Areas Of CNS Research Articles

Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue.

Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.

The unique properties of Big tau in the visual system.

Tau is a microtubule associated protein that plays important roles in regulating the properties of microtubules and axonal transport, as well as tauopathies associated with toxic aggregates leading to neurodegenerative diseases. It is encoded by the MAPT gene forming multiple isoforms (45-60 kDa) by alternative splicing which are developmentally regulated. The high molecular weight (MW) tau isoform of 105 kDa, termed Big tau, was originally discovered in the peripheral nervous system (PNS) but later found in selective CNS areas. It contains an additional large exon 4a generating a long projecting domain of about 250 amino acids. Here we investigated the properties of Big tau in the visual system of rats, its distribution in retinal ganglion cells and the optic nerve as well as its developmental regulation using biochemical, molecular and histological analyses. We discovered that Big tau is expresses as a 95 kDa protein (termed middle MW) containing exons 4a, 6 as well as exon 10 which defines a 4 microtubule-binding repeats (4R). It lacks exons 2/3 but shares the extensive phosphorylation characteristic of other tau isoforms. Importantly, early in development the visual system expresses only the low MW isoform (3R) switching to both the low and middle MW isoforms (4R) in adult retinal ganglion neurons and their corresponding axons. This is a unique structure and expression pattern of Big tau, which we hypothesize is associated with the specific properties of the visual system different from what has been previously described in the PNS and other areas of the nervous system.

CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation.

Abstract The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bio-activities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is upregulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing antibody halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1. Both anti-CSF-1 and BLZ945 treatment greatly reduced the number of monocyte-derived cells and microglia in the CNS. However, anti-CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti-CSF-1 treatment reduced the size of demyelinated lesions and microglial activation in the grey matter. Lastly, we found that bone marrow-derived immune cells were the major mediators of CSF-1R-dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with ablation of CSF-1R-dependent cells. National Multiple Sclerosis Society (RG-1803-30491) National Institutes of Health T32 training grant (T32AI134646, NIAID)

CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation

The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is up-regulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing antibody halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1. Both anti–CSF-1 and BLZ945 treatment greatly reduced the number of monocyte-derived cells and microglia in the CNS. However, anti–CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti–CSF-1 treatment reduced the size of demyelinated lesions and microglial activation in the gray matter. Lastly, we found that bone marrow–derived immune cells were the major mediators of CSF-1R–dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with ablation of CSF-1R–dependent cells.

What Is the Brainstem Control of Locomotion?

Locomotion in humans is defined as bipedal progression through stages of a gait cycle to move from one place to another while maintaining balance and posture. Locomotion can be categorized in temporal phases (initiation, actual locomotive episode/execution, and termination) or in behavioral categories (slow exploratory and fast speed locomotion). The motivation behind a locomotive episode may be driven by internal needs (goal driven from the motor cortex or emotion driven from the limbic system) or external environmental cues. Locomotion is mediated by a spinal central pattern generator (CPG) under the influence of the brainstem reticular formation and is integrated with control of muscle tone and posture. Control of gait, muscle tone, and posture involves complex interactions among the sensorimotor cortex, basal ganglia, basal forebrain, cerebellum, brainstem, and spinal cord.1-3 Pioneering studies in cats4 and monkeys5,6 and more recently in rodents7-12 have contributed to elucidate the brainstem mechanisms controlling locomotion. This information, together with indirect evidence from human electrophysiologic and functional neuroimaging studies, provides testable pathophysiologic hypotheses and potential therapeutic targets for gait control disorders. The focus of this review is on brainstem mechanisms controlling locomotion. The role of other CNS areas in control of gait and posture and their abnormalities in disorders such as Parkinson disease (PD) have been extensively reviewed1 and are only briefly discussed here.

Relationship Between Circulating Metabolic Hormones and Their Central Receptors During Ovariectomy-Induced Weight Gain in Rats.

