Instituto Interuniversitario de Neurociencias de Castilla y León (INCyL)

Zebrafish optic nerve regeneration involves resident and retinal oligodendrocytes

Tue, 22 Oct 2024 00:00:00 GMT

[EN] The visual system of teleost fish grows continuously, which is a useful model for studying regeneration of the central nervous system. Glial cells are key for this process, but their contribution is still not well defined. We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6, 24, and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy. To understand the changes that these oligodendrocytes undergo during regeneration, we used Sox2 immunohistochemistry, a stem cell marker involved in oligodendrocyte differentiation. We also used the Click-iT™ Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation. Before optic nerve crush, sox10:tagRFP oligodendrocytes are located in the retina, in the optic nerve head, and through all the entire optic nerve. Sox2-positive cells are present in the peripheral germinal zone, the mature retina, and the optic nerve. After optic nerve crush, sox10:tagRFP cells disappeared from the optic nerve crush zone, suggesting that they died, although they were not TUNEL positive. Concomitantly, the number of Sox2-positive cells increased around the crushed area, the optic nerve head, and the retina. Then, between 24 hours post-lesion and 14 days post-lesion, double sox10:tagRFP/Sox2-positive cells were detected in the retina, optic nerve head, and whole optic nerve, together with a proliferation response at 72 hours post-lesion. Our results confirm that a degenerating process may occur prior to regeneration. First, sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them, change their “myelinating oligodendrocyte” morphology to a “nonmyelinating oligodendrocyte” morphology, and die. Then, residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination. As new axons arise from the surviving retinal ganglion cells, new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide, nourish and myelinate them. Thus, oligodendrocytes play an active role in zebrafish axon regeneration and remyelination.

Dietary adherence and disability evolution in multiple sclerosis: an exploratory 12-month prospective cohort study

Tue, 07 Jul 2026 00:00:00 GMT

[EN] Background & aims Lifestyle factors may influence disability trajectories in multiple sclerosis (MS), yet prospective data linking sustained dietary adherence to objective clinical outcomes remain limited. Homocysteine, a metabolite involved in one-carbon metabolism, represents a biologically plausible mediator between nutrition and neurodegeneration, although its longitudinal clinical relevance in MS is uncertain. This study aimed to investigate whether adherence to a structured dietary intervention is associated with longitudinal changes in plasma homocysteine levels and disability progression in patients with MS over 12 months. Methods In this prospective cohort study, 41 patients with MS were followed for 12 months. Dietary adherence was quantified using a structured follow-up scale (range 2–6). Plasma homocysteine levels and Expanded Disability Status Scale (EDSS) scores were assessed at baseline, 6 months, and 12 months. Associations between adherence, metabolic changes, and EDSS evolution were evaluated using correlation analyses and multivariate linear regression adjusting for age, sex, BMI, baseline EDSS, and treatment line. Results Baseline mean homocysteine was 10.91 ± 6.94 μmol/L and decreased to 8.24 ± 3.33 μmol/L at 6 months, remaining stable at 8.27 ± 2.42 μmol/L at 12 months. Between-group differences in homocysteine showed a trend toward significance at 12 months (ANOVA p = 0.059). Mean EDSS increased slightly from 1.14 to 1.23 in the overall cohort (p > 0.05). However, EDSS evolution differed according to dietary adherence (ANOVA p = 0.009): low-adherence patients showed a mean EDSS increase (+0.53 ± 0.72), whereas high-adherence patients showed a mean EDSS decrease (−0.56 ± 1.08). Given the low baseline EDSS, short follow-up, and small high-adherence subgroup, these changes should be interpreted as exploratory differences in short-term EDSS trajectory rather than confirmed clinical improvement and do not establish causality. Adherence score was inversely correlated with EDSS change (r = −0.57, p = 0.0006) and remained independently associated in multivariate analysis (β = −0.45, 95% CI −0.68 to −0.22, p = 0.0005). Conclusions Higher adherence to the dietary counselling programme was associated with a more favourable short-term disability trajectory over 12 months. However, causality cannot be inferred, and the clinical significance of these modest changes remains uncertain. Because the adherence score was not formally validated and may partly reflect broader health-related behaviours or engagement with care, and because the dietary intervention was individualized, the study cannot identify specific dietary components or dietary patterns associated with disability trajectories. These exploratory findings require confirmation in larger controlled studies using validated dietary assessment instruments.

