Medullary Structures Research Articles

Expression of Autophagy Markers LC3B, LAMP2A, and GRP78 in the Human Kidney during Embryonic, Early Fetal, and Postnatal Development and Their Significance in Diabetic Kidney Disease.

Autophagy is the primary intracellular degradation system, and it plays an important role in many biological and pathological processes. Studies of autophagy involvement in developmental processes are important for understanding various processes. Among them are fibrosis, degenerative diseases, cancer development, and metastasis formation. Diabetic kidney disease is one of the main causes of chronic kidney disease and end-stage renal failure. The aim of this study was to investigate the immunohistochemical expression patterns of LC3B, LAMP2A, and GRP78 during different developmental stages of early-developing human kidneys and in samples from patients with type II diabetes mellitus. During the 7/8th DW, moderate expression of LC3B and LAMP2A and strong expression of GRP78 were found in the mesonephric glomeruli and tubules. In the 9/10th DW, the expression of LC3B and LAMP2A was even more pronounced in the mesonephric tubules. LC3B, LAMP2A, and GRP78 immunoreactivity was also found in the paramesonephric and mesonephric ducts and was stronger in the 9/10th DW compared with the 7/8th DW. In addition, the expression of LC3B, LAMP2A, and GRP78 also appeared in the mesenchyme surrounding the paramesonephric duct in the 9/10th DW. In the 15/16th DW, the expression of LC3B in the glomeruli was weak, that of LAMP2A was moderate, and that of GRP78 was strong. In the tubuli, the expression of LC3B was moderate, while the expression of LAMP2A and GRP78 was strong. The strongest expression of LC3B, LAMP2A, and GRP78 was observed in the renal medullary structures, including developing blood vessels. In postnatal human kidneys, the most extensive LC3B, LAMP2A, and GRP78 expression in the cortex was found in the epithelium of the proximal convoluted tubules, with weak to moderate expression in the glomeruli. The medullary expression of LC3B was weak, but the expression of LAMP2A and GRP78 was the strongest in the medullary tubular structures. Significantly lower expression of LC3B was found in the glomeruli of the diabetic patients in comparison with the nondiabetic patients, but there was no difference in the expression of LC3B in the tubule-interstitial compartment. The expression of LAMP2A was significantly higher in the tubule-interstitial compartments of the diabetic patients in comparison with the nondiabetic patients, while its expression did not differ in the glomeruli. Extensive expression of GRP78 was found in the glomeruli and the tubule-interstitial compartments, but there was no difference in the expression between the two groups of patients. These data give us new information about the expression of LC3B, LAMP2A, and GRP78 during embryonic, fetal, and early postnatal development. The spatiotemporal expression of LC3B, LAMP2A, and GRP78 indicates the important role of autophagy during the early stages of renal development. In addition, our data suggest a disturbance in autophagy processes in the glomeruli and tubuli of diabetic kidneys as an important factor in the pathogenesis of diabetic kidney disease.

Cerebellar contribution to the regulation of defensive states.

Despite fine tuning voluntary movement as the most prominently studied function of the cerebellum, early human studies suggested cerebellar involvement emotion regulation. Since, the cerebellum has been associated with various mood and anxiety-related conditions. Research in animals provided evidence for cerebellar contributions to fear memory formation and extinction. Fear and anxiety can broadly be referred to as defensive states triggered by threat and characterized by multimodal adaptations such as behavioral and cardiac responses integrated into an intricately orchestrated defense reaction. This is mediated by an evolutionary conserved, highly interconnected network of defense-related structures with functional connections to the cerebellum. Projections from the deep cerebellar nucleus interpositus to the central amygdala interfere with retention of fear memory. Several studies uncovered tight functional connections between cerebellar deep nuclei and pyramis and the midbrain periaqueductal grey. Specifically, the fastigial nucleus sends direct projections to the ventrolateral PAG to mediate fear-evoked innate and learned freezing behavior. The cerebellum also regulates cardiovascular responses such as blood pressure and heart rate-effects dependent on connections with medullary cardiac regulatory structures. Because of the integrated, multimodal nature of defensive states, their adaptive regulation has to be highly dynamic to enable responding to a moving threatening stimulus. In this, predicting threat occurrence are crucial functions of calculating adequate responses. Based on its role in prediction error generation, its connectivity to limbic regions, and previous results on a role in fear learning, this review presents the cerebellum as a regulator of integrated cardio-behavioral defensive states.

