Hypertension increases sympathetic neuron activity by enhancing intraganglionic cholinergic collateral connections.

Autonomic dysregulation, including sympathetic hyperactivity, is a common feature of hypertension (HT) and other cardiovascular diseases. The CNS plays a role in driving chronic sympathetic activation in disease, but several lines of evidence suggest that neuroplasticity in the periphery may also contribute. The potential contribution of postganglionic sympathetic neurons to sustained sympathetic hyperactivity is not well understood. We recently discovered that noradrenergic sympathetic neurons in the stellate ganglion (SG) have excitatory cholinergic collateral connections to other neurons within the ganglion. We hypothesize that remodelling of these neurons and increased cholinergic collateral transmission contributes to sustained sympathetic hyperactivity in cardiovascular diseases, including HT. To test that hypothesis, we examined the activity of sympathetic neurons in isolated SG under control conditions and after 1 week of HT induced by peripheral angiotensin II infusion, using whole-cell patch clamp recordings. Despite the absence of central inputs, we observed elevated spontaneous activity and synaptic transmission in sympathetic SG neurons from hypertensive mice that required generation of action potentials. Genetically disrupting cholinergic transmission in noradrenergic neurons decreased basal neuronal activity and prevented angiotensin II-mediated enhancement of activity. Similar changes in activity, driven by increased collateral transmission, were identified in cardiac projecting neurons and neurons projecting to brown adipose tissue. These changes were not driven by altered A-type K+ currents. This suggests that HT stimulates increased activity throughout the intraganglionic network of collateral connections, contributing to the sustained sympathetic hyperactivity characteristic in cardiovascular disease. KEY POINTS: Sympathetic neurons in ganglia isolated from angiotensin II-treated hypertensive mice are more active than neurons from control mice despite the absence of central activation. The enhanced activity is the result of a ganglionic network of cholinergic collaterals, rather than altered intrinsic excitability. Increased neuronal activity was observed in both cardiac neurons and brown adipose tissue-projecting neurons, which are not involved in cardiovascular homeostasis.

The relevance of the superior cervical ganglion for cardiac autonomic innervation in health and disease: a systematic review.

PURPOSE: The heart receives cervical and thoracic sympathetic contributions. Although the stellate ganglion is considered the main contributor to cardiac sympathetic innervation, the superior cervical ganglia (SCG) is used in many experimental studies. The clinical relevance of the SCG to cardiac innervation is controversial. We investigated current morphological and functional evidence as well as controversies on the contribution of the SCG to cardiac innervation. METHODS: A systematic literature review was conducted in PubMed, Embase, Web of Science, and COCHRANE Library. Included studies received a full/text review and quality appraisal. RESULTS: Seventy-six eligible studies performed between 1976 and 2023 were identified. In all species studied, morphological evidence of direct or indirect SCG contribution to cardiac innervation was found, but its contribution was limited. Morphologically, SCG sidedness may be relevant. There is indirect functional evidence that the SCG contributes to cardiac innervation as shown by its involvement in sympathetic overdrive reactions in cardiac disease states. A direct functional contribution was not found. Functional data on SCG sidedness was largely unavailable. Information about sex differences and pre- and postnatal differences was lacking. CONCLUSION: Current literature mainly supports an indirect involvement of the SCG in cardiac innervation, via other structures and plexuses or via sympathetic overdrive in response to cardiac diseases. Morphological evidence of a direct involvement was found, but its contribution seems limited. The relevance of SCG sidedness, sex, and developmental stage in health and disease remains unclear and warrants further exploration.

Anatomical study with clinical significance of communicating and visceral branching of the cervical and upper thoracic sympathetic trunk.