Medical dispensation in La Rioja, Spain: epidemiology and its relationship with social determinants: a descriptive study

Mon, 03 Nov 2025 00:00:00 GMT

[EN] Introduction: Spain stands out as the European Union country with the highest life expectancy, reaching 83.2 years in 2022. This context is accompanied by population aging and an increase in chronic and degenerative diseases, which translates into greater medication use. In 2022, the National Health System (NHS) dispensed over 1,127.8 million packages. This study aims to evaluate the state of medication dispensation in La Rioja and its relationship with health determinants such as economic conditions, area of residence, age, and gender.Methods: We conducted an observational, retrospective, cross-sectional study between January 2016 and December 2023. A total of 4,108,656 raw e-dispensations (2016–2023) were recorded, from which 1,433,531 unique patient–ATC4–year records (26 frequent subgroups) were analyzed. We included patients aged 14 years and older with electronic dispensations. Variables analyzed included age, gender, socioeconomic level, type and number of dispensations, and the patient’s basic health zone. Statistical analyses employed Chi-square tests for categorical associations and Kruskal–Wallis tests to compare age distributions across ATC4 medication groups, with a significance level of p < 0.05.Results: Proton pump inhibitors (PPIs) were the most dispensed medications in La Rioja, with 82,195 dispensations between 2016 and 2023, followed by propionic acid derivative anti-inflammatory drugs. Antidepressant dispensations increased from 5,281 in 2016 to 7,486 in 2023. Regarding gender differences, women accounted for more dispensations (53.7%). The largest differences favoring women were observed in thyroid hormones, vitamin D, and antidepressant groups. Conversely, medication groups indicated for cardiovascular pathology—such as platelet aggregation inhibitors and angiotensin-converting enzyme inhibitors—showed a significant difference favoring men. Among the elderly, the most dispensed medications also corresponded to families indicated for cardiovascular diseases. By health zones, PPI dispensation was high and homogeneous in the Rioja 1 and Rioja 2 clusters, while anxiolytics and antidepressants stood out in the municipality of San Román and the Guindalera area of Logroño. In socioeconomic terms, pensioners with limited incomes (IHC 002) primarily consumed PPIs, paracetamol, and benzodiazepines, while low-income workers (IHC 003) showed notable dispensation of propionic acid derivatives, PPIs, and paracetamol.Discussion: Our findings align with national and European trends: PPIs and propionic acid derivative anti-inflammatories are the most frequently dispensed medications. Between 2016 and 2023, we observed an increase in the absolute number of unique users in ATC4 subgroup N06AX (Other antidepressants) (+41.8%) and, to a lesser extent, in N06AB (Selective serotonin reuptake inhibitors) (+25.5%), while the annual relative share of N06AB remained essentially stable. Socioeconomic determinants—such as low income and unemployment—appear to directly influence access to and dispensation of medications.Conclusion: Medication dispensation patterns in La Rioja mirror broader national and EU trends, with PPIs and propionic acid derivatives leading. Gender, age, geographic zone, and socioeconomic status are associated with distinct dispensation profiles. Targeted public health strategies should consider these determinants to optimize rational medication use and equity in access.