Dynamics of differentiated-renal epithelial cell monolayer after calcium oxalate injury: The role of cyclooxygenase-2

AimsCalcium oxalate (Oxa), constituent of most common kidney stones, damages renal tubular epithelial cells leading to kidney disease. Most in vitro studies designed to evaluate how Oxa exerts its harmful effects were performed in proliferative or confluent non-differentiated renal epithelial cultures; none of them considered physiological hyperosmolarity of renal medullary interstitium. Cyclooxygenase 2 (COX2) has been associated to Oxa deleterious actions; however, up to now, it is not clear how COX2 acts. In this work, we proposed an in vitro experimental system resembling renal differentiated-epithelial cells that compose medullary tubular structures which were grown and maintained in a physiological hyperosmolar environment and evaluated whether COX2 → PGE2 axis (COX2 considered a cytoprotective protein for renal cells) induces Oxa damage or epithelial restitution. Main methodsMDCK cells were differentiated with NaCl hyperosmolar medium for 72 h where cells acquired the typical apical and basolateral membrane domains and a primary cilium. Then, cultures were treated with 1.5 mM Oxa for 24, 48, and 72 h to evaluate epithelial monolayer restitution dynamics and COX2-PGE2 effect. Key findingsOxa completely turned the differentiated phenotype into mesenchymal one (epithelial-mesenchymal transition). Such effect was partially and totally reverted after 48 and 72 h, respectively. Oxa damage was even deeper when COX2 was blocked by NS398. PGE2 addition restituted the differentiated-epithelial phenotype in a time and concentration dependence. SignificanceThis work presents an experimental system that approaches in vitro to in vivo renal epithelial studies and, more important, warns about NSAIDS use in patients suffering from kidney stones.

Programmed death ligand 1 intracellular interactions with STAT3 and focal adhesion protein Paxillin facilitate lymphatic endothelial cell remodeling

Lymphatic endothelial cells (LECs) comprise lymphatic capillaries and vessels that guide immune cells to lymph nodes (LNs) and form the subcapsular sinus and cortical and medullary lymphatic structures of the LN. During an active immune response, the lymphatics remodel to accommodate the influx of immune cells from the tissue, but factors involved in remodeling are unclear. Here, we determined that a TSS motif within the cytoplasmic domain of programmed death ligand 1 (PD-L1), expressed by LECs in the LN, participates in lymphatic remodeling. Mutation of the TSS motif to AAA does not affect surface expression of PD-L1, but instead causes defects in LN cortical and medullary lymphatic organization following immunostimulant, Poly I:C, administration invivo. Supporting this observation, invitro treatment of the LEC cell line, SVEC4-10, with cytokines TNFα and IFNα significantly impeded SVEC4-10 movement in the presence of the TSS-AAA cytoplasmic mutation. The cellular movement defects coincided with reduced F-actin polymerization, consistent with differences previously found in dendritic cells. Here, in addition to loss of actin polymerization, we define STAT3 and Paxillin as important PD-L1 binding partners. STAT3 and Paxillin were previously demonstrated to be important at focal adhesions for cellular motility. We further demonstrate the PD-L1 TSS-AAA motif mutation reduced the amount of pSTAT3 and Paxillin bound to PD-L1 both before and after exposure to TNFα and IFNα. Together, these findings highlight PD-L1 as an important component of a membrane complex that is involved in cellular motility, which leads to defects in lymphatic organization.

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Adult-onset Still\u2019s disease with multiple lymphadenopathy: a case report and literature review