Although increasing research focuses on the phenomenon of body weight gain in women after menopause, the complexity of body weight regulation and the array of models used to investigate it has proven to be challenging. Here, we used ovariectomized (OVX) rats, which rapidly gain weight, to determine if receptors for ghrelin, insulin, or leptin in the dorsal vagal complex (DVC), arcuate nucleus (ARC), or paraventricular nucleus (PVN) change during post-ovariectomy weight gain. Female Sprague-Dawley rats with ad libitum access to standard laboratory chow were bilaterally OVX or sham OVX. Subgroups were weighed and then terminated on day 5, 33, or 54 post-operatively; blood and brains were collected. ELISA kits were used to measure receptors for ghrelin, insulin, and leptin in the DVC, ARC, and PVN, as well as plasma ghrelin, insulin, and leptin. As expected, body weight increased rapidly after ovariectomy. However, ghrelin receptors did not change in any of the areas for either group, nor did circulating ghrelin. Thus, the receptor:hormone ratio indicated comparable ghrelin signaling in these CNS areas for both groups. Insulin receptors in the DVC and PVN decreased in the OVX group over time, increased in the PVN of the Sham group, and were unchanged in the ARC. These changes were accompanied by elevated circulating insulin in the OVX group. Thus, the receptor:hormone ratio indicated reduced insulin signaling in the DVC and PVN of OVX rats. Leptin receptors were unchanged in the DVC and ARC, but increased over time in the PVN of the Sham group. These changes were accompanied by elevated circulating leptin in both groups that was more pronounced in the OVX group. Thus, the receptor:hormone ratio indicated reduced leptin signaling in the DVC and PVN of both groups, but only in the OVX group for the ARC. Together, these data suggest that weight gain that occurs after removal of ovarian hormones by ovariectomy is associated with selective changes in metabolic hormone signaling in the CNS. While these changes may reflect behavioral or physiological alterations, it remains to be determined whether they cause post-ovariectomy weight gain or result from it.

A comprehensive study of a 29-capsid AAV library in a non-human primate central nervous system

Non-human primates (NHPs) are a preferred animal model for optimizing adeno-associated virus (AAV)-mediated CNS gene delivery protocols before clinical trials. In spite of its inherent appeal, it is challenging to compare different serotypes, delivery routes, and disease indications in a well-powered, comprehensive, multigroup NHP experiment. Here, a multiplex barcode recombinant AAV (rAAV) vector-tracing strategy has been applied to a systemic analysis of 29 distinct, wild-type (WT), AAV natural isolates and engineered capsids in the CNS of eight macaques. The report describes distribution of each capsid in 15 areas of the macaques’ CNS after intraparenchymal (putamen) injection, or cerebrospinal fluid (CSF)-mediated administration routes (intracisternal, intrathecal, or intracerebroventricular). To trace the vector biodistribution (viral DNA) and targeted tissues transduction (viral mRNA) of each capsid in each of the analyzed CNS areas, quantitative next-generation sequencing analysis, assisted by the digital-droplet PCR technology, was used. The report describes the most efficient AAV capsid variants targeting specific CNS areas after each route of administration using the direct side-by-side comparison of WT AAV isolates and a new generation of rationally designed capsids. The newly developed bioinformatics and visualization algorithms, applicable to the comparative analysis of several mammalian brain models, have been developed and made available in the public domain. Non-human primates (NHPs) are a preferred animal model for optimizing adeno-associated virus (AAV)-mediated CNS gene delivery protocols before clinical trials. In spite of its inherent appeal, it is challenging to compare different serotypes, delivery routes, and disease indications in a well-powered, comprehensive, multigroup NHP experiment. Here, a multiplex barcode recombinant AAV (rAAV) vector-tracing strategy has been applied to a systemic analysis of 29 distinct, wild-type (WT), AAV natural isolates and engineered capsids in the CNS of eight macaques. The report describes distribution of each capsid in 15 areas of the macaques’ CNS after intraparenchymal (putamen) injection, or cerebrospinal fluid (CSF)-mediated administration routes (intracisternal, intrathecal, or intracerebroventricular). To trace the vector biodistribution (viral DNA) and targeted tissues transduction (viral mRNA) of each capsid in each of the analyzed CNS areas, quantitative next-generation sequencing analysis, assisted by the digital-droplet PCR technology, was used. The report describes the most efficient AAV capsid variants targeting specific CNS areas after each route of administration using the direct side-by-side comparison of WT AAV isolates and a new generation of rationally designed capsids. The newly developed bioinformatics and visualization algorithms, applicable to the comparative analysis of several mammalian brain models, have been developed and made available in the public domain.

