INCyL. Artículos del Instituto de Neurociencias de Castilla y León

Performance assessment of no-fee GNSS augmentation systems for tractor guidance

2026-03-24T00:00:00Z

[EN] This study assesses the performance of no-fee GNSS augmentation systems for tractor guidance. Five no-fee augmentation systems: EGNOS, GLIDE, RTK, VRS-NRTK, and on-site RTK were evaluated in both static and guidance tests over short- and long‑term periods using three GNSS receiver types: low-cost Navilock NL8022MP, mid-range Novatel Smart2, and high-end Harxon TS108PRO. Static tests recorded 24 h of position data from 14 receiver-augmentation configurations on a fixed surface. Guidance tests recorded trajectory data from the 14 configurations during straight-line guidance using a tractor equipped with two GNSS receivers, one under test and one high-precision reference. Results found that: (i) unaugmented GNSS resulted in guidance errors of 2–3 m, reduced below 1 m in pass-to-pass intervals shorter than 15 min; (ii) EGNOS reduced these guidance errors by ∼41%; (iii) GLIDE reduced guidance errors to below 20 cm for pass-to-pass intervals shorter than 15 min, with no long-term improvement; (iv) RTK guidance error decreased as baseline length shortened: >100 km yielded > 17 cm, 20–100 km yielded 3–20 cm, and < 20 km yielded 2–3 cm; (v) VRS-NRTK slightly outperformed RTK with similar baseline lengths; and (vi) on-site RTK enabled 1 cm guidance error. In summary: low-cost receivers without augmentation or with EGNOS result in metre-level errors; mid-range receivers with GLIDE deliver decimetre-level guidance errors in the short term; and high-end receivers using on-site RTK or VRS-NRTK on baselines up to 100 km achieve centimetre-level errors, enabling farmers to replicate tractor trajectories consistently year to year.

Prosodia rítmico frecuencial en lingüística clínica: en búsqueda de biomarcadores fonéticos para alzheimer y depresión mayor

2025-01-01T00:00:00Z

[EN]This paper delves into the prosodic features of speech affected in AD and MD, the type of pathology they are associated with (aphasia, apraxia or aprosodia), as well as the contribution of these alterations to the neurolinguistic field (hemispheric specialization).We used a corpus of spontaneous speech from patients with AD (n=10) and MD (n=10), and a control group with HS (n=10). The results showed a discriminatory significance of VnPVI (in MD), and (Δ)f0 and %V; furthermore, %V is a strong variable to distinguish between speakers with and without pathology, as well as to discriminate between AD and MD along with other variables. There is, however, no correlation with verbal fluency (semantic and phonological) or with MMSE, which would imply a motor type deficit: apraxic type in AD and aprosodic type in MD. These results show certain phonological and typological conditioning, among other issues.

Melatonin at the Crossroads of Oxidative Stress, Immunity, and Cancer Therapy

2026-01-03T00:00:00Z

[EN] Melatonin, an ancient and evolutionarily conserved indolamine, has long attracted attention for its multifunctional roles in redox homeostasis. More recently, it has been studied in relation to immune regulation and cancer biology. Beyond its well-known circadian function, melatonin modulates oxidative stress by directly scavenging reactive oxygen and nitrogen species and by upregulating antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. At the same time, it exerts wide-ranging immunomodulatory functions by influencing both innate and adaptive immune responses. All these actions converge within the tumor microenvironment, where oxidative stress and immune suppression drive cancer progression. Although the antitumoral effects of melatonin have traditionally been interpreted through its actions on T cells and NK cells, recent studies identify macrophages as an underappreciated and pivotal target. Notably, melatonin influences macrophage polarization, favoring antitumor M1 phenotypes over pro-tumoral M2 states, while attenuating chronic inflammation and restoring mitochondrial function. This review summarizes current knowledge on melatonin’s antioxidant and immunoregulatory mechanisms, highlighting its impact on the tumor immune microenvironment, with a particular focus on the growing recognition of macrophages as a compelling new axis through which melatonin may exert anticancer effects

