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ApTOLL is an aptamer specifically designed to antagonize toll-like receptor 4 (TLR4), which is involved in the innate immunity that promotes inflammatory responses in several diseases, including multiple sclerosis (MS). MS is a chronic, immune, demyelinating and neurodegenerative disease of the central nervous system that represents the second most important cause of neurological disability in young adults. The drugs currently available to treat this disease are immunomodulators and, to date, there are no therapeutic remyelinating drugs available to manage MS. In this study, we show that TLR4 is located in post-mortem cortical lesions of MS patients and as a result, we evaluated the effect of its inhibition by ApTOLL in two different animal models of MS, that of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. ApTOLL administration ameliorated the clinical symptomatology of the affected mice, which was associated with better preservation and restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals. This revealed not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL which was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs). In summary, the molecular nature of ApTOLL and its mechanism of action strongly supports its further study and use in novel strategies to treat MS and eventually, other demyelinating diseases.

El profesor Juan Vicente Sánchez-Andrés murió el pasado 4 de septiembre de 2023. Para quienes escribimos esto y para muchos otros neurocientíficos y fisiólogos españoles es una noticia tan inesperada como dura: Juanvi era un amigo, una persona con la que hemos compartido muchos momentos, y a quien debemos una parte muy significativa de nuestras carreras científicas, de una u otra forma. Pero, precisamente por ello, creemos que este pequeño recuerdo es justo y necesario para celebrar el legado que dejó entre nosotros. Porque Juanvi fue muchas cosas además de un académico e investigador destacado. Fue creativo y pasional, valiente en sus apuestas, digno en la adversidad, inspirador y visionario. Y creemos que eso puede ser, también, un ejemplo para todos aquellos que apenas le trataron o, para los más jóvenes, que tal vez ni le han conocido.

The beginnings of cybernetics were marked by the publication of two papers in 1943. In the first one, Rosenblueth, Wiener, and Bigelow claimed that purposeful behavior is a circular process controlled by negative feedback. In the second seminal paper, McCulloch and Pitts proposed that neurons are interconnected working as logical operators. Both articles raised human-machine analogies and mathematically formulated cognitive mechanisms. These ideas ignited the interest of von Neumann, who was developing the first stored-program computer. Thus, after a preliminary meeting in 1945, a series of meetings were held between 1946 and 1953. The role of the Spanish neurophysiologist Rafael Lorente de Nó in the beginnings of cybernetics is attested not only by his participation in the core members of these Macy conferences but also for his previous description of reverberating circuits formed by a closed chain of internuncial neurons. This was the first neurobiologic demonstration of a feedback loop. Most researchers considered the central nervous system as a mere reflex organ until then; nevertheless, he demonstrated a self-sustained central activity in the nervous system, supporting the idea of self-regulating mechanisms as a key concept not just in machines but also in the brain.

The Portuguese Glial Network invites you to attend the VII Symposium of the Portuguese Glial Network, in collaboration with Red Glial Española. The Symposium will be held in Albufeira (Algarve) on May 2, 2023, as a satellite meeting of the FENS Regional Meeting 2023. This year, we will have six invited speakers to bring us the latest on glial cell physiology, biology, signaling, and ultrastructure: Amanda Sierra (Achucarro Basque Center for Neuroscience and Department of Biochemistry and Molecular Biology, Spain), Ana Luísa Cardoso (University of Coimbra, Portugal), Christa Rhiner (Champalimaud Research Program, Portugal), Corrado Calì (Università degli Studi di Torino, Italy), Juliana Rosa (Hospital Nacional de Parapléjicos – IDISCAM, Spain) and Renzo Mancuso (Universiteit Antwerpen, Belgium). Six short talks will also be selected from the submitted abstracts by our Scientific Committee. We are delighted to welcome you to our VII Symposium and gather again friends and colleagues of the Portuguese glial family for another great meeting. Registration is, as always, free (but mandatory), and the best poster and oral communication will receive awards! Join us in the vibrant setting of the city of Albufeira and experience the sun and energy of the Algarve.

