http://hdl.handle.net/10366/4616 Thu, 23 Apr 2026 17:34:16 GMT 2026-04-23T17:34:16Z https://gredos.usal.es:443/bitstream/id/871576/ http://hdl.handle.net/10366/4616 http://hdl.handle.net/10366/170947 [EN]Age-related hearing loss (ARHL) disrupts ascending auditory inputs, impairing auditory signal transmission, triggering cortical hyperexcitability, and increasing the risk of age-related cognitive decline. In early aging, multisession epidural direct current stimulation (DCS) of the auditory cortex (AC) preserves auditory thresholds and prevents cortical hyperexcitability in Wistar rats. Here, we hypothesized that multisession DCS could halt transcriptional dysregulation in the AC at the earliest stages of aging. We have characterized age-related transcriptional changes in the AC to assess DCS-mediated effects by RNA-seq. At 18.13 months, non-stimulated, aged rats (NES) showed 194 differentially expressed genes (DEGs) in relation to young controls (YG), with enrichment in pathways associated with GABAergic, glutamatergic, and dopaminergic synapses, long-term potentiation/depression, inflammaging, autophagy, apoptosis and neurodegeneration. The upregulated genes included Gabrb1, Grin2b, Rac3c, Tnr, and Ndst1, suggesting compensatory hyperactivity, excitatory/inhibitory imbalance, and stiffening of perineuronal nets (PNN) around parvalbumin (PV) interneurons. Electrically stimulated (ES) rats showed 86 DEGs in relation to YG, with no significant enrichment in aging-related pathways. By contrast, NES vs ES showed 1393 DEGs, with strong enrichment in aging-related pathways. Also, many of the 121 common DEGs across comparisons, which are upregulated in NES and downregulated in ES, are related to neurotransmission (Gabrb1, Grin2b), synaptic scaffolding (Dlg2, Prkca), trophic signaling (Ntrk2, Igf1r) and PNN (Tnr, Ndst1). Based on these findings, multisession DCS curbs maladaptive genomic reprogramming in the aged AC most likely by preserving excitatory/inhibitory balance and maintaining PNN integrity, thereby protecting the AC from ARHL and cognitive vulnerability. Thu, 19 Feb 2026 00:00:00 GMT http://hdl.handle.net/10366/170947 2026-02-19T00:00:00Z http://hdl.handle.net/10366/170888 [EN] Atypical sensory processing is a common feature of autism, yet the neural computations that give rise to these differences, particularly in relation to biological sex and etiological origin, remain unclear. Here we examine predictive auditory processing at the single-neuron level in the inferior colliculus of two adult rat models of autism: a genetic model with a heterozygous Grin2b deletion (Grin2b + /-) and an environmental model based on prenatal valproic acid exposure. We recorded neuronal responses to an auditory oddball paradigm and a cascade control sequence across lemniscal and non-lemniscal IC divisions under high-intensity stimulation, allowing us to derive indices of repetition suppression, prediction error and neuronal mismatch. Using generalized linear mixed-effects models that accounted for animal identity, inferior colliculus division, sex, and rat model, followed by hierarchical group-level comparisons, we identified robust alterations in predictive processing in both autism-like models. These effects varied across inferior colliculus divisions and differed between sexes, revealing distinct phenotype-specific signatures. The results indicate that sex and etiology jointly modulate early auditory computations in autism. More broadly, our findings highlight the translational value of predictive coding frameworks and support the use of complementary animal models to capture neurobiological heterogeneity across the autism spectrum Fri, 30 Jan 2026 00:00:00 GMT http://hdl.handle.net/10366/170888 2026-01-30T00:00:00Z http://hdl.handle.net/10366/169921 [EN]This work presents three open datasets featuring various levels of processing, containing neural recordings from the auditory cortex of rats. These recordings were obtained during experiments using the auditory oddball paradigm before, during and after the local microiontophoretic application of acetylcholine. The primary objective of these datasets is to investigate how the brain processes predictable versus unexpected auditory stimuli, and the role of cholinergic inputs during such processing. The data include multi-unit recordings of neuronal activity during the presentation of standard and deviant tones, classified by