HSP25 and HSP25-P-Ser15 Prompt Innate Neuroprotection in Lobe X of the Cerebellum

2026-01-01T00:00:00Z

[EN]The cerebellar cortex presents a repetitive structure, but the main projecting neurons of this tissue, the Purkinje cells, are not identical and behave differently to various types of injury. Common patterns of neurodegeneration exist, where certain Purkinje cells die earlier than others. By contrast, lobe X of the cerebellum is a particularly resistant structure, independently of the cerebellar disease or damage. However, the mechanisms underlying the survival capability of these especially resistant Purkinje cells are still unknown. In this work, we have used the Purkinje Cell Degeneration (PCD) mouse, a model of severe cerebellar degeneration that also reproduces the human disease called childhood-onset neurodegeneration with cerebellar atrophy, to study Purkinje cell resistance. After an exhaustive immunochemical analysis of the different subpopulations of Purkinje cells, the Heat Shock Protein 25 (HSP25) and its phosphorylated version HSP25-P-Ser15 were found to be especially induced in lobe X of PCD mice. As this protein has neuroprotective properties, it may be responsible for resistance against cerebellar neurodegeneration. Taking into account the constant resistance of lobe X, the use of HSP25 may lead to new possibilities for achieving natural protection both in cerebellum and in other brain structures, or even for developing future neuroprotective therapies.

Model of selective neurodegeneration driven by a Ccp1 mutation leads to atypical microglia with an increased response to pathological stimuli

2025-01-07T00:00:00Z

Microglia are the primary immune cells of the central nervous system and maintain tissue homeostasis through phagocytosis and regulation of inflammatory signalling. Although these functions are well established, the molecular mechanisms that control microglial activation during neurodegeneration remain poorly understood. We focused on the Purkinje Cell Degeneration (PCD) mouse, which carries a loss-of-function mutation in Ccp1 that disrupts tubulin post-translational modifications essential for cytoskeletal stability. Because cytoskeletal dynamics are fundamental for microglial motility, phagocytosis, and proliferation, the Ccp1 mutation offers a model to directly examine how intrinsic cytoskeletal defects alter microglial behaviour and how these alterations manifest within regions undergoing distinct patterns of neurodegeneration. To this end, we combined in vitro and in vivo approaches. Microglia were isolated from neonatal cortex and adult cerebellum and olfactory bulb, and microglia-like cells were generated from bone marrow-derived haematopoietic stem cells. In vivo microglial depletion was achieved with the CSF1R inhibitor PLX5622. Immunohistochemistry quantified microglial density, morphology, and marker expression; transcriptomic profiling assessed identity and functional pathways; and functional assays evaluated phagocytosis, motility, and proliferation. Motor behaviour tests were performed to determine whether microglial dysfunction contributes to circuit-level impairments. Statistical analyses used parametric or non-parametric tests according to distribution. Ccp1-deficient microglia exhibited intrinsic deficits in phagocytosis, motility, and proliferation, independent of overt neuronal loss. These impairments were amplified in degenerating regions, where microglia adopted a predominantly anti-inflammatory rather than pro-inflammatory activation profile. This atypical state suggests a maladaptive response that may compromise tissue homeostasis and intensify disease progression. Consistent with this, animals showed altered motor behaviour, indicating functional consequences of microglial dysfunction. Together, these findings identify Ccp1 as a key regulator of microglial homeostasis and demonstrate how cytoskeletal disruption can reshape microglial responses in neurodegenerative environments, providing mechanistic insight and potential therapeutic targets.

Nucleolin reorganization and nucleolar stress in Purkinje cells of mutant PCD mice.

