Investigación

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Investigación contiene los documentos generados por los docentes e investigadores de la Universidad en su labor de investigación. Este depósito tiene como objetivos el almacenamiento, la gestión, la preservación y la difusión de estos documentos, y pretende contribuir al aumento de la visibilidad del trabajo desarrollado por los miembros de la comunidad universitaria.

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A computerized analysis of the entire retinal ganglion cell population and its spatial distribution in adult rats
(Elsevier, 2009-01) Mayor Torroglosa, S.; Jiménez López, M.; Avilés Trigueros, Marcelino; Holmes, T. M.; Lund, R. D.; Villegas Pérez, M. P.; Vidal Sanz, M.; Salinas Navarro, Manuel Ángel; Anatomía Humana y Psicobiología
In adult albino (SD) and pigmented (PVG) rats the entire population of retinal ganglion cells (RGCs) was quantified and their spatial distribution analyzed using a computerized technique. RGCs were back-labelled from the optic nerves (ON) or the superior colliculi (SCi) with Fluorogold (FG). Numbers of RGCs labelled from the ON [SD: 82,818 ± 3,949, n = 27; PVG: 89,241 ± 3,576, n = 6) were comparable to those labelled from the SCi [SD: 81,486 ± 4,340, n = 37; PVG: 87,229 ± 3,199; n = 59]. Detailed methodology to provide cell density information at small scales demonstrated the presence of a horizontal region in the dorsal retina with highest densities, resembling a visual streak.
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A freely available semi-automated method for quantifying retinal ganglion cells in entire retinal flatmounts
(Elsevier, 2016-04-20) Geeraerts, E. ; Dekeyster, E. ; Gaublomme, D. ; De Groef, L.; Moons, L.; Salinas Navarro, Manuel Ángel; Anatomía Humana y Psicobiología
Glaucomatous optic neuropathies are characterized by progressive loss of retinal ganglion cells (RGCs), the neurons that connect the eye to the brain. Quantification of these RGCs is a cornerstone in experimental optic neuropathy research and commonly performed via manually quantifying parts of the retina. However, this is a time-consuming process subject to inter- and intra-observer variability. Here we present a freely available ImageJ script to semi-automatically quantify RGCs in entire retinal flatmounts after immunostaining for the RGC-specific transcription factor Brn3a. The blob-like signal of Brn3a-immunopositive RGCs is enhanced via eigenvalues of the Hessian matrix and the resulting local maxima are counted as RGCs. After the user has outlined the retinal flatmount area, the total RGC number and retinal area are reported and an isodensity map, showing the RGC density distribution across the retina, is created. The semi-automated quantification shows a very strong correlation (Pearson's r ≥ 0.99) with manual counts for both widefield and confocal images, thereby validating the data generated via the developed script. Moreover, application of this method in established glaucomatous optic neuropathy models such as N-methyl-D-aspartate-induced excitotoxicity, optic nerve crush and laser-induced ocular hypertension revealed RGC loss conform with literature. Compared to manual counting, the described automated quantification method is faster and shows user-independent consistency. Furthermore, as the script detects the RGC number in entire retinal flatmounts, the method allows detection of regional differences in RGC density. As such, it can help advance research investigating the degenerative mechanisms of glaucomatous optic neuropathies and the effectiveness of new neuroprotective treatments. Because the script is flexible and easy to optimize due to a low number of critical parameters, it can potentially be applied in combination with other tissues or alternative labeling protocols.
Open Access
A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models
(MDPI, 2018-07-25) Vinet, Jonathan; Costa, Anna Maria; Leo, Giuseppina; Moons, Lieve; Arckens, Lutgarde; Biagini, Giuseppe; Salinas Navarro, Manuel Ángel; Anatomía Humana y Psicobiología
Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood–brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected Cornu Ammonis 3 (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 stratum lacunosum-moleculare of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss.