stimulus type and cortical sub-region. These resources enable quantitative investigations of deviance detection, stimulus-specific adaptation, cholinergic modulation and predictive-coding mechanisms at multiple temporal scales. Sat, 10 Jan 2026 00:00:00 GMT http://hdl.handle.net/10366/169921 2026-01-10T00:00:00Z http://hdl.handle.net/10366/169672 [EN] Background: Urine-derived stem cells (UDSC) are an emerging, non-invasive source of human stem cells combining easy collection, broad accessibility and high patient compliance with multilineage differentiation capacity. However, key gaps remain in UDSC research, particularly in understanding sex-related differences and the lack of a validated cryopreservation protocol, a critical aspect for primary cells, given their variability in colony formation, proliferation rates and experimental timing. To address these limitations, this study aimed to establish, for the first time, a reliable protocol for UDSC cryopreservation and to explore potential sex-related differences, with a specific focus on glycolysis and mitochondrial respiration. Methods: UDSC were isolated from urine samples of healthy donors (aged 27–50, 4 males and 4 females), cultured in 1:1 DMEM:KSFM supplemented with 10% fetal bovine serum and cryopreserved at passages 2–4 using the same medium with the sole addition of 5% dimethyl sulfoxide. Cells were evaluated for viability, apoptosis/necrosis, metabolic profile and multilineage differentiation potential. Comparisons were performed based on donor sex, as well as before and after cryopreservation. Results: Male- and female-derived UDSC displayed no significant differences in viability and cell death or metabolic profile. Moreover, supervised and unsupervised machine learning methods were unable to discriminate between the two groups, allowing for pooled data analysis and improved statistical power. Similarly, fresh and cryopreserved UDSC displayed comparable viability, metabolic activity and multilineage differentiation relative to fresh cells, with no detectable differences in computational analyses. Conclusions: These findings support UDSC adoption for biobanking, disease modelling and regenerative medicine. Mon, 26 Jan 2026 00:00:00 GMT http://hdl.handle.net/10366/169672 2026-01-26T00:00:00Z http://hdl.handle.net/10366/169493 [EN] The hippocampus is classically linked to memory, yet increasing evidence points to a broader role in perceptual inference and deviance detection. Predictive coding theories propose that perception minimizes mismatches between expected and actual sensory input, expressed in neural signatures such as mismatch negativity (MMN) and P300. Although MMN arises mainly from sensory and prefrontal cortices, the hippocampus is anatomically interconnected with both and may also contribute to prediction error processing. We recorded single- and multi-unit activity and local field potentials (LFPs) from DG and CA1 in urethane-anesthetized rats during an auditory oddball paradigm and a no-repetition control sequence to dissociate prediction error from repetition suppression. Approximately 20% of hippocampal neurons were sound responsive, and a subset showed deviant selectivity. Spiking activity predominantly reflected prediction errors, while LFPs revealed complementary contributions from repetition suppression and prediction error. Early LFP components were enhanced for randomly presented deviants, whereas later components within the P300 latency range were stronger for predictable deviants, indicating temporally distinct phases of error signaling and top-down modulation. These findings identify the hippocampus as an active contributor to auditory deviance detection and support a hierarchical model in which hippocampal circuits participate in predictive sensory processing beyond memory. Wed, 24 Dec 2025 00:00:00 GMT http://hdl.handle.net/10366/169493 2025-12-24T00:00:00Z http://hdl.handle.net/10366/169127 [EN] Background: TAT-Cx43266-283 is a novel Src inhibitor, which has shown noteworthy antitumor effects in preclinical models of glioblastoma. Because Src plays a pivotal role in several tumor types, including lung cancer brain metastasis derived from non-small cell lung cancer (NSCLC) cells, we investigated the effect of TAT-Cx43266-283 in NSCLC-derived brain metastasis, a disease of unmet clinical need. Methods: The effect of TAT-Cx43266-283 was studied in Lewis Lung Carcinoma (LLC), LSZ4, A549 and H441 NSCLC cells. The non-adherent stem-like LLC cells (LLC-CSCs) were intracranially implanted in immunocompetent mice to study the effect of TAT-Cx43266-283 in vivo. Phosphoproteomic analysis was employed to identify signaling pathways affected by TATCx43266-283, and the most prominent were validated by Western blot and immunohistochemistry. Datasets of human NSCLC adenocarcinoma were also analyzed. Results: TAT-Cx43266-283 significantly reduced LLC-CSCs viability and increased the survival of mice bearing brain tumors derived from these cells. Phosphoproteomic analysis identified MEK and ERK as key effectors of this treatment. TAT-Cx43266-283 induced apoptosis, impaired cytoskeletal dynamics and disrupted tumor vascularization. Patient datasets revealed that the targets of TAT-Cx43266-283 were significantly enriched in KRAS-altered lung tumors. Functional validation in several human and mouse KRAS-mutated non-adherent NSCLC cells confirmed that TAT-Cx43266-283 reduced their growth and invasiveness. Conclusions: Our results suggest that TAT-Cx43266-283 is a promising antitumor drug for lung cancer brain metastasis, as judged by the dual inhibition of Src and the MEK-ERK pathway in KRAS-mutated NSCLC. This study opens new avenues for exploring TAT-Cx43266-283 in other tumor types driven by these molecular alterations. Thu, 01 Jan 2026 00:00:00 GMT http://hdl.handle.net/10366/169127 2026-01-01T00:00:00Z http://hdl.handle.net/10366/169126 [EN] Ubiquitylation of receptor tyrosine kinases (RTKs) regulates both the levels and functions of these receptors. The neurotrophin receptor TrkB (also known as NTRK2), a RTK, is ubiquitylated upon activation by brain-derived neurotrophic factor (BDNF) binding. Although TrkB ubiquitylation has been demonstrated, there is a lack of knowledge regarding the precise repertoire of proteins that regulates TrkB ubiquitylation. Here, we provide mechanistic evidence indicating that ubiquitin carboxyl-terminal hydrolase 8 (USP8) modulates BDNF- and TrkB-dependent neuronal differentiation. USP8 binds to the C-terminus of TrkB using its microtubule-interacting domain (MIT). Immunopurified USP8 deubiquitylates TrkB in vitro, whereas knockdown of USP8 results in enhanced ubiquitylation of TrkB upon BDNF treatment in neurons. As a consequence of USP8 depletion, TrkB levels and its activation are reduced. Moreover, USP8 protein regulates the differentiation and correct BDNF-dependent dendritic formation of hippocampal neurons in vitro and in vivo. We conclude that USP8 positively regulates the levels and activation of TrkB, modulating BDNF-dependent neuronal differentiation. Wed, 23 Dec 2020 00:00:00 GMT http://hdl.handle.net/10366/169126 2020-12-23T00:00:00Z http://hdl.handle.net/10366/168924 [EN] Aflatoxins are toxic and carcinogenic mycotoxins posing a significant threat to human health and food safety. A non-destructive hyperspectral imaging (HSI) system to automatically detect aflatoxin contamination in olive fruit and powder by machine learning was proposed. Imaging was conducted in the 418–1072 nm wavelength range. For whole fruit analysis, Linear Discriminant Analysis (LDA) achieved 100 % accuracy in binary classifying healthy and contaminated samples. The Support Vector Machine method also reached 98.75 % accuracy for the same purpose. For powdered olive samples, PLSR based on full spectral data, yielded coefficient of determination (R2) values of 0.9986 and 0.9858, for calibration and validation disjoint data sets, respectively. Furthermore, combining Decision Tree with a Learning Automata algorithm extracted the 15 optimal most discriminant (effective) wavelength (EW) values, enabling data dimension reduction without a significant loss of discrimination power. Using 15 effective wavelengths, LDA model had a maximum accuracy of 100 %. PLSR model developed using the selected effective wavelengths also had robust performance, with R2 of 0.89, validation set. Findings confirm the high potential of hyperspectral imaging for non-destructive and accurate detection of fungal toxin contamination in plant food, suggesting its potential as a rapid and reliable method in food industry. Thu, 01 Jan 2026 00:00:00 GMT http://hdl.handle.net/10366/168924 2026-01-01T00:00:00Z http://hdl.handle.net/10366/168404 [EN]BDNF is a growth factor with important roles in the nervous system in both physiological and pathological conditions, but