2019-07-01T00:00:00Z

[EN] The Purkinje cell (PC) degeneration (pcd) mouse harbors a mutation in Agtpbp1 gene that encodes for the cytosolic carboxypeptidase, CCP1. The mutation causes degeneration and death of PCs during the postnatal life, resulting in clinical and pathological manifestation of cerebellar ataxia. Monogenic biallelic damaging variants in the Agtpbp1 gene cause infantile-onset neurodegeneration and cerebellar atrophy, linking loss of functional CCP1 with human neurodegeneration. Although CCP1 plays a key role in the regulation of tubulin stabilization, its loss of function in PCs leads to a severe nuclear phenotype with heterochromatinization and accumulation of DNA damage. Therefore, the pcd mice provides a useful neuronal model to investigate nuclear mechanisms involved in neurodegeneration, particularly the nucleolar stress. In this study, we demonstrated that the Agtpbp1 gene mutation induces a p53-dependent nucleolar stress response in PCs, which is characterized by nucleolar fragmentation, nucleoplasmic and cytoplasmic mislocalization of nucleolin, and dysfunction of both pre-rRNA processing and mRNA translation. RT-qPCR analysis revealed reduction of mature 18S rRNA, with a parallel increase of its intermediate 18S-5'-ETS precursor, that correlates with a reduced expression of Fbl mRNA, which encodes an essential factor for rRNA processing. Moreover, nucleolar alterations were accompanied by a reduction of PTEN mRNA and protein levels, which appears to be related to the chromosome instability and accumulation of DNA damage in degenerating PCs. Our results highlight the essential contribution of nucleolar stress to PC degeneration and also underscore the nucleoplasmic mislocalization of nucleolin as a potential indicator of neurodegenerative processes.

Bone marrow cell transplantation restores olfaction in the degenerated olfactory bulb.

2012-06-27T00:00:00Z

[EN] Bone marrow contains heterogeneous cell types including end-lineage cells, committed tissue progenitors, and multipotent stem/progenitor cells. The immense plasticity of bone marrow cells allows them to populate diverse tissues such as the encephalon, and give rise to a variety of cell types. This unique plasticity makes bone marrow-derived cells good candidates for cell therapy aiming at restoring impaired brain circuits. In the present study, bone marrow cells were transplanted into P20 mice that exhibit selective olfactory degeneration in adulthood between P60 and P150. These animals, the so-called Purkinje Cell Degeneration (PCD) mutant mice, suffer from a progressive and specific loss of a subpopulation of principal neurons of the olfactory bulb, the mitral cells (MCs), sparing the other principal neurons, the tufted cells. As such, PCD mice constitute an interesting model to evaluate the specific role of MCs in olfaction and to test the restorative function of transplanted bone marrow-derived cells. Using precision olfactometry, we revealed that mutant mice lacking MCs exhibited a deficit in odorant detection and discrimination. Remarkably, the transplantation of wild-type bone marrow-derived cells into irradiated PCD mutant mice generated a large population of microglial cells in the olfactory bulb and reduced the degenerative process. The alleviation of MC loss in transplanted mice was accompanied by functional recovery witnessed by significantly improved olfactory detection and enhanced odor discrimination. Together, these data suggest that: (1) bone marrow-derived cells represent an effective neuroprotective tool to restore degenerative brain circuits, and (2) MCs are necessary to encode odor concentration and odor identity in the mouse olfactory bulb.

The olfactory system as a puzzle: playing with its pieces.

2013-09-01T00:00:00Z

The mammalian olfactory bulb (OB) has all the features of a whole mammalian brain but in a more reduced space: neuronal lamination, sensory inputs, afferences, or efferences to other centers of the central nervous system, or a contribution of new neural elements. Therefore, it is widely considered as "a brain inside the brain." Although this rostral region has the same origin and general layering as the other cerebral cortices, some distinctive features make it very profitable in experimentation in neurobiology: the sensory inputs are driven directly on its surface, the main output can be accessed anatomically, and new elements appear in it throughout adult life. These three morphological characteristics have been manipulated to analyze further the response of the whole OB. The present review offers a general outlook into the consequences of such experimentation in the anatomy, connectivity and neurochemistry of the OB after (a) sensory deprivation, mainly by naris occlusion; (b) olfactory deinnervation by means of olfactory epithelium damage, olfactory nerve interruption, or even olfactory tract disruption; (c) the removal of the principal neurons of the OB; and (d) management of the arrival of newborn interneurons from the rostral migratory stream. These experiments were performed using surgical or chemical methods, but also by means of the analysis of genetic models, some of whose olfactory components are missing, colorless or mismatching within the wild-type scenario of odor processing.