Open Access
Activation of adenosine A3 receptor protects retinal ganglion cells from degeneration induced by ocular hypertension
(Glaucoma is a progressive chronic retinal degenerative disease and a leading cause of global irreversible blindness. This disease is characterized by optic nerve damage and retinal ganglion cell (RGC) death. The current treatments available target the lowering of intraocular pressure (IOP), the main risk factor for disease onset and development. However, in some patients, vision loss progresses despite successful IOP control, indicating that new and effective treatments are needed, such as those targeting the neuroprotection of RGCs. Adenosine A3 receptor (A3R) activation confers protection to RGCs following an excitotoxic stimulus. In this work, we investigated whether the activation of A3R could also afford protection to RGCs in the laser-induced ocular hypertension (OHT) model, a well-characterized animal model of glaucoma. The intravitreal injection of 2-Cl-IB-MECA, a selective A3R agonist, abolished the alterations induced by OHT in the negative and positive components of scotopic threshold response (STR) without changing a- and b-wave amplitudes both in scotopic and photopic conditions. Moreover, the treatment of OHT eyes with the A3R agonist promoted the survival of RGCs, attenuated the impairment in retrograde axonal transport, and improved the structure of the optic nerve. Taking into consideration the beneficial effects afforded by 2-Cl-IB-MECA, we can envisage that A3R activation can be considered a good therapeutic strategy to protect RGCs from glaucomatous damage., 2020) Boia, Raquel ; Salinas Navarro, Manuel Ángel; Gallego Ortega, Alejandro; Galindo Romero, Caridad; Aires, Inês D.; Agudo Barriuso, Marta; Ambrósio, António Francisco; Vidal Sanz, Manuel; Santiago, Ana Raquel; Anatomía Humana y Psicobiología; Facultades de la UMU::Facultad de Medicina
Open Access
Acute pre-learning stress and declarative memory: impact of sex, cortisol response and menstrual cycle phase
(Elsevier, 2013-04-12) Espín López, Laura; Almela, Mercedes; Hidalgo, Vanesa; Villada, Carolina; Salvador, Alicia; Gómez Amor, Jesús; Anatomía Humana y Psicobiología; Facultades de la UMU::Facultad de Psicología y Logopedia
This study explores the influence of pre-learning stress on performance on declarative memory tasks in healthy young adults in relation to sex and menstrual cycle phase. The sample was composed of 119 students (32 men and 87 women) from 18 to 25 years of age. The women were tested in different hormonal stages (30 in follicular phase, 34 in luteal phase, and 23 using oral contraceptives). The participants were exposed to the Trier Social Stress Test (TSST) or a control condition. Afterwards, their memory performance was measured using a standardized memory test (Rey's Auditory Verbal Learning Test). In the control condition, all groups of women recalled more words than men, but these differences disappeared in the group exposed to TSST because men's performance on the memory test improved, but only to the level of women. In addition, our data suggest that in women the relationship between cortisol and memory can be modulated by sex hormone levels, since in luteal women a negative relationship was found between memory performance and peak cortisol level. These results confirm that sex differences need to be considered in the relationship between pre-learning stress and memory performance.
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Acute stress affects free recall and recognition of pictures differently depending on age and sex
(Elsevier, 2015) Espín López, Laura; Vanesa Hidalgoa,∗, Matias M. Pulopulosa, Sara Puig-Pereza, Laura Espinb, Jesus Gomez-Amorb, Alicia Salvadora; Anatomía Humana y Psicobiología; Facultades de la UMU::Facultad de Psicología y Logopedia
Little is known about age differences in the effects of stress on memory retrieval. Our aim was to perform an in-depth examination of acute psychosocial stress effects on memory retrieval, depending on age and sex. For this purpose, data from 52 older subjects (27 men and 25 women) were reanalyzed along with data from a novel group of 50 young subjects (26 men and 24 women). Participants were exposed to an acute psychosocial stress task (Trier Social Stress Test) or a control task. After the experimental manip- ulation, the retrieval of positive, negative and neutral pictures learned the previous day was tested. As expected, there was a significant response to the exposure to the stress task, but the older participants had a lower cortisol response to TSST than the younger ones. Stress impaired free recall of emotional (positive and negative) and neutral pictures only in the group of young men. Also in this group, corre- lation analyses showed a marginally significant association between cortisol and free recall. However, exploratory analyses revealed only a negative relationship between the stress-induced cortisol response and free recall of negative pictures. Moreover, stress impaired recognition memory of positive pictures in all participants, although this effect was not related to the cortisol or alpha-amylase response. These results indicate that both age and sex are critical factors in acute stress effects on specific aspects of long-term memory retrieval of emotional and neutral material. They also point out that more research is needed to better understand their specific role.
