistochemical analysis. Of 3858 NG neurons, 5% (202 neurons) were labeled with FG. Among the FG-labeled neurons, 180 (89%) were TRPV1 positive, of which 123 co-expressed 200-kDa neurofilaments (NF200), which is specific for myelinated nerve fibers. Among the FG-labeled neurons that expressed both TRPV1 and NF200, 37 had relatively large cell diameters (>26μm) (range: 12–38μm). In conclusion, in infant rats, most cardiac afferent neurons (both myelinated and unmyelinated) in the NG may express TRPV1 receptors. Although functional properties such as those related to the arterial baroreflex may vary among the neurons, our results suggest that, in immature animals, TRPV1 receptors help convey cardiac sensations and control autonomic reflexes. [Copyright &y& Elsevier]

Abstract: Vagus nerve stimulation has been used for the treatment of neuropsychiatric disorders, such as epilepsy. However, little is known whether it is also effective for the treatment of heroin dependence, in particular for relapse to heroin seeking. In the present study, we investigated the effects of vagus nerve stimulation on reinstatement (relapse) of heroin-seeking behavior induced by heroin priming or heroin-associated cues. The rats were trained for heroin self-administration for 14days and followed by extinction training in which heroin was replaced by saline and heroin-associated cues were turned off. In addition, animals were also received daily electric stimulation of vagus nerve (30Hz, pulse width of 0.5ms, 0.5mA (low-intensity) or 1mA (high-intensity); 30s on, 5min off; 10 continuous cycle per day) or false stimulation during extinction training. We found that such vagus nerve stimulation significantly inhibited heroin priming (0.25mg/kg, s.c.) – or heroin-associated conditioned cue-induced reinstatement of drug-seeking behavior, when compared to false stimulation control. Further, such a behavioral inhibition was correlated to a reduction in the expression of FosB and an increase in the expression of phosphorylation of cAMP response element binding protein (p-CREB) in nucleus accumbens. The data suggest that vagus nerve stimulation may inhibit heroin- or heroin cue-induced relapse, possibly by regulation of the expression of Fos and CREB in nucleus accumbens. [Copyright &y& Elsevier]

Abstract: Niijima previously reported that intragastric infusion of glutamate has increased the activity of the efferent parasympathetic nerves that innervate the stomach and pancreas in urethane-anesthetized rats. In the present study, the effects of intragastric injection of glutamate on the efferent sympathetic nerve outflow to the kidney and the white adipose tissue in rats were analyzed. Although the sympathetic nerve activities of the renal and white adipose tissues were not affected after intragastric glutamate injection in rats that were fasted for 3h, these activities were significantly accelerated after intragastric glutamate injection in rats that were fasted for 48h. Moreover, to test the role of the afferent neural pathway on sympathoexcitation caused by glutamate injection, the effects of vagotomy, or sympathetic denervation, were also examined. In vagotomized rats, the sympathetic nerve activities of the renal and white adipose tissues were eliminated after glutamate injection, but these activities remained unaffected in rats that underwent sympathetic denervation. Thus, the stimulating effects of glutamate administration on the sympathetic nerve activities of the renal and white adipose tissues could depend on the length of the fast and the vagal afferent pathway. [Copyright &y& Elsevier]

Abstract: Physical exercise can induce immunohistochemical changes and cell proliferation in the hippocampus. One of the main effects of prolonged exercise is resting bradycardia, most probably caused by enhanced vagal activity. To investigate whether physical exercise can cause neurochemical and morphological changes in vagal afferent neurons, we performed immunohistochemical studies of nodose neurons using isolectin B4 (IB4), 200-kDa neurofilament protein (N52) and calretinin in adult female rats. To distinguish subpopulations of neurons projecting to the left ventricle, we applied a Fast Blue patch to the epicardial surface of the left ventricle. Treadmill running for 8 weeks significantly increased the size of N52-positive cardiac projecting neurons. Furthermore, the proportion of IB4-positive neurons among all nodose ganglia neurons was significantly higher in trained animals. These data indicate that exercise leads to plastic changes in nodose ganglia neurons that may initiate changes of vagal activity caused by prolonged exercise. [ABSTRACT FROM AUTHOR]