COVID-19 is an ongoing viral pandemic that emerged from East Asia and quickly spread to the rest of the world. SARS-CoV-2 is the virus causing COVID-19. Acute respiratory distress syndrome (ARDS) is definitely one of the main clinically relevant consequences in patients with COVID-19. Starting from the earliest reports of the COVID-19 pandemic, two peculiar neurological manifestations (namely, hyposmia/anosmia and dysgeusia) were reported in a relevant proportion of patients infected by SARS-CoV-2. At present, the physiopathologic mechanisms accounting for the onset of these symptoms are not yet clarified. CXCL10 is a pro-inflammatory chemokine with a well-established role in the COVID-19-related cytokine storm and in subsequent development of ARDS. CXCL10 is also known to be involved in coronavirus-induced demyelination. On these bases, a role for CXCL10 as the common denominator between pulmonary and olfactory dysfunctions could be envisaged. The aim of the present report will be to hypothesize a role for CXCL10 in COVID-19 olfactory dysfunctions. Previous evidences supporting our hypothesis, with special emphasis to the role of CXCL10 in coronavirus-induced demyelination, the anatomical and physiological peculiarity of the olfactory system, and the available data supporting their link during COVID-19 infections, will be overviewed.

Los oligodendrocitos son las células gliales encargadas de la mielinización de los axones y desempeñan un papel fundamental en el desarrollo y la correcta transmisión de los impulsos nerviosos. Estas células se generan durante el desarrollo embrionario a partir de las células precursoras de oligodendrocitos (OPCs), las cuales continúan dividiéndose y diferenciándose a lo largo de toda la vida del individuo. El proceso de mielinización es muy importante tanto en el desarrollo embrionario y en el mantenimiento fisiológico de la transmisión eléctrica, como en el proceso de reparación durante patologías desmielinizantes. Las enfermedades neurodegenerativas son un conjunto heterogéneo de patologías del sistema nervioso central (SNC), caracterizadas en su mayoría por una etiología multifactorial y poligénica. Uno de los procesos que favorece la degeneración neuronal es la desmielinización, proceso de origen desconocido que conlleva una pérdida de mielina, bien por alteraciones en la funcionalidad de los oligodendrocitos, o bien por una actividad insuficiente de los mismos..., Oligodendrocytes are the glial cells responsible for the myelination of axons and play a fundamental role in the development and proper transmission of nerve impulses. These cells are generated during embryonic development from Oligodendrocyte Precursor Cells (OPCs), which continue to divide and differentiate throughout its individual's life. The myelination process is very important both in embryonic development and in the physiological maintenance of electrical transmission, as well as in the process of repairing damaged areas produced in demyelinating pathologies. Neurodegenerative diseases are a heterogeneous set of pathologies of the Central Nervous System (CNS), mostly characterized by a multifactorial and polygenic etiology. One of the processes that favours neuronal degeneration is demyelination, a process of unknown origin that leads to a loss of myelin, either due to alterations in the functionality of the oligodendrocytes, or due to insufficient activity thereof...

Pio del Rio-Hortega was not only the discoverer of the microglia and oligodendroglia but also possibly the most prolific mentor of all Santiago Ramon y Cajal’s disciples (Nobel awardee in Physiology or Medicine 1906 and considered as the father of modern Neuroscience). Among Río-Hortega’s mentees, three exceptional women are frequently forgotten, chronologically: Pio’s niece Asunción Amo del Río who worked with Río-Hortega at Madrid, Paris, and Oxford; the distinguished British neuropathologist Dorothy Russell who also worked with Don Pío at Oxford; and Amanda Pellegrino de Iraldi, the last mentee in his career. Our present work analyzes the figures of these three women who were in contact and collaborated with Don Pío del Río-Hortega, describing the influences received and the impact on their careers and the History of Neuroscience. The present work completes the contribution of women neuroscientists who worked with Cajal and his main disciples of the Spanish Neurological School both in Spain (previous work) and in other countries (present work).