Current advances in the management of the autonomic nervous system in various cardiovascular diseases, and in treatments for pain or sympathetic disturbances in the head, neck, or upper limbs, necessitate a thorough understanding of the anatomy of the cervicothoracic sympathetic trunk. Our objective was to enhance our understanding of the origin and distribution of communicating branches and visceral cervicothoracic sympathetic nerves in human fetuses. This was achieved through a comprehensive topographic systematization of the branching patterns observed in the cervical and upper thoracic ganglia, along with the distribution of communicating branches to each cervical spinal nerve. We conducted detailed sub-macroscopic dissections of the cervical and thoracic regions in 20 human fetuses (40 sides). The superior and cervicothoracic ganglia were identified as the cervical sympathetic ganglia that provided the most communicating branches on both sides. The middle and accessory cervical ganglia contributed the fewest branches, with no significant differences between the right and left sides. The cervicothoracic ganglion supplied sympathetic branches to the greatest number of spinal nerves, spanning from C5 to T2 . The distribution of communicating branches to spinal nerves was non-uniform. Notably, C3 , C4 , and C5 received the fewest branches, and more than half of the specimens showed no sympathetic connections. C1 and C2 received sympathetic connections exclusively from the superior ganglion. Spinal nerves that received more branches often did so from multiple ganglia. The vertebral nerve provided deep communicating branches primarily to C6 , with lesser contributions to C7 , C5 , and C8 . The vagus nerve stood out as the cranial nerve with the most direct sympathetic connections. The autonomic branching pattern and connections of the cervicothoracic sympathetic trunk are significantly variable in the fetus. A comprehensive understanding of the anatomy of the cervical and upper thoracic sympathetic trunk and its branches is valuable during autonomic interventions and neuromodulation. This knowledge is particularly relevant for addressing various autonomic cardiac diseases and for treating pain and vascular dysfunction in the head, neck, and upper limbs.

Novel ultrasound-guided supraclavicular stellate ganglion block.

INTRODUCTION: Stellate ganglion block (SGB) provides diagnostic and therapeutic benefits in pain syndromes in the head, neck, and upper extremity, including complex regional pain syndrome Types I and II, Raynaud's disease, hyperhidrosis, arterial embolism in the region of the arm. METHODS: We present a novel ultrasound-guided supraclavicular stellate ganglion block. Considering the existing anatomical structures of the targeted area. RESULTS AND CONCLUSIONS: We hope that we can provide fewer complications and additional benefits with this new approach.

Stellate ganglion block to mitigate thalamic pain syndrome of an oncological origin.

BACKGROUND: Thalamic pain syndrome (TPS) is an enigmatic and rare condition. Thalamic pain syndrome is under the umbrella of central pain syndrome, which is classically associated with multiple sclerosis, spinal cord injury, postamputation, epilepsy, stroke, tumor, and Parkinson's disease. The mainstay treatment of TPS is polypharmacy. There is uncertainty about the intermediate options to manage medication-resistant TPS before resorting to invasive, and often expensive, intracranial therapies. Stellate ganglion block (SGB) has shown promise in reducing TPS symptoms of the upper extremity and face following a thalamic ischemic event. AIMS: Discuss the effect and potential utility of SGB on ipsilateral headache, facial, and upper extremity neuropathic pain due to thalamic malignancies. MATERIALS AND METHODS: A review of two patient records that underwent SGB for treatment of TPS of oncologic origin. RESULTS: We present two cases of the successful use of SGB for the treatment of oncologic-related TPS for patients who had failed other conservative pharmacologic measures. DISCUSSION: Chronic pain is a complex experience that often simultaneously involves psychosocial, neuropathic, and nociceptive constituents. Among advanced cancer patients, factors such as an individual's spirituality, psychological stressors, and views on their mortality add layers of intricacy in addressing their pain. While TPS has been characterized in both stroke populations and oncologic populations, the treatment of SGB for pain relief in TPS has been limited to the stroke population. Repeated SGB worked to alleviate the ipsilateral headache, facial, and upper extremity pain in these two patients. The benefits of utilization of SGB, with the possibility of pain relief, within the thalamic malignancy population cannot be understated. CONCLUSION: In summary, ultrasound-guided SGB may be considered in patients with TPS due to thalamic cancer, before pursuing more invasive intracranial surgeries to treat pain.

Cholinergic collaterals arising from noradrenergic sympathetic neurons in mice.