Liquid Biopsy and Other Non-Invasive Diagnostic Measures in PCNSL.

Simple SummaryPrimary central nervous system lymphoma (PCNSL) is an uncommon disease accounting for around 3% of primary CNS tumors. PCNSL exhibits aggressive clinical behavior and has an overall poor prognosis. The clinical presentation is variable, and there are no specific symptoms. Despite progress in radiographic neuroimaging, stereotactic brain biopsy remains obligatory for definitive diagnosis. Advanced standard diagnostics, including CSF cytology and flow cytometry, have limited sensitivity. Accordingly, there is an urgent need to improve the diagnostic tools for PCNSL, including novel non-invasive procedures. The aim of this review is to present and discuss modern methods that have the potential to contribute standard clinical diagnostics within the next few years.Primary central nervous system lymphoma is a rare but highly aggressive form of non-Hodgkin lymphoma that remains confined to the CNS neuroaxis. The diagnosis of PCNSL requires a high level of suspicion as clinical presentation varies depending on the involved CNS areas. Neurological symptoms and MRI findings may mimic gliomas, demyelinating lesions, or infectious and granulomatous diseases. Almost all PCNSL patients undergo invasive surgical procedures for definite diagnosis. Stereotactic biopsy is still the gold standard in achieving a diagnostic accuracy of 73–97%. Both the potential procedural morbidity and mortality, as well as the time to definite histopathologic diagnosis resulting in delays of treatment initiation, have to be considered. On the contrary, minimally invasive procedures, such as MRI, CSF cytology, and flow cytometry, still have limited value due to inferior specificity and sensitivity. Hence, novel diagnostic approaches, including mutation analyses (MYD88) in circulating tumor DNA (ctDNA) and the determination of microRNAs (miR-21, miR-19b, and miR-92) as well as cytokine levels (IL10 and IL6) in blood, cerebrospinal fluid (CSF), and vitreous fluid (VRF), move into the focus of investigation to facilitate the diagnosis of PCNSL. In this review, we outline the most promising approaches that are currently under clinical consideration.

Evidence for Unknown Sarcocystis-Like Infection in Stranded Striped Dolphins (Stenella coeruleoalba) from the Ligurian Sea, Italy.

Simple SummaryTwo stranded striped dolphins presented meningoenchepalitic lesions associated with the presence of unknown protozoan tissue cysts. The present study aimed at fully characterizing these previously undescribed parasites. Light microscopy re-examination of affected CNS areas showed high numbers of tissue cysts with morphological features resembling those of Sarcocystis species. Tissue cyst bradyzoites positively stained when labeled with polyclonal antisera but cross-reactivity could not be precluded. Sarcocystis sp. sequences with high homology to species infecting livestock were amplified by means of PCR from myocardial and muscle tissues. This is the first report of Sarcocystis-like tissue cysts in the cerebral tissue of stranded cetaceans with muscular sarcocystosis in Mediterranean dolphins. The obtained results may suggest a land-to-sea cycling of Apicomplexan parasites in this region and the need for further investigations in order to foster marine mammal conservation.Two striped dolphins (SD1, SD2), stranded along the Ligurian coast of Italy, were diagnosed with a nonsuppurative meningoencephalitis associated with previously undescribed protozoan tissue cysts. As tissue cysts were morphologically different from those of Toxoplasma gondii, additional histopathological, immunohistochemical, ultrastructural, and biomolecular investigations were performed, aiming to fully characterize the organism. Histopathology revealed the presence of large Sarcocystis-like tissue cysts, associated with limited inflammatory lesions in all CNS areas studied. IHC was inconclusive, as positive staining with polyclonal antisera did not preclude cross-reaction with other Sarcocystidae coccidia. Applied to each animal, 11 different PCR protocols precluded a neural infection by Sarcocystis neurona, Sarcocystis falcatula, Hammondia hammondi, and Neospora caninum. T. gondii coinfection was confirmed only in dolphin SD2. Sarcocystis sp. sequences, showing the highest homology to species infecting the Bovidae family, were amplified from SD1 myocardium and SD2 skeletal muscle. The present study represents the first report of Sarcocystis-like tissue cysts in the brain of stranded cetaceans along with the first description of Sarcocystis sp. infection in muscle tissue of dolphins from the Mediterranean basin.