The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform effective clinical trials. Here, we show how optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to assess remyelination in vivo in MS patients. Our pioneer approach validates OCT as a technique to study remyelination of the optic nerve and reflects what is occurring in non-accessible central nervous system (CNS) structures, like the spinal cord. In this study we used the orally bioavailable small molecule VP3.15, confirming its therapeutical potential as a neuroprotective, anti-inflammatory, and probably remyelinating drug for MS. Altogether, our results confirm the usefulness of OCT to monitor the efficacy of remyelinating therapies in vivo and underscore the relevance of VP3.15 as a potential disease modifying drug for MS therapy

The most frequent variant of multiple sclerosis (MS) is the relapsing-remitting form, characterized by symptomatic phases followed by periods of total/partial recovery. Hence, it is possible that these patients can benefit from endogenous agents that control the inflammatory process and favor spontaneous remyelination. In this context, there is increasing interest in the role of myeloid-derived suppressor cells (MDSCs) during the clinical course of experimental autoimmune encephalomyelitis (EAE). MDSCs speed up infiltrated T-cell anergy and apoptosis. In different animal models of MS, a milder disease course is related to higher presence/density of MDSCs in the periphery, and smaller demyelinated lesions in the central nervous system (CNS). These observations lead us to wonder whether MDSCs might not only exert an anti-inflammatory effect but might also have direct influence on oligodendrocyte precursor cells (OPCs) and remyelination. In the present work, we reveal for the first time the relationship between OPCs and MDSCs in EAE, relationship that is guided by the distance from the inflammatory core. We describe the effects of MDSCs on survival, proliferation, as well as potent promoters of OPC differentiation toward mature phenotypes. We show for the first time that osteopontin is remarkably present in the analyzed secretome of MDSCs. The ablation of this cue from MDSCs-secretome demonstrates that osteopontin is the main MDSC effector on these oligodendroglial cells. These data highlight a crucial pathogenic interaction between innate immunity and the CNS, opening ways to develop MDSC- and/or osteopontin-based therapies to promote effective myelin preservation and repair in MS patients.

Santiago Ramón y Cajal developed his initial scientific career working alone. After the publication of his opus magna (“Textura del sistema nervioso del hombre y los vertebrados”) and the general recognition of the scientific environments that crystallized with the concession of the International Moscow Prize (1900), the Spanish Government decided to officially support Cajal with a laboratory and the first salaries to pay collaborators. Is then when the Spanish Neurological School births: in 1902, Francisco Tello is the first one to be incorporated. With new additions, Cajal's work is complimented in new aspects, including Neuropathologies. Fernando de Castro is one of his youngest direct disciples, one of the closest and more beloved. Fernando de Castro worked from 1916 in Cajal's lab, until the death of El Maestro. He was specially committed by Cajal to unravel different aspects of the structure of the peripheral ganglia: sensitive and vegetative. Afterward, Fernando de Castro described by first time the nature of arterial chemoreceptors in the carotid body. While trying to confirm his anatomical description with physiological demonstrations, and accumulating delays because of scientific decision and the sociopolitical circumstances in Spain, Corneille Heymans was awarded with the Nobel Prize in Physiology or Medicine 1938 for his contributions to the knowledge of cardiorespiratory reflexes. The Karolinska Institutet forgot Heinrich Hering and Fernando de Castro in their decision. Undoubtedly, Fernando de Castro was the most important disciple of Cajal working in the different structures of the peripheral nervous system, and this work is now reviewed here. Anat Rec, 303:1206–1214, 2020. © 2019 American Association for Anatomy