Simulation-Based Training for Nursing Students to Improve Patient Safety: Systematic Review

Tue, 26 May 2026 00:00:00 GMT

[EN] Background: Patient safety is a fundamental pillar of health care quality. Simulation-based training provides a controlled environment for nursing students to develop safety competencies and error-recognition skills before clinical practice. Objective: This systematic review aimed to describe and characterize the simulation-based education features and modalities used to address patient safety outcomes in undergraduate nursing students, identifying the strategies that contribute to improvements in safety-related competencies. Methods: A systematic review was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines across PubMed, Web of Science, Scopus, CINAHL, Cochrane, and Lilacs (2019‐2024). Inclusion criteria focused on original studies involving undergraduate nursing students and simulation interventions measuring patient safety outcomes. Studies in languages other than English, Spanish, or Portuguese were excluded. Two reviewers independently performed study selection and data extraction. Methodological quality was assessed using Joanna Briggs Institute tools, applying a 60% quality threshold for inclusion. Results were synthesized through a narrative approach. Results: A total of 20 studies from 12 countries were included. The methodological quality was high (n=14) and moderate (n=6). Findings revealed that high-fidelity simulation and virtual reality are the primary strategies used. Simulation proved effective in enhancing both technical skills (medication administration accuracy) and nontechnical skills (communication via SBAR [Situation, Background, Assessment, Recommendation] and ISBAR [Identification, Situation, Background, Assessment, Recommendation] tools, teamwork, and adverse event reporting). Key strategies contributing to safety included repetitive practice and interprofessional simulation, which significantly improved error detection and clinical judgment. Conclusions: Simulation is an essential pedagogical strategy for preparing nursing students to deliver safe care. Practical implications include the need to integrate structured simulation into nursing curricula to bridge the theory-practice gap. Future research should prioritize longitudinal designs to assess the retention of these safety skills in clinical settings and develop standardized metrics for measuring patient safety outcomes.

Tumour endothelial cell reprogramming orchestrates angiocrine signalling to drive chemoresistance in breast cancer

Mon, 22 Jun 2026 00:00:00 GMT

[EN]Despite its established role in breast cancer treatment, Doxorubicin treatment remains subject to adaptive resistance mechanisms that extend beyond cancer cell intrinsic alterations ultimately reducing therapy efficacy. Our study in a MMTV-PyMT-driven mouse breast cancer model reveals that prolonged Doxorubicin (Dox) exposure triggers significant reprogramming of the tumour vasculature, substantially altering the angiocrine landscape and shaping treatment outcomes. Notably, tumours that initially respond, but later revert, display an endothelial cell subclustering with activation of proliferative and NF-κB-dependent cytokine pathways. We further identify a novel endothelial subpopulation characterised by higher expression of drug clearance and oxidative metabolism markers, suggesting an active role in mitigating Dox efficacy and angiogenesis promotion. These findings substantiate endothelial plasticity as a critical mediator of therapeutic failure. By uncovering these vascular adaptations, our work provides a new perspective on the underlying mechanisms of Dox resistance and the prolonged efficacy of chemotherapy in breast cancer.

Activación electromiográfica del miembro inferior durante imaginería motora: de la mente al músculo

Thu, 01 Jan 2026 00:00:00 GMT

[ES]Introducción La imaginería motora (IM) es una herramienta ampliamente utilizada en campos como el deporte o la neurorrehabilitación ya que se ha demostrado que provoca una activación cerebral similar a la que se produce durante el movimiento. Sin embargo, la evidencia sobre su capacidad para inducir activación muscular periférica en el miembro inferior es limitada. El objetivo de este estudio fue analizar la actividad electromiográfica (EMG) durante diferentes condiciones de ejecución real e IM del miembro inferior. Materiales y métodos Participaron 17 adultos sanos, en los que se registró la actividad EMG superficial del recto y el bíceps femoral durante cuatro condiciones: ejecución real e IM guiada de un patrón motor simple (extensión de rodilla) y de un programa motor orientado a objetivo (golpeo de balón). Todos los participantes realizaron una única sesión experimental. La señal EMG se procesó de forma estandarizada y se normalizó respecto al máximo observado durante la ejecución real. Resultados La IM del patrón simple se asoció a incrementos subumbrales, pero significativos de la actividad EMG respecto al reposo, mientras que la IM del programa motor mostró mayor variabilidad interindividual y ausencia de diferencias consistentes frente al nivel basal. No se observaron correlaciones significativas entre la actividad EMG y la capacidad global de IM. Conclusión Estos resultados sugieren que la IM puede inducir activación muscular periférica de baja amplitud, especialmente en tareas motoras simples, mientras que el aumento de la complejidad funcional podría reducir la consistencia de dicha activación.