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Age-related brain pathology in Octodon degu: blood vessel, white matter and Alzheimer-like pathology
(Elsevier, 2009-11-11) Van Groen, Thomas; Kadish, Inga; Caballero Bleda, María; Baño-Otalora, Beatriz; Vivanco, Pablo; Rol, María Ángeles; Madrid, Juan Antonio; Popovic, Natalija; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
Recently it has been shown that over 3-year-old wild-type South American rodents, Octodon degus, the "common degu" or degu, of their own accord develop Alzheimer's disease neuropathological hallmarks: amyloid-β-peptide depositions and accumulation of tau-protein. Here we analyzed brains of 1-, 3- and 6-year-old degu's, bred in standard animal facilities. Significant amounts of Aβ and tau deposits are present in the hippocampal formation of 6-year-old O. degus, primarily in the white matter, but these hippocampal Aβ and tau deposits are not present in younger ones. In contrast, significant Aβ deposits in blood vessel walls are already found in 3-year-old animals. The tau deposits in the hippocampal formation coincide with a significant decrease in staining for myelin in the same areas, indicating hippocampal disconnection and, likely, dysfunction. Our findings indicate that (1) cerebral amyloid angiopathy precedes brain parenchyma pathology in aged degu's and (2) the onset of disease seems to be delayed in the laboratory vs. wild-type degu's.
Open Access
An anatomical study using computed tomography, magnetic resonance imaging, and rhinoscopy of the nasal cavity of domestic cat (Felis silvestris catus L.) and big cats: lion (Panthera leo leo L.), leopard (Panthera pardus kotiya L.), and cheetah (Acinonyx jubatus jubatus S.)
(MDPI, 2024-04-13) Díaz Martínez, Elena; Arencibia Espinosa, Alberto; Kilroy, David; Soler Laguía, Marta; Kilroy, David; Martínez Gomariz, Francisco; Casas García, Diego Luis; Sánchez Collado, Cayetano; Gil Cano, Francisco; Raduán Jaber, José; Ramírez Zarzosa, Gregorio José; Anatomía Humana y Psicobiología; Facultad de Veterinaria
The objective of this work was to study the normal anatomy of the nasal cavity of the three species of big cats (leopard, lion, and cheetah) compared to the domestic cat through the use of computed tomography, magnetic resonance imaging, and rhinoscopy. Computed tomography allowed us to clearly visualize the entire bony and cartilaginous framework that supports the nasal cavity. Magnetic resonance imaging permitted better visualization of the soft tissues of this cavity. On the other hand, rhinoscopy enabled the direct visualization of the mucosa of the vestibule and nasal cavity, which is very useful in the diagnosis of masses or foreign bodies. Furthermore, with this technique, it has been possible to observe several small orifices from the nasolacrimal duct, the pharyngeal auditory tube, and the lateral nasal gland. Computed tomography, magnetic resonance imaging, and rhinoscopy are useful tools in analysis of the anatomical characteristics of the nasal cavity in these species.
Open Access
Analysis of speech rhythm and heart rate as indicators of stress on student interpreters
(Taylor and Francis Group Routledge, 2021-03-30) Rojo López, Ana María; Foulquié Rubio, Ana Isabel; Espín López, Laura; Martínez Sánchez, Francisco (1960); Traducción e Interpretación; Anatomía Humana y Psicobiología; Psicología Básica y Metodología
Stress is assumed to be intrinsic to interpreting and the ability to manage it a presumed predictor of performance. And yet, empirical research on the role of stress in interpreting has remained scarce. This study explores the impact of stress and anxiety on the academic scores, heart rate (HR) and speech rhythm of 23 student interpreters in a liaison interpreting task. Participants’ stress and anxiety are measured using HR measures and the STAI test. Their speech rhythm is automatically analyzed through different indexes deriving from the variability of syllabic intervals. Results show that students’ grades negatively correlate with their levels of state anxiety, which are, in turn, significantly related to their rhythmic parameters in L1-L2 interpreting. Greater rhythmic variability correlates with students’ lower examination scores when speech is delivered into their L2. A significant increase in mean HR is reported during the interpreting task phase as compared with baseline and recovery phase, suggesting that HR was a sensitive marker to detect the students’ stress response, but not to the level of influencing performance. Results point to the need to triangulate different measures to obtain a complete picture of how stress and anxiety may impact interpreting performance.