Multiple Sclerosis (MS) is the second cause of paraplegia among young adults, after all types of CNS traumatic lesions. In its most frequent relapsing-remitting form, the severity of the disease course is very heterogeneous, and its reliable evaluation remains a key issue for clinicians. Myeloid-Derived sSuppressor Cells (MDSCs) are immature myeloid cells that suppress the inflammatory response, a phenomenon related to the resolution or recovery of the clinical symptoms associated with experimental autoimmune encephalomyelitis (EAE), the most common model for MS. Here, we establish the severity index as a new parameter for the clinical assessment in EAE. It is derived from the relationship between the maximal clinical score and the time elapsed since disease onset. Moreover, we relate this new index with several histopathological hallmarks in EAE and with the peripheral content of MDSCs. Based on this new parameter, we show that the splenic MDSC content is related to the evolution of the clinical course of EAE, ranging from mild to severe. Indeed, when the severity index indicates a severe disease course, EAE mice display more intense lymphocyte infiltration, demyelination and axonal damage. A direct correlation was drawn between the MDSC population in the peripheral immune system, and the preservation of myelin and axons, which was also correlated with T cell apoptosis within the CNS (being these cells the main target for MDSC suppression). The data presented clearly indicated that the severity index is a suitable tool to analyze disease severity in EAE. Moreover, our data suggest a clear relationship between circulating MDSC enrichment and disease outcome, opening new perspectives for the future targeting of this population as an indicator of MS severity.

El impresionante avance de la investigación en Neurociencia del último siglo ha arrojado luz acerca de la estructura y funcionamiento del sistema nervioso central. La Neurociencia ha experimentado increíbles avances que han permitido no sólo ampliar nuestro conocimiento acerca de cómo funcionan procesos mentales como la memoria o el aprendizaje, sino también diseñar terapias específicas para enfermedades neurodegenerativas o desarrollar tecnologías de elevado impacto social como es el caso de la inteligencia artificial. En este curso, se hará un recorrido general sobre la historia de la Neurociencia, incidiendo en la estructura macroscópica y microscópica del cerebro y médula espinal, así como patologías asociadas al desarrollo y en el adulto. También se comentarán los últimos datos acerca de disciplinas asociadas como la inteligencia artificial y los trastornos de la conducta alimentaria, así como campos emergentes como la Neuroeducación. Finalmente, se plantearán las técnicas y modelos disponibles para el estudio de la Neurociencia, y se propondrán fuentes para la búsqueda de noticias y recursos científicos fiables.

El impresionante avance de la investigación en Neurociencia del último siglo ha arrojado luz acerca de la estructura y funcionamiento del sistema nervioso central. La Neurociencia ha experimentado increíbles avances que han permitido no sólo ampliar nuestro conocimiento acerca de cómo funcionan procesos mentales como la memoria o el aprendizaje, sino también diseñar terapias específicas para enfermedades neurodegenerativas o desarrollar tecnologías de elevado impacto social como es el caso de la inteligencia artificial. En este curso, se hará un recorrido general sobre la historia de la Neurociencia, incidiendo en la estructura macroscópica y microscópica del cerebro y médula espinal, así como patologías asociadas al desarrollo y en el adulto. También se comentarán los últimos datos acerca de disciplinas asociadas como la inteligencia artificial y los trastornos de la conducta alimentaria, así como campos emergentes como la Neuroeducación. Finalmente, se plantearán las técnicas y modelos disponibles para el estudio de la Neurociencia, y se propondrán fuentes para la búsqueda de noticias y recursos científicos fiables.