The sympathetic nervous system vitally regulates autonomic functions, including cardiac activity. Postganglionic neurons of the sympathetic chain ganglia relay signals from the central nervous system to autonomic peripheral targets. Disrupting this flow of information often dysregulates organ function and leads to poor health outcomes. Despite the importance of these sympathetic neurons, fundamental aspects of the neurocircuitry within peripheral ganglia remain poorly understood. Conventionally, simple monosynaptic cholinergic pathways from preganglionic neurons are thought to activate postganglionic sympathetic neurons. However, early studies suggested more complex neurocircuits may be present within sympathetic ganglia. The present study recorded synaptic responses in sympathetic stellate ganglia neurons following electrical activation of the pre- and postganglionic nerve trunks and used genetic strategies to assess the presence of collateral projections between postganglionic neurons of the stellate ganglia. Orthograde activation of the preganglionic nerve trunk, T-2, uncovered high jitter synaptic latencies consistent with polysynaptic connections. Pharmacological inhibition of nicotinic acetylcholine receptors with hexamethonium blocked all synaptic events. To confirm that high jitter, polysynaptic events were due to the presence of cholinergic collaterals from postganglionic neurons within the stellate ganglion, we knocked out choline acetyltransferase in adult noradrenergic neurons. This genetic knockout eliminated orthograde high jitter synaptic events and EPSCs evoked by retrograde activation. These findings suggest that cholinergic collateral projections arise from noradrenergic neurons within sympathetic ganglia. Identifying the contributions of collateral excitation to normal physiology and pathophysiology is an important area of future study and may offer novel therapeutic targets for the treatment of autonomic imbalance. KEY POINTS: Electrical stimulation of a preganglionic nerve trunk evoked fast synaptic transmission in stellate ganglion neurons with low and high jitter latencies. Retrograde stimulation of a postganglionic nerve trunk evoked direct, all-or-none action currents and delayed nicotinic EPSCs indistinguishable from orthogradely-evoked EPSCs in stellate neurons. Nicotinic acetylcholine receptor blockade prevented all spontaneous and evoked synaptic activity. Knockout of acetylcholine production in noradrenergic neurons eliminated all retrogradely-evoked EPSCs but did not change retrograde action currents, indicating that noradrenergic neurons have cholinergic collaterals connecting neurons within the stellate ganglion.

Long-term potentiation and its neurotrophin-dependent modulation in the superior cervical ganglion of the rat are influenced by KCNQ channel function.

Ganglionic long-term potentiation (gLTP) in the rat superior cervical ganglion (SCG) is differentially modulated by neurotrophic factors (Nts): brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KCNQ/M channels, key regulators of neuronal excitability, and firing pattern are modulated by Nts; therefore, they might contribute to gLTP expression and to the Nts-dependent modulation of gLTP. In the SCG of rats, we characterized the presence of the KCNQ2 isoform and the effects of opposite KCNQ/M channel modulators on gLTP in control condition and under Nts modulation. Immunohistochemical and reverse transcriptase polymerase chain reaction analyses showed the expression of the KCNQ2 isoform. We found that 1 µmol/L XE991, a channel inhibitor, significantly reduced gLTP (∼50%), whereas 5 µmol/L flupirtine, a channel activator, significantly increased gLTP (1.3- to 1.7-fold). Both modulators counterbalanced the effects of the Nts on gLTP. Data suggest that KCNQ/M channels are likely involved in gLTP expression and in the modulation exerted by BDNF and NGF.

Innervation of the heart: Anatomical study with application to better understanding pathologies of the cardiac autonomics.