Abstract: The anti-cancer chemotherapeutic agent cisplatin induces an acute (∼24h) and delayed (∼24–72h+) emetic response in humans; whereas the mechanism mediating the acute phase has been characterised, the delayed phase is relatively poorly understood. We have used nerve lesions (abdominal vagus, VX; greater splanchnic nerve, GSNX) and area postrema ablation (APX) in the ferret model of cisplatin (5mg/kg, i.p.) delayed emesis and demonstrated that VX and VX+GSNX did not significantly modify the delayed emetic response (24–72h), which consisted of 276.0±62.8retches+vomits (R+V) in sham-operated ferrets and 167.2±34.0R+V and 214.8±40.2R+V, in the VX and VX+GSNX groups, respectively. APX virtually abolished the delayed phase of emesis and sham-operated ferrets had 93.0±22.9R+V whilst only 6.0±3.6R+V (p =0.009) were observed in APX animals. These data suggest that, in contrast to the acute emetic response triggered by cisplatin, the delayed phase does not rely on abdominal visceral afferents but is mediated via the area postrema. [Copyright &y& Elsevier]

Abstract: Background and purpose: We sought to determine the effect of vagus nerve stimulation (VNS) on infarct size after transient focal cerebral ischemia in rats. Methods: Ischemia was produced by transient filament occlusion of the right middle cerebral artery. Stimulating electrodes were implanted on the cervical part of the right vagus nerve. Electrical stimulation was initiated 30min after the induction of ischemia, and delivered for 30s at every 30min for 3h in experimental group 1 and at every 5min for 1h in experimental group 2. All the procedures were duplicated but no stimulus was delivered in the control group. Functional deficit was evaluated and animals were killed to determine the infarct size 24h after ischemia. Results: Ischemic lesion volume was smaller in VNS-treated animals as compared with control animals; the relative percentage of contralateral hemispheric volume that underwent infarction was 16.2±3.2% in the VNS and 33.0±5.0% in the control arms in experimental group 1 (p <0.05). The respective values for experimental group 2 were 19.8±0.5% and 37.9±2.6% (p <0.05). VNS-treated animals were significantly more likely to have better functional scores at 24h as compared with control animals. The functional score improved by 50% in experimental group 1 and 44% in experimental group 2 (p <0.05 for both groups). Conclusion: VNS appears to offer protection against acute ischemic brain injury. [Copyright &y& Elsevier]

Abstract: Using voltage-sensitive dye recording, we traced the ontogenetic expression of neural excitability related to the glossopharyngeal nerve (N. IX) and the vagus nerve (N. X) in the embryonic chick brainstem. At the 3.5-day embryonic stage, by averaging optical signals, we succeeded in recording very small action potential-related optical responses (ΔI/I <10−4) induced by N. IX stimulation in the nucleus of the glossopharyngeal nerve (motor nucleus). This suggests that glossopharyngeal excitability in the motor nucleus is first generated no later than this developmental stage. On the other hand, action potential-related optical responses induced by N. X stimulation were first detected at the 4-day embryonic stage. Comparison with morphogenesis indicated that glossopharyngeal and vagal motoneurons acquire their excitability and send their axons to the periphery soon after they leave the proliferative pool. [Copyright &y& Elsevier]

Abstract: Neurotrophin-4 (NT-4) deficient mice exhibit substantial loss of intestinal vagal afferent innervation and short-term deficits in feeding behavior, suggesting reduced satiation. However, they do not show long-term changes in feeding or body weight because of compensatory behaviors. The present study examined whether high-fat hyperphagia induction would overcome compensation and reveal long-term effects associated with the reduced vagal sensory innervation of NT-4 mutants. First, modifications of a feeding schedule previously developed in rats were examined in wild-type mice to identify the regimen most effective at producing hyperphagia. The most successful schedule, which was run for 26 days, included access to a 43%-fat diet and pelleted chow every other day and access to only powdered chow on the alternate days. On high-fat access days mice consumed 25% more calories than mice with continuous daily access to the same high-fat diet and pelleted chow. This feeding regimen also induced hyperphagia in NT-4 deficient mice and their wild-type controls: on high-fat exposure days mutants consumed 35% more calories relative to continuous-access mutants, and wild types ate 25% more than continuous-access wild types. Moreover, on high-fat access days the alternating NT-4 mutants significantly increased caloric intake by 9% compared to alternating wild types. Thus, high-fat hyperphagia appeared to override compensation, permitting short-term changes in meal consumption by mutants that accrued into long-term changes in total daily food intake. This raises the possibility that intestinal vagal sensory innervation contributes to long-term, as well as to short-term regulation of food intake. [Copyright &y& Elsevier]