At the beginning of the 20th century, in view of the growing international recognition of Santiago Ramón y Cajal, the Spanish authorities took some important steps to support Cajal’s scientific work. This recognition peaked in 1906, when Camillo Golgi and Santiago Ramón y Cajal shared the Nobel Prize in Physiology or Medicine. The Spanish government provided Cajal a state-of-the-art laboratory in Madrid to allow him to continue with his research and they funded salaries to pay his first tenured collaborators, the number of which increased further after the creation of the Junta para Ampliación de Estudios (JAE). The JAE was an organism set up to help promising researchers develop their careers in different ways, thereby contributing to the development of science in Spain. Although largely forgotten or relatively unknown, there has been a recent revival in the recognition of the school that developed around Cajal, collectively referred to as the Spanish Neurological School (or colloquially, as the Cajal School or School of Madrid). Almost all Cajal’s collaborators were men, although a limited number of female scientists spent part of their careers at the heart of the Cajal School. Here we discuss these women and their work in the laboratory in Madrid. We have tracked the careers of Laura Forster (from Australia/United Kingdom), Manuela Serra, María Soledad Ruiz-Capillas and María Luisa Herreros (all Spanish), through their scientific publications, both in the journal founded by Cajal and elsewhere, and from other documentary sources. To complete the picture, we also outline the careers of other secondary figures that contributed to the production and running of Cajal’s laboratory in Madrid. We show here that the dawn of Spanish neuroscience included a number of contributions from female researchers who to date, have received little recognition.

Santiago Ramón y Cajal was still young when he came across the reazione nera, discovered by the Italian Camillo Golgi. Cajal became absolutely entranced by the fine structure of the nervous system this technique revealed, which led him to embark on one of the last truly epic endeavors in Modern History: the characterization of nervous cells, and of their organization to form the brain. Cajal remained in Spain throughout his scientific career, working for years alone. With international recognition, Cajal began recruiting brilliant students as collaborators. A handful of his pupils also made decisive discoveries that served to lay the foundations of modern Neuroscience. Cajal’s brother Pedro, Tello, Domingo Sánchez, Achúcarro, Lafora, Río-Hortega, de Castro and Lorente de Nó worked side by side with El Maestro. While Cajal himself pronounced some of the basic rules that have helped us to understand the nervous system (the neuron theory, the law of dynamic polarization of the neuron), as well as providing innumerable details about the histological organization of the different neural structures, it was Pío del Río-Hortega who identified two of the four main cell types in the CNS (oligodendrocytes and microglia), and Fernando de Castro who described the innervation of the blood vessels and identified the first chemoreceptors in the carotid body. Together, this group of scientists is known as the Spanish Neurological School, and if they had not existed, the History of Neuroscience would surely have been quite a different story; and proof that Cajal was a truly exceptional scientist but he was not an exception for Spanish Science.

Ca2+-activated ion channels shape membrane excitability in response to elevations in intracellular Ca2+. The most extensively studied Ca2+-sensitive ion channels are Ca2+-activated K+ channels, whereas the physiological importance of Ca2+-activated Cl- channels has been poorly studied. Here we show that a Ca2+-activated Cl- currents (CaCCs) modulate repetitive firing in mouse sympathetic ganglion cells. Electrophysiological recording of mouse sympathetic neurons in an in vitro preparation of the superior cervical ganglion (SCG) identifies neurons with two different firing patterns in response to long depolarizing current pulses (1 s). Neurons classified as phasic (Ph) made up 67% of the cell population whilst the remainders were tonic (T). When a high frequency train of spikes was induced by intracellular current injection, SCG sympathetic neurons reached an afterpotential mainly dependent on the ratio of activation of two Ca2+-dependent currents: the K+ [IK(Ca)] and CaCC. When the IK(Ca) was larger, an afterhyperpolarization was the predominant afterpotential but when the CaCC was larger, an afterdepolarization (ADP) was predominant. These afterpotentials can be observed after a single action potential (AP). Ph and T neurons had similar ADPs and hence, the CaCC does not seem to determine the firing pattern (Ph or T) of these neurons. However, inhibition of Ca2+-activated Cl- channels with anthracene-9′-carboxylic acid (9AC) selectively inhibits the ADP, reducing the firing frequency and the instantaneous frequency without affecting the characteristics of single- or first-spike firing of both Ph and T neurons. Furthermore, we found that the CaCC underlying the ADP was significantly larger in SCG neurons from males than from females. Furthermore, the CaCC ANO1/TMEM16A was more strongly expressed in male than in female SCGs. Blocking ADPs with 9AC did not modify synaptic transmission in either Ph or T neurons. We conclude that the CaCC responsible for ADPs increases r