the mechanisms controlling its secretion are not completely understood. Here, we show that ARMS/Kidins220 negatively regulates BDNF secretion in neurons from the CNS and PNS. Downregulation of the ARMS/Kidins220 protein in the adult mouse brain increases regulated BDNF secretion, leading to its accumulation in the striatum. Interestingly, two mouse models of Huntington’s disease (HD) showed increased levels of ARMS/Kidins220 in the hippocampus and regulated BDNF secretion deficits. Importantly, reduction of ARMS/Kidins220 in hippocampal slices from HD mice reversed the impaired regulated BDNF release. Moreover, there are increased levels of ARMS/Kidins220 in the hippocampus and PFC of patients with HD. ARMS/Kidins220 regulates Synaptotagmin-IV levels, which has been previously observed to modulate BDNF secretion. These data indicate that ARMS/Kidins220 controls the regulated secretion of BDNF and might play a crucial role in the pathogenesis of HD Wed, 06 Jun 2018 00:00:00 GMT http://hdl.handle.net/10366/168404 2018-06-06T00:00:00Z http://hdl.handle.net/10366/168403 [EN]Objective Aiming to delineate novel neuro-immune mechanisms for NGF/TrkA signalling in osteoarthritis (OA) pain, we evaluated inflammatory changes in the knee joints following injection of monoiodoacetate (MIA) in mice carrying a TrkA receptor mutation (P782S; TrkA KI mice). Method In behavioural studies we monitored mechanical hypersensitivity following intra-articular MIA and oral prostaglandin D2 (PGD2) synthase inhibitor treatments. In immunohistochemical studies we quantified joint mast cell numbers, calcitonin gene-related peptide expression in synovia and dorsal root ganglia, spinal cord neuron activation and microgliosis. We quantified joint leukocyte infiltration by flow cytometry analysis, and PGD2 generation and cyclooxygenase-2 (COX-2) expression in mast cell lines by ELISA and Western blot. Results In TrkA KI mice we observed rapid development of mechanical hypersensitivity and amplification of dorsal horn neurons and microglia activation 7 days after MIA. In TrkA KI knee joints we detected significant leukocyte infiltration and mast cells located in the vicinity of synovial nociceptive fibres. We demonstrated that mast cells exposure to NGF results in up-regulation of COX-2 and increase of PGD2 production. Finally, we observed that a PGD2 synthase inhibitor prevented MIA-mechanical hypersensitivity in TrkA KI, at doses which were ineffective in wild type (WT) mice. Conclusion Using the TrkA KI mouse model, we delineated a novel neuro-immune pathway and suggest that NGF-induced production of PGD2 in joint mast cells is critical for referred mechanical hypersensitivity in OA, probably through the activation of PGD2 receptor 1 in nociceptors: TrkA blockade in mast cells constitutes a potential target for OA pain Thu, 24 Aug 2017 00:00:00 GMT http://hdl.handle.net/10366/168403 2017-08-24T00:00:00Z http://hdl.handle.net/10366/168399 [EN]Omission responses have been proposed as neural signatures of predictive coding mechanisms that arise when expected sensory events fail to occur. These responses support the view that the brain actively generates and updates internal models to anticipate future events, rather than passively processing incoming sensory input. Importantly, omission responses offer a direct index of prediction error and prediction. They are modulated by the behavioral relevance and predictability of the omitted stimulus. Emerging studies have shown that omission responses occur across a range of auditory paradigms and involve complex interactions between excitatory and inhibitory neurons, particularly via feedforward inhibition of pyramidal cells by specific interneuron populations. When an anticipated stimulus is omitted, the resulting disinhibition of pyramidal neurons generates a prediction error signal; crucial for updating internal models and driving synaptic plasticity. This mechanism shares key features with mismatch negativity and corollary discharge, suggesting that overlapping cortical circuits are engaged in predictive processing. Taken together, these findings highlight the value of omission responses as electrophysiological markers of the brain's active prediction and prediction error signaling in auditory perception. Fri, 05 Dec 2025 00:00:00 GMT http://hdl.handle.net/10366/168399 2025-12-05T00:00:00Z http://hdl.handle.net/10366/168359 [EN]We explored the