Terapia Votja vs. Método Bobath. Efectos sobre marcadores lipídicos y parámetros funcionales en sujetos con Esclerosis Múltiple: ensayo clínico aleatorizado

Thu, 01 Jan 2026 00:00:00 GMT

[ES] Introducción: La esclerosis múltiple (EM) es una patología neurodegenerativa de carácter crónico, cuya fisiopatología se caracteriza por la presencia de procesos inflamatorios recurrentes y desmielinización a nivel del sistema nervioso central. En el abordaje terapéutico de esta enfermedad, las intervenciones de neurorehabilitación, como los métodos Vojta y Bobath, son comúnmente empleadas en la práctica clínica. No obstante, la evidencia científica disponible sobre su impacto en biomarcadores relacionados con la mielinización, así como en parámetros clínicos específicos, sigue siendo limitada, lo que pone de manifiesto la necesidad de investigaciones adicionales que permitan esclarecer su efectividad en este contexto. Objetivo: Comparar los efectos de la Terapia de Locomoción Refleja de Vojta frente al Método Bobath en sujetos con Esclerosis Múltiple, sobre la presión inspiratoria máxima (PIMax), el equilibrio, la espasticidad, el tiempo de reacción y el perfil lipidómico de ácidos grados relacionados con procesos neuroinflamatorios. Métodos: Se llevó a cabo un ensayo clínico aleatorizado con el objetivo de evaluar la eficacia comparativa de dos enfoques terapéuticos de neurorehabilitación en pacientes diagnosticados con EM. El estudio fue desarrollado en la Clínica de Fisioterapia Aymara Abreu, mientras que el análisis lipidómico se realizó en el Instituto de Neurociencias de Castilla y León (INCYL). La muestra estuvo compuesta por dos grupos: Un grupo de intervención, correspondiente al enfoque de locomoción refleja, el cual recibió sesiones individuales de fisioterapia (n = 16); y el segundo grupo “tratamiento habitual”, basado en el concepto Bobath (n = 12), que recibió un número equivalente de sesiones. Ambos grupos participaron en un programa de intervención de dos sesiones semanales durante un período de 12 meses. Las variables de resultado incluyeron: la Escala de Equilibrio de Berg, la Escala Tardieu, los tiempos de reacción (visual, auditivo y táctil) evaluados mediante el programa Cognifit, la presión inspiratoria máxima (PImax) y los biomarcadores lipídicos presentes en la lágrima. Resultados: La intervención basada en la Terapia de Locomoción Refleja de Vojta, en comparación con el enfoque terapéutico del concepto Bobath, evidenció mejoras significativas en diversos parámetros clínicos y fisiológicos. En particular, se observó un incremento en la presión inspiratoria máxima (PImax), una optimización de la estabilidad postural evaluada mediante la Escala de Equilibrio de Berg, y una disminución de la espasticidad, según los registros obtenidos a través de la Escala de Tardieu. Adicionalmente, se constató una reducción en la latencia de los tiempos de reacción visual, auditivo y táctil, medidos mediante el programa Cognifit. En el ámbito bioquímico, el análisis lipidómico de la lágrima reveló una disminución en los niveles de ácido araquidónico, lo cual podría indicar un menor proceso neuroinflamatorio. Conclusiones: La Terapia Vojta mostró una evolución funcional más consistente que el Método Bobath, observándose ligeras modificaciones en los ácidos grasos estudiados. Asimismo, se evidenciaron mejoras en parámetros fisiológicos funcionales como equilibrio, espasticidad, tiempo de reacción y PIMax. Su aplicación podría representar una estrategia terapéutica prometedora en la neurorrehabilitación.