BackgroundAdult-onset Still’s disease (AOSD) often presents with systemic multiple lymphadenopathy. In addition to the common paracortical and mixed patterns in AOSD lymph node histopathological features, other morphological patterns include diffuse, necrotic, and follicular patterns. However, to date, there have been few reports on the histopathological description of AOSD lymph nodes.Case presentationAn 18-year-old woman presented 2 months earlier with pain in her large joints with painless rash formation; bilateral posterior cervical lymph node, left supraclavicular lymph node, and left posterior axillary lymph node enlargement, and no tenderness. Left cervical lymph node resection was performed for pathological examination. The lymph node structure was basically preserved, and subcapsular and medullary sinus structures were observed. Many histiocytes in the sinus were observed, the cortical area was reduced, a few lymphoid follicles of different sizes were observed, and some atrophy and hyperplasia were noted. The lymphoid tissue in the paracortical region of the lymph node was diffusely proliferative and enlarged, mainly comprising histiocytes with abundant cytoplasm, immunoblasts and numerous lymphocytes with slightly irregular, small- to medium-sized nuclei. Nuclear karyorrhexis was easily observed, showing a few nuclear debris and the “starry sky” phenomenon, accompanied by abundantly branching high endothelial small vessels with few scattered plasma cells and eosinophil infiltration. Lymphoid follicle immunophenotype with reactive proliferative changes was observed. Approximately 40% of the cells in the paracortical region were positive for Ki-67, and the histiocytes expressed CD68, CD163, and some expressed S-100, with the absence of myeloperoxidase. The immunoblasts expressed CD30 and CD20, not ALK or CD15. Background small- to medium-sized T cells expressed CD2, CD3, CD5, CD7, CD4, and CD8; the number of CD8-positive T cells was slightly predominant, and a small number of T cells expressed granzyme B and T-cell intracellular antigen 1. The patient received a comprehensive medical treatment after the operation, and her condition was stable without progression at the 11-month follow-up evaluation.ConclusionsThe pathological features of AOSD lymphadenopathy raises the awareness of AOSD among pathologists and clinicians and aids in the diagnosis and differential diagnosis of AOSD lymphadenopathy from other reactive lymphadenopathies (lupus lymphadenitis, etc.) and lymphomas.

The role of the anterior pretectal nucleus in pain modulation: A comprehensive review.

Descending pain modulation involves multiple encephalic sites and pathways that range from the cerebral cortex to the spinal cord. Behavioral studies conducted in the 1980s revealed that electrical stimulation of the pretectal area causes antinociception dissociation from aversive responses. Anatomical and physiological studies identified the anterior pretectal nucleus and its descending projections to several midbrain, pontine, and medullary structures. The anterior pretectal nucleus is morphologically divided into a dorsal part that contains a dense neuron population (pars compacta) and a ventral part that contains a dense fiber band network (pars reticulata). Connections of the two anterior pretectal nucleus parts are broad and include prominent projections to and from major encephalic systems associated with somatosensory processes. Since the first observation that acute or chronic noxious stimuli activate the anterior pretectal nucleus, it has been established that numerous mediators participate in this response through distinct pathways. Recent studies have confirmed that at least two pain inhibitory pathways are activated from the anterior pretectal nucleus. This review focuses on rodent anatomical, behavioral, molecular, and neurochemical data that have helped to identify mediators of the anterior pretectal nucleus and pathways related to its role in pain modulation.

3D Exploration of the Brainstem in 50-Micron Resolution MRI.

The brainstem, a structure of vital importance in mammals, is currently becoming a principal focus in cognitive, affective, and clinical neuroscience. Midbrain, pontine and medullary structures serve as the conduit for signals between the forebrain and spinal cord, are the epicenter of cranial nerve-circuits and systems, and subserve such integrative functions as consciousness, emotional processing, pain, and motivation. In this study, we parcellated the nuclear masses and the principal fiber pathways that were visible in a high-resolution T2-weighted MRI dataset of 50-micron isotropic voxels of a postmortem human brainstem. Based on this analysis, we generated a detailed map of the human brainstem. To assess the validity of our maps, we compared our observations with histological maps of traditional human brainstem atlases. Given the unique capability of MRI-based morphometric analysis in generating and preserving the morphology of 3D objects from individual 2D sections, we reconstructed the motor, sensory and integrative neural systems of the brainstem and rendered them in 3D representations. We anticipate the utilization of these maps by the neuroimaging community for applications in basic neuroscience as well as in neurology, psychiatry, and neurosurgery, due to their versatile computational nature in 2D and 3D representations in a publicly available capacity.

Ability of human umbilical cord mesenchymal stem cells to repair chemotherapy-induced premature ovarian failure.