Neuronal megalin mediates synaptic plasticity-a novel mechanism underlying intellectual disabilities in megalin gene pathologies.

Donnai-Barrow syndrome, a genetic disorder associated to LRP2 (low-density lipoprotein receptor 2/megalin) mutations, is characterized by unexplained neurological symptoms and intellectual deficits. Megalin is a multifunctional endocytic clearance cell-surface receptor, mostly described in epithelial cells. This receptor is also expressed in the CNS, mainly in neurons, being involved in neurite outgrowth and neuroprotective mechanisms. Yet, the mechanisms involved in the regulation of megalin in the CNS are poorly understood. Using transthyretin knockout mice, a megalin ligand, we found that transthyretin positively regulates neuronal megalin levels in different CNS areas, particularly in the hippocampus. Transthyretin is even able to rescue megalin downregulation in transthyretin knockout hippocampal neuronal cultures, in a positive feedback mechanism via megalin. Importantly, transthyretin activates a regulated intracellular proteolysis mechanism of neuronal megalin, producing an intracellular domain, which is translocated to the nucleus, unveiling megalin C-terminal as a potential transcription factor, able to regulate gene expression. We unveil that neuronal megalin reduction affects physiological neuronal activity, leading to decreased neurite number, length and branching, and increasing neuronal susceptibility to a toxic insult. Finally, we unravel a new unexpected role of megalin in synaptic plasticity, by promoting the formation and maturation of dendritic spines, and contributing for the establishment of active synapses, both in in vitro and in vivo hippocampal neurons. Moreover, these structural and synaptic roles of megalin impact on learning and memory mechanisms, since megalin heterozygous mice show hippocampal-related memory and learning deficits in several behaviour tests. Altogether, we unveil a complete novel role of megalin in the physiological neuronal activity, mainly in synaptic plasticity with impact in learning and memory. Importantly, we contribute to disclose the molecular mechanisms underlying the cognitive and intellectual disabilities related to megalin gene pathologies.

Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol.

BackgroundBlood-brain barrier (BBB) limits over 95% of drugs’ penetration into brain, which has been a major obstacle in treating patients with glioblastoma. Transient BBB opening in glioblastoma (GBM) is feasible by combining focused ultrasound (FUS) with systemic infusion of microbubbles (MB). NaviFUS, a novel device that integrates neuronavigation and FUS-MB system, is able to intraoperatively direct the ultrasound energy precisely and repeatedly at targeted CNS areas. This clinical trial evaluates the safety and feasibility of NaviFUS in recurrent glioblastoma patients.MethodsThe study is a first-in-human, prospective, open-label, single-center, single-arm, dose escalation phase 1 clinical trial. A total of 6 patients will be enrolled. Patients will be enrolled into three groups, each group receiving an escalating dose of FUS energy (acoustic power is 4, 8, and 12 W) with concomitant systemic microbubbles (0.1 mL/kg) applied 1 week before surgical resection.ResultsDynamic contrast-enhanced MRI will be obtained immediately and 24 hours after FUS procedures, while heavily T2-weighted sequence will be obtained to evaluate for any micro-hemorrhages. We anticipate that there will be minimal side effects associated with NaviFUS-mediated transient BBB opening.ConclusionsObtained results will support a planned phase 2 trial to evaluate whether NaviFUS can effectively enhance the delivery of chemotherapeutic agents and improve tumor control.

In Silico Studies for Bacterystic Evaluation against Staphylococcus aureus of 2-Naphthoic Acid Analogues.

Staphylococcus aureus is a gram-positive spherical bacterium commonly present in nasal fossae and in the skin of healthy people; however, in high quantities, it can lead to complications that compromise health. The pathologies involved include simple infections, such as folliculitis, acne, and delay in the process of wound healing, as well as serious infections in the CNS, meninges, lung, heart, and other areas. This research aims to propose a series of molecules derived from 2-naphthoic acid as a bioactive in the fight against S. aureus bacteria through in silico studies using molecular modeling tools. A virtual screening of analogues was done in consideration of the results that showed activity according to the prediction model performed in the KNIME Analytics Platform 3.6, violations of the Lipinski rule, absorption rate, cytotoxicity risks, energy of binder-receptor interaction through molecular docking, and the stability of the best profile ligands in the active site of the proteins used (PDB ID 4DXD and 4WVG). Seven of the 48 analogues analyzed showed promising results for bactericidal action against S. aureus. It is possible to conclude that ten of the 48 compounds derived from 2-naphthoic acid presented activity based on the prediction model generated, of which seven presented no toxicity and up to one violation to the Lipinski rule.