Current advances in management of the cardiac neuroaxis in different cardiovascular diseases require a deeper knowledge of cardiac neuroanatomy. The aim of the study was to increase knowledge of the human fetal extrinsic cardiac nervous system. We achieved this by systematizing the origin and formation of the cardiac nerves, branches, and ganglia and their sympathetic/parasympathetic connections. Thirty human fetuses (60 sides) were subjected to detailed sub-macroscopic dissection of the cervical and thoracic regions. Cardiac accessory ganglia lying on a cardiac nerve or in conjunction with two or more (up to four) nerves before entering the mediastinal cardiac plexus were observed in 13 sides. Except for the superior cardiac nerve, the sympathetic cardiac nerves were individually variable and inconstant. In contrast, the cardiac branches of the vagus nerve appeared grossly more constant and invariable, although the individual cardiac branches varied in number and position of origin. Each cervical cardiac nerve or cardiac branch of the vagus nerve could be singular or multiple (up to six) and originated from the sympathetic trunk or the vagus nerve by one, two, or three roots. Sympathetic nerves arose from the cervical-thoracic ganglia or the interganglionic segment of the sympathetic trunk. Connections were found outside the cardiac plexus. Some cardiac nerves were connected to non-cardiac nerves, while others were connected to each other. Common sympathetic/parasympathetic cardiac nerve trunks were more frequent on right (70%) versus left sides (20%). The origin, frequency, and connections of the cardiac nerves and branches are highly variable in the fetus. Detailed knowledge of the normal neuroanatomy of the heart could be useful during cardiac neuromodulation procedures and in better understanding nervous pathologies of the heart.

Horner Syndrome subsequent to ultrasound-guided cervical lymph node fine-needle aspiration - A case report and literature review.

Horner Syndrome (HS) is characterized by symptoms of ipsilateral miosis, ptosis, enophthalmos, and facial anhidrosis, which is caused by the damaged oculosympathetic pathway. HS is rarely reported as postoperative complications of fine-needle aspiration (FNA). We report a case of HS triggered by Ultrasound-guided FNA during thyroid cancer management and conducted the literature review. A 31-year-old male with differentiated thyroid cancer underwent total thyroidectomy and regional lymph node dissection as well as radioactive iodine ablation, presented with persistently elevated tumor marker of thyroglobulin and suspicious left level IV and V cervical lymph nodes by neck ultrasound. Ultrasound-guided left cervical lymph nodes FNA for cellular diagnosis was performed, and typical manifestations of HS appeared immediately after the procedure. Subsequent ultrasound evaluation of the same area demonstrated a subtle strip of the hypo-echogenic area in the superior pole of the suspected level IV structure, suggesting sympathetic ganglia with the visible originating nerve fiber on the superior pole. All of the patient's symptoms of HS were resolved 2 months after the incidence. Cervical sympathetic ganglia can be similar in size, shape, and ultrasound characteristics to a malignant lymph node. Thorough ultrasound examination by directly comparing the potential ganglia with a typical malignant lymph node, and paying attention to any potential root fibers on the target is key to avoiding ganglia injury before the neck invasive procedures.

Application of machine learning algorithms in thermal images for an automatic classification of lumbar sympathetic blocks.

PURPOSE: There are no previous studies developing machine learning algorithms in the classification of lumbar sympathetic blocks (LSBs) performance using infrared thermography data. The objective was to assess the performance of different machine learning algorithms to classify LSBs carried out in patients diagnosed with lower limbs Complex Regional Pain Syndrome as successful or failed based on the evaluation of thermal predictors. METHODS: 66 LSBs previously performed and classified by the medical team were evaluated in 24 patients. 11 regions of interest on each plantar foot were selected within the thermal images acquired in the clinical setting. From every region of interest, different thermal predictors were extracted and analysed in three different moments (minutes 4, 5, and 6) along with the baseline time (just after the injection of a local anaesthetic around the sympathetic ganglia). Among them, the thermal variation of the ipsilateral foot and the thermal asymmetry variation between feet at each minute assessed and the starting time for each region of interest, were fed into 4 different machine learning classifiers: an Artificial Neuronal Network, K-Nearest Neighbours, Random Forest, and a Support Vector Machine. RESULTS: All classifiers presented an accuracy and specificity higher than 70%, sensitivity higher than 67%, and AUC higher than 0.73, and the Artificial Neuronal Network classifier performed the best with a maximum accuracy of 88%, sensitivity of 100%, specificity of 84% and AUC of 0.92, using 3 predictors. CONCLUSION: These results suggest thermal data retrieved from plantar feet combined with a machine learning-based methodology can be an effective tool to automatically classify LSBs performance.

Imperatorin Improves Obesity-Induced Cardiac Sympathetic Nerve Injury Mediated by P2X4 Receptor in Stellate Sympathetic Ganglion.