Premature ovarian insufficiency (POI) and premature ovarian failure (POF) have become one of the major problems threatening women of childbearing age. Studies have shown that stem cells transplanted from bone marrow, umbilical cord, peripheral blood and amniotic fluid can migrate and proliferate to the ovary, promote ovarian function repair, increase the number of follicles and granulosa cells at all levels of ovary, improve endocrine function, and can differentiate into oocytes in specific ovarian environment to restore fertility to some extent. To study the ability of human umbilical cord mesenchymal stem cells (hUCMSCs) to repair ovarian injury after chemotherapy. A total of 110 female BALB/c mice (aged 7-8 wk old) with body masses of 16.0-20.0 g were selected. The mice were fed until 12 wk of age, and cyclophosphamide was administered by intraperitoneal injection for 14 consecutive days to induce premature ovarian failure in mice. Seventy-five mice with estrous cycle disorder were screened and randomly divided into 3 groups according to their body weight: model group, positive control group and hUCMSC group, and each group had 25 mice. Another 25 mice were used as negative controls. The mice in the hUCMSC group were injected with hUCMSCs in the tail vein, and the mice in the positive control group were given an oestradiol valerate solution and a medroxyprogesterone acetate solution in the tail vein. On the 1st, 15th, 30th, 45th, and 60th days after intravenous administration, vaginal smears were made to monitor the estrous cycles of the mice. The ovaries were weighed, and pathological sections were made to observe the morphology of the follicles; blood samples were collected to monitor the concentration of sex hormones (oestradiol and follicle-stimulating hormone). The estrous cycles of the model group mice were disrupted throughout the experiment. Mice in the hUCMSC group and the positive control group resumed normal estrous cycles. The ovarian weight of the model group mice continued to decline. The ovarian weight of the hUCMSC group mice and the positive control group mice decreased first and then gradually increased, and the ovarian weight of the hUCMSC group mice was heavier than that of the positive control group mice. The difference was statistically significant (P < 0.05). Compared with the negative control group, the model group experienced a decrease in oestradiol and an increase in follicle-stimulating hormone, and the difference was statistically significant (P < 0.05). Compared with the model group, the hUCMSC and positive control groups experienced a slight increase in oestradiol and a decrease in follicle-stimulating hormone; the difference was statistically significant (P < 0.05). The pathological examination revealed that the mouse ovaries from the model group were atrophied, the volume was reduced, the cortical and medullary structures were disordered, the number of follicles at all stages was significantly reduced, the number of atretic follicles increased, the number of primordial follicles and corpus luteum significantly decreased, and the corpus luteum had an irregular shape. Compared with those of the model group, the lesions of the hUCMSC and positive control groups significantly improved. hUCMSCs can repair ovarian tissue damaged by chemotherapy to a certain extent, can improve the degree of apoptosis in ovarian tissue, and can improve the endocrine function of mouse ovaries.

Johann Peter Frank (1745-1821) and the Pathogenesis of Back Pain.

: Johann Peter Frank (1745-1821) is generally known as one of the founders of the modern Hygiene and Public Health. It is less known his contribution in investigating the pathogenesis of spinal disorders. In his "De Vertebralis Columnae in Morbis Dignitate" (1791), Frank first proposed to use the Latin term "rhachialgia" (back pain) to indicate all the painful states of spine. He focused on the "plethora spinali" in the vessels of the spinal cord and its membrane, sustaining that blood congestion was the origin of all the spinal disorders. He also believed that the excess of blood was able to generate a "diffuse inflammation" of vertebral and medullary structures. The innovative concepts developed by Johann Peter Frank demonstrated that he could be worthily considered as a pioneer in the study of spinal disorders.Level of Evidence: 5.

Neurophysiological Adaptation and Neuromodulatory Treatment Approaches in Patients Suffering from Post-stroke Dysphagia

This review gives an outline of the current state of knowledge on swallowing-related neurophysiology, neuroplasticity mechanisms following dysphagic stroke and neuromodulatory treatment approaches to enhance recovery processes for faster and better rehabilitation of post-stroke dysphagia. A widely distributed network including bilateral cortical and subcortical as well as medullary structures is involved in the act of swallowing. Distinct brain areas are related to specific aspects of swallowing control. Stroke lesions in these areas may lead to post-stroke dysphagia. Compensatory reorganization takes place mainly in the contralesional hemisphere making this a promising target of central neuromodulatory treatment approaches. Also, the peripheral pharyngeal electrical stimulation has shown to promote functional neuronal reorganization for clinical improvement of swallowing function. With promising results from recent studies—at least in distinct stroke patient collectives—central and peripheral neuromodulatory interventions seem to be at the threshold to implementation in clinical practice.

Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice.

Polymorphisms impacting thymic function may decrease peripheral tolerance and hasten autoimmune disease. The NF-κB transcription factor subunit, RelB, is essential for the development and differentiation of medullary thymic epithelial cells (mTECs): RelB-deficient mice have reduced thymic cellularity and markedly fewer mTECs, lacking AIRE. The precise mechanism of this mTEC reduction in the absence of RelB is unclear. To address this, we studied mTECs and dendritic cells (DCs), which critically regulate negative selection, and thymic regulatory T-cells (tTreg) in RelB−/− mice, which have spontaneous multiorgan autoimmune disease. RelB−/− thymi were organized, with medullary structures containing AIRE− mTECs, DCs, and CD4+ thymocytes, but fewer tTreg. Granulocytes infiltrated the RelB−/− thymic cortex, capsule, and medulla, producing inflammatory thymic medullary atrophy, which could be treated by granulocyte depletion or RelB+ DC immunotherapy, with concomitant recovery of mTEC and tTreg numbers. These data indicate that central tolerance defects may be accelerated by autoimmune thymic inflammation where impaired RelB signaling impairs the medullary niche, and may be reversible by therapies enhancing peripheral Treg or suppressing inflammation.

The nature, consequences, and management of neurological disorders in chronic kidney disease.

Perhaps no other organ in the body is affected as often and in as many ways as the brain is in patients with chronic kidney disease (CKD). Several factors contribute to the neurological disorders in CKD including accumulation of uremic toxins, metabolic and hemodynamic disorders, oxidative stress, inflammation, and impaired blood brain barrier among others. The neurological disorders in CKD involve both peripheral and central nervous system. The peripheral neurological symptoms of CKD are due to somatic and cranial peripheral neuropathies as well as a myopathy. The central neurological symptoms of CKD are due to the cortical predominantly cortical, or subcortical lesions. Cognitive decline, encephalopathy, cortical myoclonus, asterixis and epileptic seizures are distinct features of the cortical disorders of CKD. Diffuse white matter disease due to ischemia and hypoxia may be an important cause of subcortical encephalopathy. A special and more benign form of subcortical disorder caused by brain edema in CKD is termed posterior reversible encephalopathy. Subcortical pathology especially when it affects the basal ganglia causes a number of movement disorders including Parkinsonism, chorea and dystonia. A stimulus-sensitive reflex myoclonus is believed to originate from the medullary structures. Sleep disorder and restless leg syndrome are common in CKD and have both central and peripheral origin. This article provides an overview of the available data on the nature, prevalence, pathophysiology, consequences and treatment of neurological complications of CKD.

Mechanistic Studies of Capsaicin-Induced Apnea in Rodents.

Inhalation of capsaicin-based sprays can cause central respiratory depression and lethal apneas. There are contradictory reports regarding the sites of capsaicin action. Furthermore, an understanding of the neurochemical mechanisms underlying capsaicin-induced apneas and the development of pharmacological interventions is lacking. The main objectives of this study were to perform a systematic study of the mechanisms of action of capsaicin-induced apneas and to provide insights relevant to pharmacological intervention. In vitro and in vivo rat and transient receptor potential vanilloid superfamily member 1 (TRPV1)-null mouse models were used to measure respiratory parameters and seizure-like activity in the presence of capsaicin and compounds that modulate glutamatergic neurotransmission. Administration of capsaicin to in vitro and in vivo rat and wild-type mouse models induced dose-dependent apneas and the production of seizure-like activity. No significant changes were observed in TRPV1-null mice or rat medullary slice preparations. The capsaicin-induced effects were inhibited by the TRPV1 antagonist capsazepine, amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonists CNQX, NBQX, perampanel, and riluzole, a drug that inhibits glutamate release and increases glutamate uptake. The capsaicin-induced effects on breathing and seizure-like activity were accentuated by positive allosteric modulators of the AMPA receptors, CX717 and cyclothiazide. To summarize, capsaicin-induced apneas and seizure-like behaviors are mediated via TRPV1 activation acting at lung afferents, spinal cord-ascending tracts, and medullary structures (including nucleus tractus solitarius). AMPA receptor-mediated conductances play an important role in capsaicin-induced apneas and seizure-like activity. A pharmaceutical strategy targeted at reducing AMPA receptor-mediated glutamatergic signaling may reduce capsaicin-induced deleterious effects.