Abstract: Activation of the pulmonary stretch receptors by lung inflation or vagal stimulation evokes Hering-Breuer (HB) reflex, which is characterized by inspiratory inhibition and expiratory prolongation. In this work, whether the HB reflex could be modulated by the serotonergic raphe pallidus (RP) was studied by comparing the strength of this reflex before and after electrical or chemical stimulation of the RP. Experiments were performed on urethane anesthetized adult rabbits. The HB reflex was simulated with electrical stimulation of the central end of cervical vagus nerve. The RP was stimulated electrically or chemically by microinjection of glutamate. We found that after either electrical stimulation or chemical stimulation of the RP, the inspiratory inhibition and expiratory prolongation of the HB reflex were significantly attenuated. This attenuation showed post-stimulation time dependency or short-term memory, as well as RP stimulation intensity dependency. Results of the present study suggested that the serotonergic RP could exert its respiratory effects by modulating the strength of HB reflex. [Copyright &y& Elsevier]

Multiple-site optical recording of neural activity was performed in the nucleus of the tractus solitarius (NTS) of the chick embryo with stimulation of the glossopharyngeal nerve (N. IX) and vagus nerve (N. X). We measured the amplitudes of the optical signals related to glutamate-mediated excitatory postsynaptic responses, and calculated the ratio of the signal evoked by simultaneous N. IX/N. X stimulation to the signal obtained after mathematical summation of the individual N. IX and N. X responses. The ratio was significantly lower than 100% in the rostral region of the NTS, in which postsynaptic responses were elicited by both N. IX and N. X stimulations. This result means that there is a convergence of visceral inputs via the N. IX and N. X in the embryonic chick NTS. The existence of the convergence suggests that the NTS performs complex integration of information from multiple sensory inputs from the early stages of embryogenesis. [Copyright &y& Elsevier]

The analgesic effect of vagus nerve stimulation (VNS) has not yet been demonstrated in animals with the devices used in the clinic. We studied in awake rats the effects of two VNS protocols on the hind paw hot water test and compared the results with those previously obtained in the oro-facial formalin test. A stringent duty cycle (20 s on/18 s off) increased heat pain tolerance in both hind paws (average 188%) after 2 h of stimulation. VNS with parameters used in epilepsy (30 s on/5 min off) decreased heat tolerance after 2 h, but produced a significant antinociceptive effect after days of stimulation. VNS may thus be useful in pain disorders, even with the less stringent protocol. [Copyright &y& Elsevier]

Phosphorylated extracellular signal-regulated kinases1/2 (pERK1/2) -like immunoreactivity (LI) was enhanced in the neurons of the nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus nerve (DMV) 8 min after an intraperitoneal injection of acetic acid in the mouse; the enhancement in pERK1/2-LI was suppressed after vagotomy. With immunofluorescent double labeling technique, the co-localization of acetic acid-induced pERK1/2 and tyrosine hydroxylase-LIs was observed in some of the NTS and DMV neurons. These results suggest that ERK1/2 signal-transducting pathway is involved in neuronal activities in NTS and DMV which are induced by vagus-conveyed nociceptive visceral information, and that some of these pERK1/2- immunoreactive neurons in NTS and DMV are catecholaminergic. [Copyright &y& Elsevier]

The effects of the intracisternal administration of synthetic orexin-A (3 nmol) on gastric motility were examined in rats. The administration of orexin but not a vehicle induced relaxation of the proximal stomach lasting for more than 30 min. Phasic contractions in the distal stomach were facilitated in response to the administration of orexin but not a vehicle. Facilitation in the distal stomach was not observed in the animals which underwent the sectioning of the bilateral vagi at the subdiaphragmatic level. Relaxation of the proximal stomach was observed in vagotomized animals but the magnitude of relaxation was significantly smaller than that in intact animals. These results suggest that central orexin facilitates distal stomach motility and relaxation of the proximal stomach via vagi. [Copyright &y& Elsevier]

In experiments on urethane anaesthetized rats the influence of electrical stimulation of the central nucleus of the amygdala (CNA) on gastric motility and activity of gastric-related neurons of the dorsal vagal complex was studied. Stimulation of the CNA effected spontaneous gastric motility and caused both excitatory and inhibitory changes of vagal-induced gastric relaxation. The most significant effects, mainly inhibitory, were observed under stimulation of the medial CNA. This amygdaloid area was found to influence activity of gastric-related neurons of the dorsal vagal complex. Excitatory and inhibitory changes of their vagal-induced responses under the amygdala stimulation manifested as general modulation of all phases of the reaction or selective modulation of some of them. These mechanisms may lie at the base of amygdalofugal modulation of gastric reflex activity. [Copyright &y& Elsevier]