LPS immune challenge reduces arcuate nucleus TSHR and CART mRNA and elevates plasma CART peptides

BackgroundThe aim was to examine the impact of lipopolysaccharide-induced systemic inflammation on expression of mRNA for cocaine- and amphetamine-regulated transcript (CART) and the thyrotropin receptor (TSHR) and its ligands in CNS areas of relevance for feeding controls and metabolism. Lipopolysaccharide effects on plasma levels of TSH and CART peptides were also examined.MethodsLipopolysaccharide (150–200 μg/mouse) was injected in C57BL/6J mice and tissue and plasma samples taken after 24 h. To establish if plasma increase in CART peptide levels were prostanoid dependent, indomethacin was given via the drinking water beginning 48 h prior to LPS. We evaluated mRNA expression for CART, TSHR, TSHβ, and thyrostimulin in brain and pituitary extracts. Plasma levels of TSH, CARTp, and serum amyloid P component were analyzed by ELISA.ResultsLipopolysaccharide suppressed TSHR mRNA expression in the arcuate nucleus and the pituitary. CART mRNA expression was reduced in the arcuate nucleus but elevated in the pituitary of mice treated with Lipopolysaccharide, whereas plasma TSH remained unchanged. Plasma CART peptide concentration increased after LPS treatment in a prostanoid-independent manner, and CART peptide levels correlated positively to degree of inflammation.ConclusionsOur findings suggest that central and peripheral CART is affected by acute inflammation. Considering the role of the arcuate nucleus in feeding controls, our data highlight TSHR and CART as putative neuroendocrine signaling components that respond to inflammation, perhaps to maintain weight and metabolic homeostasis during states of disease.

Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is one of the most common incurable motor neuron disorders in adults. The majority of all ALS cases occur sporadically (sALS). Symptoms of ALS are caused by a progressive degeneration of motor neurons located in the motor cortex and spinal cord. The question arises why motor neurons selectively degenerate in ALS, while other cells and systems appear to be spared the disease. Members of the intrinsic apoptotic pathway are frequent targets of altered microRNA expression. Therefore, microRNAs and their effects on cell survival are subject of controversial debates. In this study, we investigated the expression of numerous members of the intrinsic apoptotic cascade by qPCR, western blot, and immunostaining in two different regions of the CNS of wobbler mice. Further we addressed the expression of miR-29b-3p targeting BMF, Bax, and, Bak, members of the apoptotic pathway. We show a tissue-specific differential expression of BMF, Bax, and cleaved-Caspase 3 in wobbler mice. An opposing regulation of miR-29b-3p expression in the cerebellum and cervical spinal cord of wobbler mice suggests different mechanisms regulating the intrinsic apoptotic pathway. Based on our findings, it could be speculated that miR-29b-3p might regulate antiapoptotic survival mechanisms in CNS areas that are not affected by neurodegeneration in the wobbler mouse ALS model.

Isolation and Quantification of Zika Virus from Multiple Organs in a Mouse.

The methods being presented demonstrate laboratory procedures for the isolation of organs from Zika virus infected animals and the quantification of viral load. The purpose of the procedure is to quantify viral titers in peripheral and CNS areas of the mouse at different time points post infection or under different experimental conditions to identify virologic and immunological factors that regulate Zika virus infection. The organ isolation procedures demonstrated allow for both focus forming assay quantification and quantitative PCR assessment of viral titers. The rapid organ isolation techniques are designed for the preservation of virus titer. Viral titer quantification by focus forming assay allows for the rapid throughput assessment of Zika virus. The benefit of the focus forming assay is the assessment of infectious virus, the limitation of this assay is the potential for organ toxicity reducing the limit of detection. Viral titer assessment is combined with quantitative PCR, and using a recombinant RNA copy control viral genome copy number within the organ is assessed with low limit of detection. Overall these techniques provide an accurate rapid high throughput method for the analysis of Zika viral titers in the periphery and CNS of Zika virus infected animals and can be applied to the assessment of viral titers in the organs of animals infected with most pathogens, including Dengue virus.