Modeling Glucose Metabolism in the Kidney.

The mammalian kidney consumes a large amount of energy to support the reabsorptive work it needs to excrete metabolic wastes and to maintain homeostasis. Part of that energy is supplied via the metabolism of glucose. To gain insights into the transport and metabolic processes in the kidney, we have developed a detailed model of the renal medulla of the rat kidney. The model represents water and solute flows, transmural fluxes, and biochemical reactions in the luminal fluid of the nephrons and vessels. In particular, the model simulates the metabolism of oxygen and glucose. Using that model, we have identified parameters concerning glucose transport and basal metabolism that yield predicted blood glucose concentrations that are consistent with experimental measurements. The model predicts substantial axial gradients in blood glucose levels along various medullary structures. Furthermore, the model predicts that in the inner medulla, owing to the relatively limited blood flow and low tissue oxygen tension, anaerobic metabolism of glucose dominates.

Facilitation of the respiratory rhythm in mice by acute exposure to a progestin, the etonogestrel. Involvement of medullary areas

Background Works have underlined the facilitatory influence of progestins on central respiratory drive (CRD). The congenital central hypoventilation syndrome (CCHS) is a neuro-respiratory disease characterized by an alteration of the CO 2 /H + chemosensitivity due to dysfunction of CO 2 /H + chemosensitive/PHOX2b-positive neurons of the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). In our laboratory, a recovery of the CO 2 /H + chemosensitivity was fortuitously observed in two CCHS women who took a potent synthetic progestin, the desogestrel (Respir Physiol Neurobiol 2010;171:171–4). Objective Our aim was to appreciate the effects of an acute exposure to etonogestrel (ETO), the main active metabolite of the desogestrel, on the CRD and to determine its medullary action mechanisms. Methods We used: – an analysis of the effect of ETO (0.05–2 μM) on the CRD of ex vivo medullary-spinal cord preparations from newborn mice in both normopH and metabolic acidosis; – pharmacological co-application of ETO and muscimol or NMDA, agonists of GABA A or NMDA receptors known to be a target of some steroids; – an analysis of the c-fos expression in medullary respiratory structures. Results First, the respiratory frequency was: – dose-dependently increased in normopH by ETO (≈ +23–47%; P – increase by metabolic acidosis similarly under ETO (≈ +28–37% at 0.05–1 μM, P P P Second, changes in respiratory frequency induced by muscimol or NMDA at their EC 50 were more potent under ETO (≈ −60–63%, P P P P c-fos revealed ETO activated cells in respiratory medullary areas i.e. the ventrolateral medulla, nucleus of the solitary tract, RTN/pFRG and medullary raphe nuclei. Conclusions As a whole, data suggest that, by medullary mechanisms, the progestin ETO exerts a facilitatory influence on the CRD by acting at the level of respiratory structures. Involved mechanisms would implicate an interaction with GABA A and NMDA receptors. Besides, at least in newborn mice, ETO do not potentiate the respiratory response to metabolic acidosis by intrinsic medullary mechanisms.

Activation of Neurons in the Rat Medulla Following a Gag Reflex Stimulus

Despite the fact that a number of individuals present with a hypersensitive gag reflex, research in this area has been limited to clinical applications. An animal model that describes the neurologic underpinnings of the gag reflex has not been reported. Thus, the objective of the current study was to localize activated neurons in the rat medulla and to investigate their neurochemistry following mechanostimulation to the posterior pharyngeal wall eliciting a gag reflex response. Activated neurons, determined using c-fos immunohistochemistry, were observed in subnuclei of the nucleus tractus solitarius (NTS) and motor regions such as dorsal motor vagus, hypoglossal, and nucleus ambiguus. The lateral and dorsal paragigantocellular nuclei and the medial rostral ventrolateral nucleus involved in bitter taste processing, also showed robust activation. Tyrosine hydroxylase and/or choline acetyltransferase immunoreactivity was localized in many activated neurons. The results of the present study provide the first documentation of activated neurons and preliminary neurochemistry in brainstem nuclei that are unique to mechanostimulation to the posterior pharyngeal wall. Our results support postulated medullary structures involved with the gag reflex and propose new regions to be added to the circuitry model. Further, our results reveal an activation pattern within the NTS unique to the gag reflex. Keywords: Brain stem, Nucleus of the solitary tract, neuroanatomy, animal model, pediatric feeding. Read more →

Switching mechanisms and bout times in a pair of reciprocally inhibitory neurons.