Design and optimization of piezo-thermoelectric hybrid power generation in a small-scale thermoacoustic engine prototype

Fri, 01 May 2026 00:00:00 GMT

[EN]This study aims to design, build, and optimize the performance of a small-scale thermoacoustic engine (TAE) prototype hybrid (piezoelectric/thermoelectric) power generation. Independent variables are predicted using the quadratic model, which are selected based on ANOVA analysis for best fit of experimental data. A Box-Behnken Design (BBD) is applied with 20 treatments. The independent variables considered for evaluation included run time (5–15 min), hot-side heat exchanger (HX) temperature (400–600 °C), resonator length (0.402–0.604 m), cold-side HX temperature (0–27 °C) and working gas (air, N2, CO₂). The results show that the hot-side HX temperature had a significant impact on the total output power (P total), whereas the cold-side HX temperature and resonator length had a relatively mild effect on P total. The working gas type and run time also do not have a significant impact on P total. The optimal conditions for a maximum P total of 65 mW were achieved using nitrogen (N2) as the working gas, under a hot-side HX temperature of 585 °C, resonator length of 0.518 m, and cold-side HX temperature of 2.025 °C. The good fit between experimental and predicted values under optimal conditions confirms the accuracy of the model. Results demonstrate this TAE potential for industrial waste heat recovery application, despite long-term material stability at high temperatures need to be further investigated.

Auditory Sensitivity in Autism: A Systematic Review of Mismatch Negativity and Mismatch Field Responses

Sun, 17 May 2026 00:00:00 GMT

Auditory mismatch responses—mismatch negativity (MMN) and mismatch fields (MMF)—are well established electrophys-iological markers of automatic auditory discrimination supported by short-term sensory memory. These responses, typicallyelicited using passive oddball paradigms, are increasingly used to investigate sensory and language processing in autism. Thissystematic review synthesizes findings from 55 studies comparing MMN and MMF responses in autistic and typically developing(TD) individuals across childhood, adolescence, and adulthood. Using the Synthesis Without Meta-analysis (SWiM) framework,we identified consistent evidence for smaller MMN amplitudes and reduced MMF power in autistic children and adolescentsrelative to TD peers, particularly in response to frequency, duration, and speech-based deviants. Studies also frequently reportedlonger mismatch latencies in autistic participants and associated these delays with language difficulties and heightened auditorysensitivity. Although some studies reported age-related convergence in MMN and MMF measures between autistic and TDgroups in later childhood or adolescence, greater right-hemisphere lateralization in autistic individuals emerged as a consistentfinding across both speech and non-speech paradigms, suggesting differences in hemispheric weighting for auditory process-ing of linguistic and non-linguistic cues. To explain interindividual and developmental variability in mismatch responses, wepropose a precision-weighted predictive coding account, in which divergent assignment of confidence to sensory predictionerrors may contribute to autism-related differences. While study quality was generally fair, methodological heterogeneity, un-derrepresentation of females, and limited cross-cultural sampling constrain generalizability. Future research should prioritizelongitudinal, sex-stratified, and culturally diverse designs, using standardized protocols and collaborative data practices. MMNand MMF responses hold promise as non-invasive translational biomarkers of early-stage sensory prediction and neurodevelop-mental variation in autism

Temporal dynamics of contextual processing in the inferior colliculus of a rat model of autism: Sex- and age-dependent trajectories