Revisiting the physiology of nausea and vomiting-challenging the paradigm.

The predominant neurotransmitters and receptors for acute and delayed chemotherapy-induced nausea and vomiting (CINV) are represented in the current paradigm, which reflects successful control of emesis. However, control of nausea (N) lags behind management of vomiting (V). This review aims to re-examine and incorporate new information about the mechanisms of V and N. The initial literature search focused on CINV. Keywords in articles led to subsequent discovery of publications focused on N&V in other medical and scientific fields (e.g., gastroenterology, neurology, cannabinoid science, neuropharmacology, and motion sickness). Using keywords to identify other sources continued until no further recent, meaningful publications were found. More than 86% of references were from recent non-oncology journals and books, suggesting there are many areas for cross-fertilization research into mechanisms and management of N&V-particularly of N, which involves overlapping and dissimilar CNS areas from V. Information from cited articles was incorporated into visual representation of N&V, which is certainly not exhaustive but supports highly complex processes in the stomach and gut, the vagus nerve and spinal cord neurons, the nucleus tractus solitarii, and the anterior insular cortex and anterior cingulate cortex with input from the amygdala. These data support the idea that mechanisms for N, whatever the cause, must be highly similar. Continued research into nausea, including patient-reported evaluation and outcomes, is important; interventions for nausea could be considered adjuvants to current standard of care antiemetics and be individualized, depending on patient-reported efficacy and adverse effects and preferences.

Scaling Our World View: How Monoamines Can Put Context Into Brain Circuitry.

Monoamines are presumed to be diffuse metabotropic neuromodulators of the topographically and temporally precise ionotropic circuitry which dominates CNS functions. Their malfunction is strongly implicated in motor and cognitive disorders, but their function in behavioral and cognitive processing is scarcely understood. In this paper, the principles of such a monoaminergic function are conceptualized for locomotor control. We find that the serotonergic system in the ventral spinal cord scales ionotropic signals and shows topographic order that agrees with differential gain modulation of ionotropic subcircuits. Whereas the subcircuits can collectively signal predictive models of the world based on life-long learning, their differential scaling continuously adjusts these models to changing mechanical contexts based on sensory input on a fast time scale of a few 100 ms. The control theory of biomimetic robots demonstrates that this precision scaling is an effective and resource-efficient solution to adapt the activation of individual muscle groups during locomotion to changing conditions such as ground compliance and carried load. Although it is not unconceivable that spinal ionotropic circuitry could achieve scaling by itself, neurophysiological findings emphasize that this is a unique functionality of metabotropic effects since recent recordings in sensorimotor circuitry conflict with mechanisms proposed for ionotropic scaling in other CNS areas. We substantiate that precision scaling of ionotropic subcircuits is a main functional principle for many monoaminergic projections throughout the CNS, implying that the monoaminergic circuitry forms a network within the network composed of the ionotropic circuitry. Thereby, we provide an early-level interpretation of the mechanisms of psychopharmacological drugs that interfere with the monoaminergic systems.

The negotiated equilibrium model of spinal cord function.

The belief that the spinal cord is hardwired is no longer tenable. Like the rest of the CNS, the spinal cord changes during growth and ageing, when new motor behaviours are acquired, and in response to trauma and disease. This paper describes a new model of spinal cord function that reconciles its recently appreciated plasticity with its long‐recognized reliability as the final common pathway for behaviour. According to this model, the substrate of each motor behaviour comprises brain and spinal plasticity: the plasticity in the brain induces and maintains the plasticity in the spinal cord. Each time a behaviour occurs, the spinal cord provides the brain with performance information that guides changes in the substrate of the behaviour. All the behaviours in the repertoire undergo this process concurrently; each repeatedly induces plasticity to preserve its key features despite the plasticity induced by other behaviours. The aggregate process is a negotiation among the behaviours: they negotiate the properties of the spinal neurons and synapses that they all use. The ongoing negotiation maintains the spinal cord in an equilibrium – a negotiated equilibrium – that serves all the behaviours. This new model of spinal cord function is supported by laboratory and clinical data, makes predictions borne out by experiment, and underlies a new approach to restoring function to people with neuromuscular disorders. Further studies are needed to test its generality, to determine whether it may apply to other CNS areas such as the cerebral cortex, and to develop its therapeutic implications.