Functional redundancy of Sos1 and Sos2 for lymphopoiesis and organismal homeostasis and survival.

2013-11-01T00:00:00Z

[EN] Sos1 and Sos2 are ubiquitously expressed, universal Ras guanine nucleotide exchange factors (Ras-GEFs) acting in multiple signal transduction pathways activated by upstream cellular kinases. The embryonic lethality of Sos1 null mutants has hampered ascertaining the specific in vivo contributions of Sos1 and Sos2 to processes controlling adult organism survival or development of hematopoietic and nonhematopoietic organs, tissues, and cell lineages. Here, we generated a tamoxifen-inducible Sos1-null mouse strain allowing analysis of the combined disruption of Sos1 and Sos2 (Sos1/2) during adulthood. Sos1/2 double-knockout (DKO) animals died precipitously, whereas individual Sos1 and Sos2 knockout (KO) mice were perfectly viable. A reduced percentage of total bone marrow precursors occurred in single-KO animals, but a dramatic depletion of B-cell progenitors was specifically detected in Sos1/2 DKO mice. We also confirmed a dominant role of Sos1 over Sos2 in early thymocyte maturation, with almost complete thymus disappearance and dramatically higher reduction of absolute thymocyte counts in Sos1/2 DKO animals. Absolute counts of mature B and T cells in spleen and peripheral blood were unchanged in single-KO mutants, while significantly reduced in Sos1/2 DKO mice. Our data demonstrate functional redundancy between Sos1 and Sos2 for homeostasis and survival of the full organism and for development and maturation of T and B lymphocytes.

Bone marrow transplantation improves motor activity in a mouse model of ataxia.

2017-01-01T00:00:00Z

[EN] Ataxias are locomotor disorders that can have an origin both neural and muscular, although both impairments are related. Unfortunately, ataxia has no cure, and the current therapies are aimed at motor re-education or muscular reinforcement. Nevertheless, cell therapy is becoming a promising approach to deal with incurable neural diseases, including neuromuscular ataxias. Here, we have used a model of ataxia, the Purkinje Cell Degeneration (PCD) mutant mouse, to study the effect of healthy (wild-type) bone marrow transplantation on the restoration of defective mobility. Bone marrow transplants (from both mutant and healthy donors) were performed in wild-type and PCD mice. Then, a wide battery of behavioural tests was employed to determine possible motor amelioration in mutants. Finally, cerebellum, spinal cord, and muscle were analysed to study the integration of the transplant-derived cells and the origin of the behavioural changes. Our results demonstrated that the transplant of wild-type bone marrow restores the mobility of PCD mice, increasing their capabilities of movement (52-100% of recovery), exploration (20-71% of recovery), speed (35% of recovery), and motor coordination (25% of recovery). Surprisingly, our results showed that bone marrow transplant notably improves the skeletal muscle structure, which is severely damaged in the mutants, rather than ameliorating the central nervous system. Although a multimodal effect of the transplant is not discarded, muscular improvements appear to be the basis of this motor recovery. Furthermore, the results from our study indicate that bone marrow stem cell therapy can be a safe and effective alternative for dealing with movement disorders such as ataxias.