Open Access
Automated quantification and topographical distribution of the whole population of S- and L-cones in adult albino and pigmented rats
(Association for Research in Vision and Ophthalmology, 2010-06) Ortín Martínez, Arturo; Jiménez López, Manuel; Sauvé, Yves; Villegas Pérez, María Paz; Vidal Sanz, Manuel; Agudo Barriuso, Marta; Salinas Navarro, Manuel Ángel; Nadal-Nicolás, Francisco Manuel; Alarcón Martínez, Luis; Anatomía Humana y Psicobiología
Purpose.: To quantify the whole population of S- and L-cones in the albino (Sprague-Dawley, SD) and pigmented (Piebald Virol Glaxo, PVG) rats and to study their topographical distribution within the retina. Methods.: Retinal radial sections and whole-mounted retinas were double immunodetected with antibodies against UV-sensitive and L-opsins to detect the S- and L-cones, respectively. Two automated routines were developed to quantify the whole population of S- and L-cones. Detailed isodensity maps of each cone type were generated. In both strains, the presence of dual cones was detected, these were semiautomatically quantified and their distribution determined. The matching distribution of retinal ganglion cells (RGCs) and L-cones was attained by double immunodetection of Brn3a and L-opsin, respectively Results.: The mean number ± SEM of L- or S-cones in SD and PVG retinas was 231,736 ± 14,517 and 239,939 ± 6,494 or 41,028 ± 5,074, and 27,316 ± 2,235, respectively. There was an increasing gradient of S-cone density along the inferonasal quadrant, although the highest densities were found in the retinal rims. The distribution of L-cones seemed to be complementary to the S-cones. The highest densities were observed in the superior nasotemporal axis, paralleling the distribution of Brn3a-positive RGCs. Conclusions.: These data establish, for the first time, the total number and the topographical distribution of S- and L-cones in two rat strains and demonstrate the correlation of L-cones and RGC spatial distribution.
Open Access
Autonomic markers associated with generalized social phobia symptoms: heart rate variability and salivary alpha-amylase
(Taylor and Francis Group, 2017) Espín López, Laura; García Rubio, María J.; Hidalgo, Vanesa; Salvador, Alicia; Gómez Amor, Jesús; Anatomía Humana y Psicobiología; Facultades de la UMU::Facultad de Psicología y Logopedia
The study of autonomic nervous system changes associated with generalized social phobia (GSP) dis- order has increased in recent years, showing contradictory results. The present study aimed to evaluate how young people with GSP reacted before, during, and after exposure to the Trier Stress Social Test (TSST), focusing on their autonomic changes (heart rate variability (HRV) and salivary alpha-amylase (sAA)) compared to a control group (non-GSP). Some psychological variables were also considered. Sex was specifically studied as a possible modulator of autonomic fluctuations and psychological state. Eighty young people were randomly distributed into two counterbalanced situations: stress condition (N1⁄418 and 21 for GSP and non-GSP, respectively) and control condition (N1⁄421 and 20 for GSP and non-GSP, respectively), where cardiovascular variables were continuously recorded. Psychological ques- tionnaires about mood and perceived stress were filled out, and five saliva samples were collected to analyze sAA. GSP participants showed higher values on low- and high-frequency ratios (HR domains), compared to non-GSP people, during exposure to the TSST, but no differences were observed after the stressor. Furthermore, the two groups did not differ in sAA. Importantly, positive affect in GSP partici- pants was modulated by sex. The present study suggests that the balance between high- and low-fre- quency domains of HRV is a key cardiovascular marker reflecting the stress response of GSP people, as well the importance of sex in positive affect when facing a stressful situation.