Regional Distribution of CNS Antigens Differentially Determines T-Cell Mediated Neuroinflammation in a CX3CR1-Dependent Manner.

T cells continuously sample CNS-derived antigens in the periphery, yet it is unknown how they sample and respond to CNS antigens derived from distinct brain areas. We expressed ovalbumin (OVA) neoepitopes in regionally distinct CNS areas (Cnp-OVA and Nes-OVA mice) to test peripheral antigen sampling by OVA-specific T cells under homeostatic and neuroinflammatory conditions. We show that antigen sampling in the periphery is independent of regional origin of CNS antigens in both male and female mice. However, experimental autoimmune encephalomyelitis (EAE) is differentially influenced in Cnp-OVA and Nes-OVA female mice. Although there is the same frequency of CD45high CD11b+ CD11c+ CX3CL1+ myeloid cell-T-cell clusters in neoepitope-expressing areas, EAE is inhibited in Nes-OVA female mice and accelerated in CNP-OVA female mice. Accumulation of OVA-specific T cells and their immunomodulatory effects on EAE are CX3C chemokine receptor 1 (CX3CR1) dependent. These data show that despite similar levels of peripheral antigen sampling, CNS antigen-specific T cells differentially influence neuroinflammatory disease depending on the location of cognate antigens and the presence of CX3CL1/CX3CR1 signaling.SIGNIFICANCE STATEMENT Our data show that peripheral T cells similarly recognize neoepitopes independent of their origin within the CNS under homeostatic conditions. Contrastingly, during ongoing autoimmune neuroinflammation, neoepitope-specific T cells differentially influence clinical score and pathology based on the CNS regional location of the neoepitopes in a CX3CR1-dependent manner. Altogether, we propose a novel mechanism for how T cells respond to regionally distinct CNS derived antigens and contribute to CNS autoimmune pathology.

The Origin of Microglia Determines the Content of Exosomes and Biological Function

Background: It is interesting to know whether microglia cells migrating in different central brain system components, i.e. cortex or in the spinal cord, are subjected to the same maturation processes and share similar functional phenotypes which could account with peculiar pathologies. Methods: We used a combination of pan proteomic platform associated with systemic biology analyses, in order to investigate that microglial cells derived from cortex and spinal cord expressed different phenotypes upon the physiological or pathological conditions Findings: This difference was found in cells and in their secreted exosomes. Cortical microglia showed neurogenesis/tumorigenesis characteristics, the spinal cord microglia revealed mostly involvement in the modulation of the inflammatory response to injury. We confirmed these results by performing functional testing including neurite outgrowth assays, and 3D spheroid cultures, which was used for glioma proliferation analysis. Results indicated that microglia located at different CNS areas reveal not only diverse content but also differential biological functions. Thus, the origin of microglia affected the physio-pathological function. These results also indicate differences in which the glioma is more prevalent in the brain than in spinal cord. Conclusion: Taken together, we demonstrated that microglia cells produce exosomes which can be used as therapeutic nanoparticles in translational medicine either in cancer treatment or in regenerative medicine. In fact, exosomes issued from spinal cord microglia can be addressed for glioma treatment and the ones from cortex microglia for spinal cord or brain traumatic injuries. Microglia exosomes are clearly a new source of therapeutic agents. Funding Statement: This research was supported by a collaboration between the Fundamental and Applied Biology Mass Spectrometry Laboratory (MS) and grants from Ministere de L’Education Nationale, L’Enseignement Superieur et de la Recherche, INSERM, SIRIC ONCOLille Grant INCD) a-DGOS-Inserm 6041aa (IF) and Universite de Lille (AM), APVV 15-0613 (DC), Stefanik SK-FR-2015-0018 (DC, MS), ERANET Axon Repair (DC). Declaration of Interests: The authors declare no competing financial interests in this work. Ethics Approval Statement: The study was performed with the approval and according to the guidelines of the Institutional Animal Care and Use Committee of the Slovak Academy of Sciences and with the European Communities Council Directive (2010/63/EU) regarding the use of animals in Research, Slovak Law for Animal Protection No. 377/2012 and 436/2012.