The effect of NMDA-R antagonist, MK-801, on neuronal mismatch along the rat auditory thalamocortical pathway

2020-01-01T00:00:00Z

[EN] Efficient sensory processing requires that the brain maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. According to the predictive coding framework there are two mechanisms underlying the MMN: repetition suppression and prediction error. MMN has been found to be reduced in individuals with schizophrenia, an effect believed to be underpinned by glutamate N-methyl-d-aspartate receptor (NMDA-R) dysfunction. In the current study, we aimed to test how the NMDA-R antagonist, MK-801 in the anaesthetized rat, affected repetition suppression and prediction error processes along the auditory thalamocortical pathway. We found that low-dose systemic administration of MK-801 differentially affect thalamocortical responses, namely, increasing thalamic repetition suppression and cortical prediction error. Results demonstrate an enhancement of neuronal mismatch, also confirmed by large scale-responses. Furthermore, MK-801 produces faster and stronger dynamics of adaptation along the thalamocortical hierarchy. Clearly more research is required to understand how NMDA-R antagonism and dosage affects processes contributing to MMN. Nonetheless, because a low dose of an NMDA-R antagonist increased neuronal mismatch, the outcome has implications for schizophrenia treatment.

Endocannabinoid Modulation of Stimulus-Specific Adaptation in Inferior Colliculus Neurons of the Rat

2017-01-01T00:00:00Z

[ES] Cannabinoid receptors (CBRs) are widely distributed in the brain, including the inferior colliculus (IC). Here, we aim to study whether endocannabinoids influence a specific type of neuronal adaptation, namely, stimulus-specific adaptation (SSA) found in some IC neurons. SSA is important because it has been found as early as the level of the midbrain and therefore it may be a neuronal correlate of early indices of deviance detection. Furthermore, recent studies have demonstrated a direct link between SSA and MMN, that is widely used as an outcome measure in a variety of human neurodegenerative disorders. SSA is considered a form of short-term plasticity, and CBRs have been shown to play a role in short-term neural plasticity. Therefore, it is reasonable to hypothesize that endocannabinoids may play a role in the generation or modulation of SSA. We recorded single units in the IC under an oddball paradigm stimulation. The results demonstrate that cannabinoid agonists lead to a reduction in the neuronal adaptation. This change is due to a differential increase of the neuronal firing rate to the standard tone alone. Furthermore, we show that the effect is mediated by the cannabinoid receptor 1 (CBR1). Thus, cannabinoid agonists down-modulate SSA in IC neurons.

Daily bone marrow cell transplantations for the management of fast neurodegenerative processes.

2019-09-01T00:00:00Z

[EN] Cell therapy has been proven to be a promising treatment for fighting neurodegenerative diseases. As neuronal replacement presents undeniable complications, the neuroprotection of live neurons arises as the most suitable therapeutic approach. Accordingly, the earlier the diagnosis and treatment, the better the prognosis. However, these diseases are commonly diagnosed when symptoms have already progressed towards an irreversible degenerative stage. This problem is especially dramatic when neurodegeneration is aggressive and rapidly progresses. One of the most interesting approaches for neuroprotection is the fusion between healthy bone marrow-derived cells and neurons, as the former can provide the latter with regular/protective genes without harming brain parenchyma. So far, this phenomenon has only been identified in Purkinje cells, whose death is the cause of different diseases like cerebellar ataxias. Here we have employed a model of aggressive cerebellar neurodegeneration, the Purkinje Cell Degeneration mouse, to optimize a cell therapy based on bone marrow-derived cell and cell fusion. Our findings show that the substitution of bone marrow in diseased animals by healthy bone marrow, even prior to the onset of neurodegeneration, is not fast enough to stop neuronal loss in time. Conversely, avoiding bone marrow replacement and ensuring a regular supply of healthy cells through continuous, daily transplants, the neurodegenerative milieu of PCD is enough to attract those transplanted elements. Furthermore, in the most affected cerebellar regions, more than a half of surviving neurons undergo a process of cell fusion. Therefore, this method deserves consideration as a means to impede neuronal cell death.

Olfactory bulb plasticity ensures proper olfaction after severe impairment in postnatal neurogenesis.