application of hyperspectral imaging (400–1100 nm) for non-destructive evaluation of peroxidase (POD) and polyphenol oxidase (PPO) enzymes responsible for browning processes in bell pepper (Capsicum annuum L.) cultivars. Several preprocessing techniques, including Standard Normal Variate (SNV), were applied to spectral data to enhance signal quality. Analysis using Partial Least Squares Regression (PLSR) showed that raw spectral data provided stronger correlations and lower prediction errors compared to processed. Discriminant spectral bands were identified using Support Vector Machine (SVM) combined with metaheuristic optimization, with SVM–Learning Automata (LA) resulting as the most effective wavelength selection strategy. Enzyme activities were then predicted using selected wavelengths with Artificial Neural Network (ANN) and PLSR models. Model performance was evaluated using the coefficient of determination (R2), Root Mean Square Error (RMSE), and Ratio of Performance to Deviation (RPD) on independent validation sets. ANN consistently outperformed PLSR, achieving high cultivar-specific R2 values for POD of 0.86, 0.93, and 0.98, for Orange, Yellow, and Red pepper varieties, respectively and PPO R2 values of 0.91, 0.97, and 0.99, for the same pepper cultivars. A combined “Total Model” integrating data from all cultivars further demonstrated robust generalization, with R2 values of 0.9082 for POD and 0.9604 for PPO. Findings confirm that hyperspectral imaging, coupled with an effective wavelength selection technique and ANN modeling provides a rapid, reliable, and robust approach for industrial evaluation of enzymatic activity in bell peppers. The proposed methodology offers significant potential for quality monitoring, process optimization, and large-scale application in industrial environments. Sun, 15 Mar 2026 00:00:00 GMT http://hdl.handle.net/10366/168359 2026-03-15T00:00:00Z http://hdl.handle.net/10366/168358 [EN]Context-dependent sensory processing within the predictive coding framework relies on detecting mismatches between incoming stimuli and internal predictive models. Sensory deviants elicit prediction errors, seen as enhanced neural responses, that update these models and influence attention and behaviour. Although prediction errors have been widely observed across brain regions, the downstream processes remain poorly understood. In this study, we recorded electrocorticography in five urethane-anaesthetised rats and identified cortical slow oscillations, characterised by spontaneous transitions between ‘Up’ and ‘Down’ states. Deviant stimuli in an auditory oddball paradigm evoked an initial positive prediction error, followed by a prolonged, all-or-nothing response which spread in a travelling wave across the cortex. Identified as putative evoked cortical Up states, these responses were not evoked by standards, omissions or a many-standards control. Up states following deviants occurred more recently after a previous Up state when compared to spontaneous Up states. In preliminary data from an awake rat, long-latency Up states were not present spontaneously or evoked. In a different rat, anaesthetic depth was key to spontaneous and evoked Up states, with more robust Up/Down states and more reliable triggering of Up states under deeper anaesthesia. These results suggest that sensory deviants may cause shifts in cortical state under anaesthesia, explaining the long-latency mismatch response under anaesthesia and sleep. Tue, 25 Nov 2025 00:00:00 GMT http://hdl.handle.net/10366/168358 2025-11-25T00:00:00Z http://hdl.handle.net/10366/167968 [EN]Prenatal exposure to valproic acid (VPA) provides a well-established rodent model of autism, yet its effects on auditory brainstem/midbrain processing across sex and development remain elusive. We recorded click-evoked auditory brainstem responses (ABRs) in Long–Evans rats that received prenatal VPA (400 mg/kg, gestational day 12) and in matched controls at prepubertal (postnatal days 30–45) and adult (65–120) stages under urethane anesthesia. We analyzed peak amplitudes, latencies, inter-peak intervals, and amplitude ratios across sound levels. Auditory thresholds remained comparable among groups. In controls, females showed larger amplitudes for waves I–II, shorter latencies for waves I, II, and IV, and steeper amplitude–intensity slopes for waves II, III, and V than males, indicating stronger level-dependent