Open Access
Autonomic reactivity in blood-injection-injury and snake phobia
(Elsevier, 2018-12) Maldonado, Enrique F.; Pineda, Sara; Torrente, Ginesa; Carrillo Verdejo, María Eduvigis; Sánchez Navarro, Juan Pedro; Martínez Selva, José María; Anatomía Humana y Psicobiología
Objective: This research aimed to study the salivary flow and other autonomic reactions -heart rate (HR) and skin conductance response (SCR)- in blood-injection-injury (BII) phobia and snake phobia participants, under the assumption that exposure to blood-related pictures in BII phobia will provoke an increase in parasympathetic activity that, in turn, will lead to a greater saliva production than other affective contents. Methods: We selected 18 BII phobia and 14 snake phobia participants along with 22 non-phobia individuals. All participants were exposed to 3 blocks of pictures (12 pictures per block) depicting either mutilations, snakes or neutral, household objects. Saliva samples were taken in the 2-min interval before and after each block. Results: In comparison to other contents, blood-related pictures provoked an increase in salivary flow in BII phobia participants, as well as an increase in the number of SCRs. In the snake phobia group, snake pictures provoked HR acceleration, but the SCRs they elicited did not differ from the SCRs provoked by the blood-related pictures. Conclusion: BII phobia individuals react to their phobic object with a series of physiological changes resulting from a sympathetic-parasympathetic co-activation. This is in contrast with other specific phobias (e.g., small animal phobias) that usually show a sympathetically mediated, defensive reactivity when exposed to their disorder-relevant stimuli. These data support the use of therapeutic interventions in BII phobia that may differ in some respect from those used in other specific phobias.
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Axotomy-induced retinal ganglion cell death in adult mice: quantitative and topographic time course analyses
(Elsevier, 2011-02-24) Galindo Romero, Caridad; Avilés Trigueros, Marcelino; Jiménez López, Manuel; Valiente Soriano, Francisco Javier; Salinas Navarro, Manuel Ángel; Nadal-Nicolás, Francisco Manuel; Villegas Pérez, Maria Paz; Vidal Sanz, Manuel; Agudo Barriuso, Marta; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Anatomía Humana y Psicobiología; Facultades de la UMU::Facultad de Medicina
The fate of retinal ganglion cells after optic nerve injury has been thoroughly described in rat, but not in mice, despite the fact that this species is amply used as a model to study different experimental paradigms that affect retinal ganglion cell population. Here we have analyzed, quantitatively and topographically, the course of mice retinal ganglion cells loss induced by intraorbital nerve transection. To do this, we have doubly identified retinal ganglion cells in all retinas by tracing them from their main retinorecipient area, the superior colliculi, and by their expression of BRN3A (product of Pou4f1 gene). In rat, this transcription factor is expressed by a majority of retinal ganglion cells; however in mice it is not known how many out of the whole population of these neurons express it. Thus, in this work we have assessed, as well, the total population of BRN3A positive retinal ganglion cells. These were automatically quantified in all whole-mounted retinas using a newly developed routine. In control retinas, tracedretinal ganglion cells were automatically quantified, using the previously reported method (SalinasNavarro et al., 2009b). After optic nerve injury, though, traced-retinal ganglion cells had to be manually quantified by retinal sampling and their total population was afterwards inferred. In naïve whole-mounts, the mean ( standard deviation) total number of traced-retinal ganglion cells was 40,437 ( 3196) andofBRN3Apositive ones was 34,697( 1821). Retinal ganglion cell loss was first significant for both markers 5 days post-axotomy and by day 21, the last time point analyzed, only 15% or 12% of traced or BRN3A positive retinal ganglion cells respectively, survived. Isodensity maps showed that, in control retinas, BRN3A and traced-retinal ganglion cells were distributed similarly, being densest in the dorsal retina along the naso-temporal axis. After axotomy the progressive loss of BRN3A positive retinal ganglion cells was diffuse and affected the entire retina. In conclusion, this is the first study assessing the values, in terms of total number and density, of the retinal ganglion cells surviving axotomy from 2 till 21 days post-lesion. Besides, we have demonstrated that BRN3A is expressed by 85.6% of the total retinal ganglion cell population, and because BRN3A positive retinal ganglion cells show the same spatial distribution and temporal course of degeneration than traced ones, BRN3A is a reliable marker to identify, quantify and assess, ex-vivo, retinal ganglion cell loss in this species.