2017-07-18T00:00:00Z

[EN] The olfactory bulb (OB) neurons establish a complex network that ensures the correct processing of the olfactory inputs. Moreover, the OB presents a lifelong addition of new neurons into its existing circuitry. This neurogenesis is considered essential for the OB function. However, its functional impact on physiology and behavior is still unclear. Here, we investigate the mechanisms of OB plasticity that underlie bulbar physiology in relation to severe damage of neurogenesis. The neurogenesis of young mice was altered by ionizing radiation. Afterwards, both multi-channel olfactometry and electrophysiological studies were performed. Furthermore, neurogenesis and differentiation of the newly formed cells were assessed using bromodeoxyuridine labeling combined with a wide battery of neuronal markers. Our results demonstrate a reduction in both neurogenesis and volume of the OB in irradiated animals. The number of neuroblasts reaching the OB was reduced and their differentiation rate into interneurons selectively changed; some populations were noticeably affected whereas others remained preserved. Surprisingly, both olfactory detection and discrimination as well as electrophysiology presented almost no alterations in irradiated mice. Our findings suggest that after damaging postnatal neurogenesis, the neurochemical fate of some interneurons changes within a new biological scenario, while maintaining homeostasis and olfaction.

Changes in the serotonergic system and in brain-derived neurotrophic factor distribution in the main olfactory bulb of pcd mice before and after mitral cell loss.

2012-01-10T00:00:00Z

[EN] The serotonergic centrifugal system innervating the main olfactory bulb (MOB) plays a key role in the modulation of olfactory processing. We have previously demonstrated that this system suffers adaptive changes under conditions of a lack of olfactory input. The present work examines the response of this centrifugal system after mitral cell loss in the Purkinje cell degeneration (pcd) mutant mice. The distribution and density of serotonergic centrifugal axons were studied in the MOB of control and pcd mice, both before and after the loss of mitral cells, using serotonin (5-HT) and 5-HT transporter immunohistochemistry. Studies of the amount of 5-HT and its metabolite, 5-hydroxyindole acetic acid (5-HIAA), were performed by means of high-performance liquid chromatography (HPLC), and the relative amounts of brain-derived neurotrophin factor, BDNF, and its major receptor, tropomyosin-related kinase B (TrkB), were measured by Western blot. Our study revealed that the serotonergic system develops adaptive changes after, but not before, mitral cell loss. The lack of the main bulbar projection cells causes a decrease in the serotonergic input received by the MOB, whereas the number of serotonergic cells in the raphe nuclei remains constant. In addition, one of the molecules directly involved in serotonergic sprouting, the neurotrophin BDNF and its main receptor TrkB, underwent alterations in the MOBs of the pcd animals even before the loss of mitral cells. These data indicate that serotonergic function in the MOB is closely related to olfactory activity and that mitral cell loss induces serotonergic plastic responses.

Long-lasting changes in the anatomy of the olfactory bulb after ionizing irradiation and bone marrow transplantation.

2011-01-26T00:00:00Z

[EN] The adult brain is considered to be a radioresistant organ since it is mainly composed of non-dividing cells. However, in adult animals there are a few neurogenic brain areas that are affected by ionizing radiation whose plasticity and capacity for recovery are still unclear. Here, mice were irradiated with a minimal lethal dose of radiation in order to determine its effects on the subventricular zone (SVZ), the rostral migratory stream (RMS), and the olfactory bulb (OB). These regions underwent a dramatic reduction in cell proliferation and ensuing morphological alterations, accompanied by a patent reactive gliosis. Bone marrow stem cell (BMSC) transplants were also performed after the radiation treatment to allow the mouse survival with a view to analyzing long-term effects. Normal proliferation rates were not recovered over time and although bone marrow-derived cells reached the brain, they were not incorporated into the SVZ-RMS-OB pathway in an attempt to rescue the damaged regions. Since neurogenesis produces new interneurones in the OB, thus feeding cell turnover, the volume and lamination of the OB were analyzed. The volume of the OB proved to be dramatically reduced at postnatal day 300 (P300), and this shrinkage affected the periependymal white matter, the granule cell layer, the external plexiform layer, and the glomerular layer. These results should be taken into account in cell therapies employing BMSC, since such cells reach the encephalon, although they cannot restore the damage produced in neurogenic areas. This study thus provides new insight into the long-term effects of ionizing radiation, widely employed in animal experimentation and even in clinical therapies for human beings.