The innate immune response is mediated by primary immune modulators such as cytokines and chemokines that together with immune cells and resident glia orchestrate CNS immunity and inflammation. Growing evidence supports that the endocannabinoid 2‐arachidonoylglycerol (2‐AG) exerts protective actions in CNS injury models. Here, we used the acute phase of Theiler's virus induced demyelination disease (TMEV‐IDD) as a model of acute neuroinflammation to investigate whether 2‐AG modifies the brain innate immune responses to TMEV and CNS leukocyte trafficking. 2‐AG or the inhibition of its hydrolysis diminished the reactivity and number of microglia at the TMEV injection site reducing their morphological complexity and modulating them towards an anti‐inflammatory state via CB2 receptors. Indeed, 2‐AG dampened the infiltration of immune cells into the CNS and inhibited their egress from the spleen, resulting in long‐term beneficial effects at the chronic phase of the disease. Intriguingly, it is not a generalized action over leukocytes since 2‐AG increased the presence and suppressive potency of myeloid derived suppressor cells (MDSCs) in the brain resulting in higher apoptotic CD4+ T cells at the injection site. Together, these data suggest a robust modulatory effect in the peripheral and central immunity by 2‐AG and highlight the interest of modulating endogenous cannabinoids to regulate CNS inflammatory conditions.

It is accepted that confusion regarding the description of genetic variants occurs when researchers do not use standard nomenclature. The Human Genome Organization Gene Nomenclature Committee contacted a panel of consultants, all working on the KAL1 gene, to propose an update of the nomenclature of the gene, as there was a convention in the literature of using the ‘KAL1’ symbol, when referring to the gene, but using the name ‘anosmin-1’ when referring to the protein. The new name, ANOS1, reflects protein name and is more transferrable across species.

Sulfatides are sulfoglycolipids found in the myelin sheath. The composition ratio of sulfatide molecular species changes with age, and it has also been associated with the pathogenesis of various human central nervous system diseases. However, profiling sulfatides in biological samples is difficult, due to the great variety of molecular species. In this work, a new, easy and reliable liquid chromatography-electrospray tandem mass spectrometry (LC-ESI(+)-MS/MS) method has been developed to profile sulfatide content in biological samples of myelin. The ‘wrong-way-round’ ionization effect has been described for this type of molecules for the first time, making it possible to correctly identify as many as 37 different sulfatides in mouse brain myelin samples, including molecules with different fatty acid chain lengths and varying degrees of unsaturation and hydroxylation. A chemometric analysis of their relative abundances showed that the main difference among individuals of different ages was the content of sulfatides with odd-numbered fatty acid chains, in addition to hydroxylated species.

[Background] The ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation. Tissue plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS), where it regulates cell fate. In particular, tPA has been reported to protect oligodendrocytes from apoptosis and to facilitate the migration of neurons. Here, we investigated whether tPA can also participate in the migration of OPCs during CNS development and during remyelination after focal white matter lesion., [Methods] OPC migration was estimated by immunohistological analysis in spinal cord and corpus callosum during development in mice embryos (E13 to P0) and after white matter lesion induced by the stereotactic injection of lysolecithin in adult mice (1 to 21 days post injection). Migration was compared in these conditions between wild type and tPA knock-out animals. The action of tPA was further investigated in an in vitro chemokinesis assay., [Results] OPC migration along vessels is delayed in tPA knock-out mice during development and during remyelination. tPA enhances OPC migration via an effect dependent on the activation of epidermal growth factor receptor., [Conclusion] Endogenous tPA facilitates the migration of OPCs during development and during remyelination after white matter lesion by the virtue of its epidermal growth factor-like domain.