recruitment. Maturation enhanced early brainstem and midbrain responses by increasing amplitude growth (wave II) and shortening latencies (waves II–V), with effects more pronounced in females. Prenatal VPA exposure reduced wave II amplitude and delayed early peaks (I–III) in females, accompanied by elevated amplitude ratios, whereas in males it mainly affected later responses by reducing amplitudes for waves III–V and prolonging inter-peak latencies (I–III, III–V). These findings show that sex, age, and prenatal VPA exposure distinctly shape auditory brainstem/midbrain function. Mon, 01 Dec 2025 00:00:00 GMT http://hdl.handle.net/10366/167968 2025-12-01T00:00:00Z http://hdl.handle.net/10366/167967 [EN]The ability of the brain to process auditory information across multiple temporal scales is crucial for perception. This study introduces an innovative experimental approach using nonlinguistic structured stimuli composed of click trains that alternate at different rates to investigate auditory processing across 3 distinct temporal scales: individual clicks (tens of milliseconds), click trains forming auditory objects (hundreds of milliseconds), and higher-order click trains in neuronal novelty detection (seconds) in both rhesus monkeys and humans. Electrocorticography recordings in the auditory cortex of rhesus monkeys unveil the primate brain’s remarkable ability to process intricate auditory temporal patterns at timescales of tens and hundreds of milliseconds. Furthermore, extracellular recordings in monkeys demonstrate pronounced responsiveness to deviant click trains at longer temporal scales in the primary auditory cortex (A1), accompanied by synchronization with both individual clicks and click trains. By contrast, neurons in the auditory thalamus prefer individual clicks only. Notably, neurons in A1 exhibit the ability to synchronize with individual clicks while simultaneously integrating these clicks into cohesive train objects, a phenomenon we term “temporal integration during synchronization”. Additional human electroencephalography recordings complement and support these findings, highlighting the paradigm’s potential for clinical applications. Our research offers novel insights into the neural mechanisms underpinning auditory information processing across various temporal scales at the neuronal level. Thu, 06 Nov 2025 00:00:00 GMT http://hdl.handle.net/10366/167967 2025-11-06T00:00:00Z http://hdl.handle.net/10366/167704 [EN]Autism is an early-onset neurodevelopmental disorder characterized by restricted, repetitive behaviors and atypical patternsof social communication and interaction. A considerable proportion of autistic individuals experience divergent auditory per-ception, which can interfere with their ability to navigate everyday sound environments. Auditory brainstem responses areelectrophysiological potentials elicited by auditory stimuli that evaluate neural activity along the auditory nerve and brainstem.Importantly, the auditory brainstem response varies by sex, with females typically showing higher amplitudes and shorter laten-cies than males. This sex-specific neurophysiological profile is especially relevant in autism research, where the male-to-femalediagnosis ratio is approximately 3:1. Thus, exploring the neurobiological mechanisms underlying sex-specific variations in autis-tic traits is essential. Furthermore, autism sensory profiles may vary based on the independent and mutual effects of environmen-tal and genetic factors. To deepen this understanding, we examined auditory brainstem responses in two rat models of autism:the GRIN2B rare mutation model and the prenatal valproic acid induction model, alongside control animals. We assessed peakamplitudes and latencies (Waves I through V), inter-peak intervals (I–III, I–V, and III–V), and amplitude ratios (III:I, V:I, andV:III). Female rats generally exhibited greater amplitudes and longer latencies across waveforms. Regarding rat models, controlanimals consistently showed larger amplitudes and shorter latencies compared to autism-like models. Exploratory analyses fur-ther suggested pairwise interactions between sex and rat model, indicating modulation of auditory phenotypes linked to autism.Thus, our findings reveal key insights into the effects of sex and rat model, as well as their interactions. Fri, 17 Oct 2025 00:00:00 GMT http://hdl.handle.net/10366/167704 2025-10-17T00:00:00Z