Obesity can activate the inflammatory signal pathway, induce in the body a state of chronic inflammation, and increase the excitability of the sympathetic nervous system, which may induce sympathetic neuropathic injury. The stellate sympathetic ganglia (SG) can express the P2X4 receptor, and the abnormal expression of the P2X4 receptor is related to inflammation. Imperatorin (IMP) is a kind of furan coumarin plant which has anti-inflammatory effects. This project aimed to investigate whether IMP can affect the expression of P2X4 receptors in the SG of obese rats to display a protective effect from high-fat-triggered cardiac sympathetic neuropathic injury. Molecular docking through homology modelling revealed that IMP had good affinity for the P2X4 receptor. Our results showed that compared with the normal group, the administration of IMP or P2X4 shRNA decreased sympathetic excitement; reduced the serum levels of triglyceride, total cholesterol, and lactate dehydrogenase; downregulated the expression of P2X4 receptors in SG; and inhibited the expression of inflammatory factors in the SG and serum of obese rats significantly. In addition, the expression of factors associated with the cell pyroptosis GSDMD, caspase-1, NLRP-3, and IL-18 in obese rats were significantly higher than those of the normal rats, and such effects were decreased after treatment with IMP or P2X4 shRNA. Furthermore, IMP significantly reduced the ATP-activated currents in HEK293 cells transfected with P2X4 receptor. Thus, the P2X4 receptor may be a key target for the treatment of obesity-induced cardiac sympathetic excitement. IMP can improve obesity-induced cardiac sympathetic excitement, and its mechanism of action may be related to the inhibition of P2X4 receptor expression and activity in the SG, suppression of cellular pyroptosis in the SG, and reduction of inflammatory factor levels.

A comprehensive study of the abdominal ganglia part 1: Celiac, phrenic and superior mesenteric ganglia.

INTRODUCTION: Patients with pancreatic cancer, chronic pancreatitis and other abdominal pain syndromes may develop debilitating pain throughout the course of their illness with little to no relief by most conventional methods. While some form of relief is experienced by patients, not all benefit from these procedures and side effects, while transitory in most cases are severe and often not expected. Our aim was therefore to investigate the anatomy surrounding the abdominal sympathetic ganglia, the target for the invasive procedures in an attempt to understand the variations in results. MATERIALS AND METHODS: The abdominal cavities of nine individuals were dissected and the ganglia investigated, harvested and histologically and immunochemical stained. RESULTS: The phrenic ganglion was found inconsistently and more often in the left than the right. If present it was located in association with the inferior phrenic artery and often connected to the celiac ganglion. The celiac ganglion was located anterior to the diaphragmatic crus on both sides and specifically posteromedial to the suprarenal gland and superior to the renal artery on the left. On the right it was located posterior to the suprarenal gland and inferior vena cava also superior to the renal vessels. The superior mesenteric ganglion was only positively identified in one individual and was located on the left lateral aspect of the superior mesenteric artery. CONCLUSION: The blockade procedures for treatment of pain are developed to target the area around the celiac artery where the ganglion is commonly described to be located. However, based on our results of its location and interconnections the ganglion is not located in the targeted area.

A comprehensive study of the abdominal ganglia part 2: Aorticorenal ganglia.

Investigation into reports of pain treatment for abdominal cancer and abdominal pain syndromes revealed the lack of human studies on some of the abdominal sympathetic ganglia. Recent studies on renal artery denervation therapy as treatment for resistant hypertension has made the aorticorenal ganglia of particular importance. The aim of this study was to investigate the location, morphology, interconnections, and histological nature of aorticorenal ganglia. We dissected nine abdominal cavities and harvested 37 aorticorenal ganglia. Hematoxylin and Eosin, and Masson's staining techniques were used to study the histological structure. Additionally, ganglia harvested from five individuals were stained with immunohistochemical techniques to test for tyrosine hydroxylase activity. All aorticorenal ganglia were located in proximity to the renal artery, and the majority were close to the vessel origin. Identification of multiple aorticorenal ganglia was the norm, and ranged from 2 to 4 on the left and 1 to 3 on the right. While the pattern of aorticorenal ganglia seemed to be unique in each individual case, the interconnections between these and other ganglia were vast. The aorticorenal ganglia shared direct connections with the celiac, gonadal, inferior mesenteric, and first lumbar sympathetic trunk ganglion. Contributions from the greater, lesser, and least thoracic splanchnic nerves were also observed. While the results of our study may not have direct clinical implications in isolation, the vast number of interconnections with the other abdominal ganglia may cause complications in procedures such as celiac ganglion block. In addition, aorticorenal innervation interruption may lead to hypotension.