Within the appropriate parameter regime, a deterministic model of a pair of mutually inhibitory neurons receiving excitatory driving currents exhibits bistability-each of the two stable states corresponds to one neuron being active and the other being quiescent. The presence of noise in the driving currents results in a system that randomly switches back and forth between these two states, causing alternating bouts of spiking activity. In this work, we examine the random bout durations of the two neurons and dependence on system parameters. We find that bout durations of each neuron are exponentially distributed, with changes in system parameters altering only the mean of the distribution. Synaptic inhibition independently controls the bout durations of the two neurons-the mean bout time of a neuron is a function of efferent (or outgoing) inhibition, and is independent of afferent (or incoming) inhibition. Furthermore, we find that the mean bout time of a neuron exhibits a critical dependence on the time course (rather than amplitude) of efferent inhibition-mean bout time of a neuron grows exponentially with the time course of efferent inhibition, and the growth rate of this exponential function depends only on the excitatory driving current to that neuron (and not on any other system parameters). We discuss the relevance of our results to the regulation of sleep-wake cycling by medullary and pontine structures within the brain.

Effects of medullary lesions on conditional pacemaker activity of neonatal rat hypoglossal motoneurons in vitro

N-methyl-d-aspartate (NMDA) has been demonstrated to induce rhythmic activity in various neurons, including hypoglossal motoneurons (XIIms) and converts them to conditional pacemakers. Using whole-cell patch clamp recording in a slice preparation from neonatal rats, we confirmed that some XIIms act as conditional pacemakers, with TTX-insensitivity and a burst period that is voltage-dependent during NMDA application. Other XIIms in this study only fired tonically with NMDA application. Effects of medullary structures on conditional pacemaker XIIms were assessed using lesioned preparations. As a result, NMDA-induced rhythm (NIR) in the XIIm was observed with ventral lesions (excluding inspiratory neurons) and with dorsal lesions (excluding the swallowing center located in the nucleus of the solitary tract). The NIR was also observed with lateral lesions, but with a significantly decreased burst period. These data suggest that NMDA receptor activation selects a subset of XIIms and changes them to pacemakers whose properties can be altered by their excitability. The data also demonstrate that structures fundamental to the NIR are located within the area near the XII nucleus, indicating that the NIR is distinct from inspiratory and swallowing activities. The lateral medulla is considered to be a source of modulation of the excitability of XIIms.

Chemotherapy-induced Nausea and Vomiting—Where We Stand Now

Chemotherapy-induced nausea and vomiting (CINV) has been a major supportive care concern since the development of cisplatin, which was probably the major factor that drove antiemetic research. If strategies, particularly using combination antiemetic therapy, had not been developed and studied, cancer chemotherapy research would also likely to have been stymied. The past 30 years or more have seen our understanding of the physiology of vomiting grow from the understanding of the medullary brain structures we call the chemoreceptor trigger zone and the vomiting center, as well as the neurotransmitters located about that site. The current view of chemotherapy-induced vomiting is that two main pathways are involved—a peripheral pathway from the gut to the vomiting center that is mediated by increased release of serotonin by enterochromaffin cells in the gastrointestinal tract mucosa that binds to vagal terminals terminating in the nucleus tractus solitarius, and a central pathway in the brain that involves substance P binding at neurokinin 1 receptors near the vomiting center. Development of antiemetics that target these specific receptors, plus the use of dexamethasone, has resulted in prevention of acute vomiting in 70–80 % of patients receiving highly emetogenic chemotherapy. The scientific evidence resulting from this antiemetic research, along with clinical application knowledge, forms the basis of current chemotherapy antiemetic guidelines. Although these are useful to clinical practice, they do no replace clinical assessment and follow up of individual patients. Furthermore, about half of patients receiving moderately or highly emetogenic chemotherapy experience distressing delayed nausea, which can alter a patient’s life activities, cause debilitating physical consequences, and interfere with their ability and willingness to undergo chemotherapy.