Sun, 10 May 2026 00:00:00 GMT

[EN] In autism, sensory differences have been linked to altered contextual processing and to how temporal structure supports the formation of regularities and predictions. Here, we examined how temporal and contextual auditory processing are shaped by sex, development, and prenatal valproic acid (VPA) exposure in the non-lemniscal inferior colliculus at low sound levels. Single-unit recordings from control and VPA-exposed rats were obtained using oddball and cascade paradigms, allowing dissociation of mismatch (iMM), repetition suppression (iRS), and prediction-error (iPE) components in both response magnitude and latency.In control animals, maturation selectively reorganized contextual and predictive processing in females, shifting responses toward reduced repetition suppression and increased prediction-error signaling. This shift was accompanied by longer response latencies, indicating a broader temporal integration window. Compared to male rats, adult females displayed prediction-driven, with reduced adaptation bias, of mismatch responses.In contrast, prenatal VPA exposure disrupted this sex- and age-dependent pattern, particularly in females, producing reduced response magnitude together with earlier response peaks. These findings reveal a female-specific reorganization of subcortical contextual processing and demonstrate that sex, age, and prenatal VPA exposure-related effects can dissociate response strength from temporal deployment. Collectively, our results highlight the role of temporal dynamics in contextual computation within the auditory midbrain and support the contribution of early subcortical circuits to autism-related sensory processing

MSK1 mediates BDNF-dependent MeCP2-S421 phosphorylation in postnatal striatal development and psychiatric-relevant behaviours

Mon, 18 May 2026 00:00:00 GMT

Brain-derived neurotrophic factor (BDNF) is a master regulator of neuronal differentiation and inhibitory circuit maturation in the mammalian brain. Yet, its downstream mediators in distinct neuronal populations remain incompletely defined. Here, we identify mitogen- and stress-activated kinase 1 (MSK1) as a critical mediator of BDNF signalling during postnatal striatal development. MSK1 expression predominates in GABAergic neurons across the cortex and striatum, with region-specific dynamics: MSK1 expression in cortical GABAergic interneurons declines from postnatal day 5 (P5) to day 30 (P30), while expression in striatal GABAergic medium spiny neurons (MSNs) persists into adulthood. Using a novel Msk1IV KO mouse model, generated by deleting exon IV of Msk1, we find that striatal volume and MSN dendritic complexity decrease by P60, without cortical neuron alterations, underscoring MSK1´s striatal-specific role. Mechanistically, MSK1 drives BDNF-induced MeCP2 phosphorylation at serine 421 in MSNs via MAPK/ERK, independently of CaMKII, forming a nuclear complex with MeCP2, thus amplifying MSK1´s role in transcriptional regulation. This MSK1-MeCP2 signalling is also involved in BDNF-dependent and independent morphological developmental processes of cultured striatal neurons. Accordingly, Msk1IV KO striatum shows dysregulated GABAergic (Gad1, Gabrg3) and dopaminergic (Drd1, Drd2, Drd3) gene expression, mirroring profiles in MeCP2 deficient models. Behaviourally, Msk1IV KO mice display hypersociability, impaired nest-building, and increased depressive-like behaviour in the forced swimming test, contributing to striatal circuit dysfunction. These findings link MSK1-mediated molecular disruptions to inhibitory circuit imbalances and behaviours reminiscent of psychiatric disorders, positioning MSK1 as a potential therapeutic target for neurodevelopmental and psychiatric disorders, including those associated with MeCP2 dysfunction.

Ndfip2 in TrkA-expressing sensory neurons regulates noxious mechanosensation through control of TrkA signaling and protein levels

Tue, 31 Mar 2026 00:00:00 GMT

[EN]Nociception, the neural process underlying pain detection, is modulated by the NGF/TrkA signaling axis. Although anti-NGF antibodies can alleviate chronic pain, their clinical application is limited by adverse effects, underscoring the need to identify downstream regulators of this pathway. One such mechanism involves TrkA ubiquitination mediated by Nedd4 E3 ubiquitin ligases, whose activity is modulated by Nedd4 family interacting protein 2 (Ndfip2). Notably, Ndfip2 expression is regulated by TrkA signaling under pain conditions. Here, we characterize the physiological and molecular roles of Ndfip2 in sensory neurons. We demonstrate that Ndfip2 localizes to the endoplasmic reticulum and Golgi apparatus and interacts with TrkA in sensory neurons. Conditional deletion of Ndfip2 in TrkA-expressing cells selectively alters mechanical nociception. Mechanistically, loss of Ndfip2 decreases total TrkA protein levels, downstream activation, and cell-surface exposition, particularly in male-derived dorsal root ganglia neurons. Conversely, Ndfip2 expression reduces mature glycosylated TrkA and promotes the accumulation of non-glycosylated forms, consistent with impaired receptor maturation. Together, these findings identify Ndfip2 as a post-translational regulator of TrkA in TrkA-lineage sensory neurons and establish its in vivo role in mechanical nociception.