Investigating Primary Cilia during Peripheral Nervous System Formation.

The primary cilium plays a pivotal role during the embryonic development of vertebrates. It acts as a somatic signaling hub for specific pathways, such as Sonic Hedgehog signaling. In humans, mutations in genes that cause dysregulation of ciliogenesis or ciliary function lead to severe developmental disorders called ciliopathies. Beyond its role in early morphogenesis, growing evidence points towards an essential function of the primary cilium in neural circuit formation in the central nervous system. However, very little is known about a potential role in the formation of the peripheral nervous system. Here, we investigate the presence of the primary cilium in neural crest cells and their derivatives in the trunk of developing chicken embryos in vivo. We found that neural crest cells, sensory neurons, and boundary cap cells all bear a primary cilium during key stages of early peripheral nervous system formation. Moreover, we describe differences in the ciliation of neuronal cultures of different populations from the peripheral and central nervous systems. Our results offer a framework for further in vivo and in vitro investigations on specific roles that the primary cilium might play during peripheral nervous system formation.

Unexpected inflammation in the sympathetic ganglia in thromboangiitis obliterans: more likely sterile or infectious induced inflammation?

INTRODUCTION: The aim of this study was to determine if the inflammation of the sympathetic ganglia (SG) in thromboangiitis obliterans (TAO) is induced by an infectious pathogen inside or if it is a reactive sterile inflammation. METHODS: For the purpose of this study, the gene expression of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), toll-like receptor 9 (TLR9), and the receptor for advanced glycation end-products (RAGE) were evaluated on the complementary DNA (cDNA) of the SG tissues of 24 TAO patients and two controls with hyperhidrosis by real-time polymerase chain reaction (PCR) and analysed by the Pfaffl method. RESULTS: The gene expression of HMGB1 and TLR9 increased by about 25- and 2-fold changes in the SG of the TAO patients, respectively. However, there was no change in the gene expression of TLR4 or RAGE. CONCLUSION: It appears that the inflammation in the SG of TAO patients is more likely a sterile inflammation, and its trigger may be mitochondrial DNA (mtDNA). Cadmium in cigarettes could be responsible for the induction of mtDNA release to the cell cytoplasm. In addition, the high expression of HMGB1 may play a role in the pathogenesis of TAO and may be responsible for both clinical manifestation of the disease and the imaging findings. Moreover, HMGB1 may be a target for treatment protocols for TAO. Further studies are highly recommended.

Evaluation of the Toxicity and Neurological Effects of Fulranumab in Adult Cynomolgus Monkeys.

Fulranumab, an anti-human nerve growth factor antibody, was evaluated in a series of nonclinical toxicology studies. No treatment effects were observed in adolescent cynomolgus monkeys in standard design, repeat-dose toxicology studies of up to 6 months. Adverse effects on the developing nervous system were observed in offspring of pregnant cynomolgus monkeys treated with fulranumab. Subsequent studies including detailed morphologic investigations of the nervous system did reveal fulranumab-related changes in adult cynomolgus monkeys; this article is focused on those findings. A single dose of ≥1 mg/kg fulranumab administered subcutaneously (SC) caused a decrease in neuron and sympathetic ganglion size (superior cervical ganglion), observed morphologically and stereologically, with a resulting appearance of increased glial cell density. Similar results were observed in repeat-dose (15 to 52 weeks) toxicity studies at ≤50 mg/kg/wk fulranumab SC. These effects recovered after a 3-month treatment-free period. Fulranumab did not cause any neuronal death, necrosis, apoptosis, or any apparent decrease in function of sympathetic neurons/ganglia at any time point examined. A no observed effect level (NOEL) was established at 0.25 mg/kg fulranumab SC every 4 weeks for 28 weeks.