• Parkinson Disease (PD) is a neurodegenerative movement disorder with certain autonomous dysfunctions. • Misfolded alpha-synuclein (α-syn) may progress towards the brain via the vagus nerve at a very early stage. • Enhancement in the process of autophagy to flush out misfolded α-syn has been of particular interest in PD research. • Trehalose enters into the brain from the gut and possibly contribute towards ameliorating PD pathology. Parkinson disease (PD) is a progressive movement functionality disorder resulting in tremor and inability to execute voluntary functions combined with the preponderant non-motor disturbances encompassing constipation and gastrointestinal irritation. Despite continued research, the pathogenesis of PD is not yet clear. The available class of drugs for effective symptomatic management of PD includes a combination of levodopa and carbidopa. In recent past, the link between gut with PD has been explored. According to recent preclinical evidence, pathogens such as virus or bacterium may initiate entry into the gut via the nasal cavity that may aggravate lewy pathology in the gut that eventually propagates and progresses towards the brain via the vagus nerve resulting in the prodromal non-motor symptoms. Additionally, experimental evidence also suggests that alpha-synuclein misfolding commences at a very early stage in the gut and is transported via the vagus nerve prior to seeding PD pathology in the brain. However, this progression and resultant deterioration of the neurones can effectively be altered by an autophagy inducer, Trehalose, although the mechanism behind it is still enigmatic. Hence, this review will mainly focus on analysing the basic components of the gut that might be responsible for aggravating lewy pathology, the mediator(s) responsible for transmission of PD pathology from gut to brain and the important role of trehalose in ameliorating gut dysbiosis related PD complications that would eventually pave the way for therapeutic management of PD. [ABSTRACT FROM AUTHOR]

• VNS may cause thalamus-precentral gyrus FC changes in DRE patients. • Enhanced FC was observed between bilateral thalamus and bilateral precentral gyrus in responders. • Decreased FC was observed between bilateral thalamus and bilateral precentral gyrus in nonresponders. Vagal nerve stimulation (VNS) is an effective treatment for patients with drug-resistant epilepsy who are unsuitable for surgical epilepsy treatment. However, the mechanism of action of VNS remains unclear, and the efficacy of VNS treatment regarding seizure frequency reduction cannot be assessed before surgery. This study measured changes in functional connectivity between thalamus and precentral gyrus which are activated as vital targets of deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) using resting-state functional MRI to evaluate the effects of VNS. 16 epilepsy patients who underwent VNS were collected and scanned by resting-state functional MRI before and after operation. The functional connections (regions of interest: thalamus, precentral gyrus) were examined. After three months of stimulation, there were eight responders (≥50 % seizure reduction) and eight non-responders to VNS. No significant difference in thalamus-precentral gyrus functional connectivity was found between responders and nonresponders before operation. Enhanced functional connections were observed between bilateral thalamus and bilateral precentral gyrus in responders, which decreased in nonresponders, while functional connections between bilateral thalamus decreased in both responders and nonresponders. Short-term stimulation may cause thalamus-precentral gyrus functional connectivity changes in DRE patients, and control seizures by enhancing functional connections between bilateral thalamus and bilateral precentral gyrus. [ABSTRACT FROM AUTHOR]

• c-tDCS plus DZP is more effective in suppressing seizures than c-tDCS individually. • a-tDCS alone or plus DZP is not effective in improving seizure behavior. • c-tDCS alone or plus DZP improves NGF and BDNF levels after PTZ-kindling. • c-tDCS alone or plus DZP decreases hippocampal IL-1β levels after PTZ-kindling. • a-tDCS alone raises hippocampal IL-1β levels. Despite the introduction of new antiepileptic drugs, about 30 % of patients with epilepsy are refractory to drug therapy. Thus, the search for non-pharmacological interventions such as transcranial direct current stimulation (tDCS) may be an alternative, either alone or in combination with low doses of anticonvulsants. This study evaluated the effect of anodal (a-tDCS) and cathodal tDCS (c-tDCS) on seizure behavior and neuroinflammation parameters. Rats were submitted to the kindling model induced by pentylenetetrazole (PTZ) using diazepam (DZP) as anticonvulsant standard. tDCS groups were submitted to 10 sessions of a-tDCS or c-tDCS or SHAM-tDCS. Every 3 days they received saline (SAL), low dose of DZP (alone or in combination with tDCS) or effective dose of DZP 30 min before administration of PTZ, totaling 16 days of protocol. Neither a-tDCS nor c-tDCS reduced the occurrence of clonic forelimb seizures (convulsive motor seizures – stage 3 by the adapted Racine scale we based on). Associated with DZP, c-tDCS (c-tDCS/DZP0.15) increased the latency to first clonic forelimb seizure on the 10th and 16th days. Hippocampal IL-1β levels were reduced by c-tDCS and c-tDCS/DZP0.15. In contrast, these treatments induced an increase in cortical IL-1β levels. Hippocampal TNF-α levels were not altered by c-tDCS or a-tDCS, but c-tDCS and c-tDCS/DZP0.15 increased those levels in cerebral cortex. Cortical NGF levels were increased by c-tDCS and c-tDCS/DZP0.15. a-tDCS/DZP0.15 reduced hippocampal BDNF levels and c-tDCS/DZP0.15 increased these levels in cerebral cortex. In conclusion, c-tDCS alone or in combination with a low dose of DZP showed to affect neuroinflammation, improving central neurotrophin levels and decreasing hippocampal IL-1β levels after PTZ-induced kindling without statistically significant effect on seizure behavior. [ABSTRACT FROM AUTHOR]