Genetically modified bone marrow cells halt mitral cell loss by modulating inflammation and protecting against DNA damage

Sat, 16 May 2026 00:00:00 GMT

[EN]Cell therapy is a promising strategy for tackling neurodegenerative diseases. The most outstanding results with this approach usually involve neuroprotection of damaged neurons at risk of death, but only with limited success. Current therapies are often based on the idea of “one gene, one disease, one drug” for single targets, a concept that limits their actual effectiveness. In contrast, combining different strategies can establish an advanced cell therapy that can slow down neuronal degeneration. In this study, we took advantage of the combination of cell and gene therapy, by transplanting bone marrow stem cells genetically modified to overexpress insulin-like growth factor 1 (IGF1) into a model of selective neurodegeneration, the PCD mouse. This animal is characterized by progressive neuronal loss in the olfactory bulb and alterations in IGF1 levels, among other symptoms. Using different techniques (cell cultures, viral transduction, cell transplants, flow cytometry, qPCR, ELISA, immunohistochemistry, advanced image analysis), our findings showed that neuronal death was virtually blocked, even 130 days after cell transplantation, a result clearly more successful than previous studies. The effects of this transplant are based in part on the regulation of neuroinflammation, increasing the proportion of reactive microglia and reducing that of proinflammatory microglia. In addition, IGF1 overexpression dramatically reduced DNA damage in mutant animals via IGF binding protein 3 pathway: this enhances neuroprotection by complementing the basal effect of cell therapy itself. In summary, our work supports the idea that combining therapeutic approaches and their synergies is a more effective tactic for combating neuronal loss.

Audiogenic Kindling Stimulation Fails to Induce Cerebral Overexpression of P-Glycoprotein and Limbic Crises in the GASH/Sal Model of Epilepsy

Thu, 09 Apr 2026 00:00:00 GMT

[EN] Experimental evidence indicates that a high seizure burden can induce cerebral overexpression of P-glycoprotein (P-gp) at the blood–brain barrier, a phenomenon associated with drug-resistant epilepsy under the “transporter hypothesis”, but also at the neuronal level, linked to a reduced seizure threshold, increased seizure severity (SS), status epilepticus (SE), and a high spontaneous death (SD) rate. In contrast, we recently described a progressive reduction in SS and the absence of SE and SD in GASH/Sal hamsters subjected to 45 audiogenic seizures. Here, we examined SS, SE, and the SD, and the expression of P-gp, erythropoietin receptor (EPO-R), hypoxia-inducible factor 1 alpha subunit (HIF-1α) and cyclooxygenase 2 (COX-2), in the brains of GASH/Sal hamsters following 20 audiogenic kindling stimulations (AUK-20). SS was evaluated using the midbrain and limbic severity scales; gene expression was assessed by RT-qPCR and P-gp protein levels were measured by immunohistochemistry and Western blot (IHC/WB) analysis. A modest decrease in midbrain SS was observed, without an increase in the already low limbic SS scores, and no SE or SD events occurred. P-gp levels remained low in both IHC and WB analyses. At the mRNA level, we detected increased EPO-R expression, decreased HIF-1α, and increased COX-2 without an accompanying increased in Abcb1b. Unlike findings from other experimental epilepsy models, AUK-20 in GASH/Sal hamsters does not enhance limbic SS, trigger SE or SD, or induce P-gp overexpression in the brain. Independently of the implications for drug resistance, the lack of cerebral P-gp overexpression without increased SS in the AUK-20-GASH/Sal model supports a potential role of P-gp in modulating seizure severity and epilepsy-associated mortality risk.