Age-Dependent Effects of NO on Rhythmic Activity of Postganglionic Sympathetic Fibers.

We studied the effects of exogenous NO donor (sodium nitroprusside) and NO synthesis blocker (100 µM L-NAME) on baseline electrical activity of postganglionic fibers in the sympathetic superior cervical in rats during postnatal ontogeny. Starting the age of 20 days, sodium nitroprusside increased the mean discharge amplitude and the spectrum power in the respiratory (0.7-1.5 Hz) and cardiac (4-7 Hz) frequency bands. In contrast, application of L-NAME for 1 h decreased the spectrum power in these bands. Both agents produced no significant effect on the rhythmic sympathetic discharges at frequencies >8 Hz.

Changes of the Expression of Neuronal NO-Synthase in Rat Sympathetic Ganglia during Ontogeny.

Expression of neuronal NO synthase in the sympathetic cranial cervical ganglion and stellate ganglion in rats during postnatal ontogeny was studied by immunohistochemistry and Western blotting. In the sympathetic ganglia, neuronal NO synthase-immunoreactive neurons were absent in all rats. In the stellate and cranial cervical ganglia, the expression of neuronal NO synthase and the density of immunoreactive fibers increased in early postnatal ontogeny from the moment of birth to the age of 30 days and then decreased. Thus, we observed heterochroneous expression of neuronal NOS in the preganglionic somata in the spinal cord and in the preganglionic fibers in the sympathetic ganglia during ontogeny.

The ALK receptor in sympathetic neuron development and neuroblastoma.

The ALK gene encodes a tyrosine kinase receptor characterized by an expression pattern mainly restricted to the developing central and peripheral nervous systems. In 2008, the discovery of ALK activating mutations in neuroblastoma, a tumor of the sympathetic nervous system, represented a breakthrough in the understanding of the pathogenesis of this pediatric cancer and established mutated ALK as a tractable therapeutic target for precision medicine. Subsequent studies addressed the identity of ALK ligands, as well as its physiological function in the sympathoadrenal lineage, its role in neuroblastoma development and the signaling pathways triggered by mutated ALK. This review focuses on these different aspects of the ALK biology and summarizes the various therapeutic strategies relying on ALK inhibition in neuroblastoma, either as monotherapies or combinatory treatments.

Gα14 subunit-mediated inhibition of voltage-gated Ca2+ and K+ channels via neurokinin-1 receptors in rat celiac-superior mesenteric ganglion neurons.

The mechanisms by which G proteins modulate voltage-gated Ca(2+)channel currents (CaV), particularly CaV2.2 and CaV2.3, are voltage dependent (VD) or voltage independent (VI). VD pathways are typically mediated by Gαi/oand GαSsubfamilies. On the other hand, VI inhibition modulation is coupled to the Gαqsubfamily and signaling pathways downstream of phospholipase C stimulation. In most studies, this latter pathway has been shown to be linked to Gαqand/or Gα11protein subunits. However, there are no studies that have examined whether natively expressed Gα14subunits (Gαqsubfamily member) couple G protein-coupled receptors (GPCR) with CaV2.2 channels. We report that Gα14subunits functionally couple the substance P (SP)/neurokinin-1 (NK-1) receptor pathway to CaV2.2 channels in acutely dissociated rat celiac-superior mesenteric ganglion (CSMG) neurons. Exposure of CSMG neurons to SP blocked the CaV2.2 currents in a predominantly VD manner that was pertussis toxin and cholera toxin resistant, as well as Gαq/11independent. However, silencing Gα14subunits significantly attenuated the SP-mediated Ca(2+)current block. In another set of experiments, exposure of CSMG neurons to SP led to the inhibition of KCNQ K(+)M-currents. The SP-mediated M-current block was significantly reduced in neurons transfected with Gα14small-interference RNA. Finally, overexpression of the GTP-bound Gαq/11binding protein RGS2 did not alter the block of M-currents by SP but significantly abolished the oxotremorine methiodide-mediated M-current inhibition. Taken together, these results provide evidence of a new Gα14-coupled signaling pathway that modulates CaV2.2 and M-currents via SP-stimulated NK-1 receptors in CSMG neurons.