• Ta-VNS treatment boosted axon plasticity and improved long-term neurofunctional recovery following ischemic stroke. • Ta-VNS treatment activated α7nAChR in the chronic phase of ischemic stroke. • Blockade of α7nAChR attenuated the ta-VNS-mediated promotion of axonal plasticity and neuroprotection following ischemic stroke. • Ta-VNS treatment boosted axonal plasticity and improved neurofunctional recovery through α7nAChR-mediated activation of BDNF-associated signaling pathways following ischemic stroke. Axonal plasticity is important for neurofunctional recovery after stroke. This study aimed to explore the role of transcutaneous auricular vagus nerve stimulation (ta-VNS) on axonal plasticity and its underlying association with the α7 nicotinic acetylcholine receptor(α7nAchR) after cerebral ischemia/reperfusion (I/R) injury. Adult male Sprague-Dawley rats were pretreated by intraperitoneal injection with either phosphate-buffered saline (PBS) or an α7nAchR antagonist and then subjected to middle cerebral artery occlusion and ta-VNS treatment. α7nAchR expression and localization in the peri-infarct cortex were examined after ta-VNS treatment. Subsequently, neurologic scores were assessed with a battery of tests. Axonal regeneration, indicated by upregulation of growth-associated protein 43 (GAP-43) and neurofilament protein 200 (NF-200), was assessed. Axonal reorganization was examined on the basis of anterograde movement of the neuronal molecular probe biotin dextran amine. Additionally, brain-derived neurotrophic factor (BDNF)-associated signaling was measured 28d after I/R. Our findings showed that ta-VNS treatment enhanced α7nAchR expression in the ischemic cortex. α7nAchR colocalized with DCX and Nestin after reperfusion. Furthermore, ta-VNS-treated I/R rats displayed enhanced neurobehavioral performance and increased axonal plasticity (axonal regeneration and axonal reorganization), as indicated by elevated levels of BDNF/cyclic AMP (cAMP)/protein kinase A (PKA)/phosphorylated cAMP response element-binding protein pathway (p-CREB) pathway members. Strikingly, the beneficial effects of ta-VNS were diminished after α7nAchR blockade. In conclusion, our study is the first to show that α7nAchR is a potential mediator of ta-VNS-induced neuroprotection in the chronic phase of stroke and that its effects may be related to enhanced axonal plasticity through activation of the BDNF/cAMP/PKA/p-CREB pathway. [ABSTRACT FROM AUTHOR]

• AspireSR is a novel vagus nerve stimulation device. • Seizure reduction rate by device replacement from preceding systems to AspireSR was investigated. • Seizure frequency significantly reduced after device replacement. AspireSR is a novel vagus nerve stimulation (VNS) device which detects ictal heart rate changes and automatically apply additional stimulus. We investigated the difference of the efficacy between AspireSR and preceding VNS models in patients with device replacement. We retrospectively reviewed the clinical data of 17 patients whose VNS devices were changed because of battery discharge. The rates of seizure reduction, the number of antiepileptic drugs (AEDs) used and device parameters between the two devices were evaluated. AspireSR improved significantly the rates of seizure reduction of the patients. Four patients out of 11 patients with low response to the preceding VNS models (no change or <50 % reduction) achieved>50 % seizure reduction. The AEDs used were not different in the observed periods. The device parameters were low setting in AspireSR compared to preceding VNS models. AspireSR decrease significantly seizure frequencies compared to the preceding VNS models. Change of the devices to AspireSR at the time of battery empty could be recommendable. [ABSTRACT FROM AUTHOR]