Specific Glutamylation Patterns of the Cytoskeleton Confer Neuroresistance to Lobe X of the Cerebellum in a Model of Childhood-Onset Neurodegeneration with Cerebellar Atrophy

Wed, 01 Jan 2025 00:00:00 GMT

[EN]The cytoskeleton relies heavily on the dynamic nature of microtubules, regulated by posttranslational modifications such as polyglutamylation and deglutamylation. Disruption of its internal balance, particularly through the absence of cytosolic carboxypeptidase 1 (CCP1), leads to cytoskeletal collapse and cell death. An example of this occurrence exists in the Purkinje Cell Degeneration (PCD) mouse, a direct animal model for childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) human disease. Both CONDCA patients and PCD mice suffer a dramatic degeneration of Purkinje cells. Intriguingly, lobe X appears less vulnerable to this insult. This study revealed in wild-type mice that lobe X expresses less Ccp1 compared to other lobes, correlating with its delayed degeneration in PCD mice. Further expression analysis of other deglutamylating enzymes (CCP4 and CCP6) and glutamylating enzymes (TTLL1) revealed distinctive patterns: Ccp4 showed minimal relevance in cerebellum, while Ccp6 displayed a compensatory increase during critical stages. Meanwhile, Ttll1 expression remained consistent across lobes, suggesting that the resistance of lobe X may be related to a more dynamic, hyperglutamylated cytoskeleton. Unraveling the neuroresistance mechanisms of Purkinje cells may help mitigate neuronal loss in CONDCA patients and may offer a glimmer of hope for alleviating the symptoms of other neurodegenerative diseases.

Sex, age, and etiology effects on auditory processing in two rat models of autism: evidence from auditory brainstem responses and contextual neural and behavioral measures

Thu, 01 Jan 2026 00:00:00 GMT

[ES]La tesis titulada “Sex, age, and etiology effects on auditory processing in two rat models of autism: evidence from auditory brainstem responses and contextual neural and behavioral measures” investiga cómo el procesamiento auditivo varía en función del sexo biológico, la etapa del desarrollo y la etiología en modelos animales de autismo. Partiendo del marco teórico de la codificación predictiva, el trabajo analiza cómo el sistema auditivo extrae regularidades del entorno y detecta desviaciones, integrando niveles de análisis que abarcan desde el tronco encefálico hasta el comportamiento. Para ello, se emplean dos modelos de autismo en rata: uno ambiental, basado en la exposición prenatal al ácido valproico (VPA), y otro genético, mediante deleción heterocigota del gen Grin2b. Además, se incluye un modelo farmacológico basado en la administración del antagonista NMDA MK-801 para estudiar el uso conductual de regularidades auditivas. Metodológicamente, la tesis combina tres aproximaciones complementarias: (1) registros de respuestas auditivas del tronco encefálico (ABRs) para evaluar la sincronía y el tiempo de conducción subcortical; (2) registros de actividad neuronal de unidad única en el colículo inferior para caracterizar el procesamiento contextual auditivo mediante índices de mismatch (iMM), supresión por repetición (iRS) y error de predicción (iPE); y (3) tareas conductuales tipo oddball para evaluar el uso de regularidades auditivas en la toma de decisiones. Los resultados muestran que el procesamiento auditivo no se altera de manera uniforme, sino que depende de la interacción entre sexo, edad y etiología. Se observan diferencias específicas en la latencia y amplitud de las ABRs, así como en los mecanismos neuronales de procesamiento contextual en el colículo inferior, especialmente en regiones no lemniscales. Asimismo, las manipulaciones farmacológicas revelan alteraciones en la capacidad de utilizar regularidades auditivas para guiar la conducta. En conjunto, la tesis demuestra que la variabilidad auditiva en el autismo refleja interacciones estructuradas entre factores biológicos y del desarrollo, y no una alteración única. Estos hallazgos aportan un marco integrador que conecta mecanismos neurofisiológicos con procesos conductuales, contribuyendo a una comprensión multiescala del procesamiento auditivo en el autismo.