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Barnes maze performance of Octodon degus is gender dependent
(Elsevier, 2010-04-10) Madrid, Juan Antonio; Rol, María Ángeles; Caballero Bleda, María; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
Gender differences in spatial navigation have been widely reported in nocturnal rodent species. Here, for the first time we report gender differences in spatial learning and memory of Octodon degus, a long-lived diurnal hystricomorph rodent. In the present study, 16 months old male and female O. degus were tested in the 18-holes Barnes circular maze. The acquisition session consisted of four daily 4 min trials, during 10 days. Seven days later, the retention test was performed. To avoid the effect of hormonal fluctuation on spatial navigation, both the acquisition and the retention tests, were performed in 21-day regular cycling females in a period that corresponds to the diestrus phase of the estrus cycle. At the beginning of the acquisition, female degus were significantly slower than males to find the escape hole, but the situation reversed afterwards. Moreover, during the course of acquisition, females made significantly less reference memory errors, working memory errors as well as omission errors, than males. In both sexes, motivation and learning ceiling effects were reached at days 5–6 of the training. During the acquisition, females used more frequently a spatial strategy, while males preferably applied either serial, random or opposite strategies. The observed cognitive differences between male and female O. degus existed only during the acquisition period but not during the retention, indicating that acquisition and consolidation are differently influenced by gender.
Open Access
Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates
(Oxford University Press, 2020-05-07) Arotcarena, Marie-Laure; Dovero, Sandra; Prigent, Alice; Bourdenx, Mathieu; Camus, Sandrine; Porras, Gregory; Thiolat, Marie-Laure; Tasselli, Maddalena; Aubert, Philippe; Kruse, Niels; Mollenhauer, Brit; Trigo Damas, Ines; Estrada, Cristina; Garcia-Carrillo, Nuria; Vaikath, Nishant; El-Agnaf, Omar M.A.; Vila, Miquel; Obeso, Jose A.; Derkinderen, Pascal; Dehay, Benjamin; Bezard, Erwan; Herrero Ezquerro, María Trinidad; Anatomía Humana y Psicobiología
In Parkinson’s disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via the vagus nerve, to the CNS. Here, we compare, in baboon monkeys, the pathological consequences of either intrastriatal or enteric injection of a-synucleincontaining Lewy body extracts from patients with Parkinson’s disease. This study shows that patient-derived a-synuclein aggregates are able to induce nigrostriatal lesions and enteric nervous system pathology after either enteric or striatal injection in a non-human primate model. This finding suggests that the progression of a-synuclein pathology might be either caudo-rostral or rostro-caudal, varying between patients and disease subtypes. In addition, we report that a-synuclein pathological lesions were not found in the vagal nerve in our experimental setting. This study does not support the hypothesis of a transmission of a-synuclein pathology through the vagus nerve and the dorsal motor nucleus of the vagus. Instead, our results suggest a possible systemic mechanism in which the general circulation would act as a route for long-distance bidirectional transmission of endogenous a-synuclein between the enteric and the central nervous systems. Taken together, our study provides invaluable primate data exploring the role of the gut-brain axis in the initiation and propagation of Parkinson’s disease pathology and should open the door to the development and testing of new therapeutic approaches aimed at interfering with the development of sporadic Parkinson’s disease.
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Brain injections of glial cytoplasmicinclusions induce a multiple systematrophy-like pathology
(Oxford University Pres, 2022-03-14) Margaux, Teil; Dovero, Sandra; Bourdenx, Mathieu; Arotcarena, Marie-Laure; Camus, Sandrine; Porras, Gregory; Thiolat, Marie-Laure; Trigo-Damas, Ines; Perier, Celine; Estrada, Cristina; Garcia-Carrillo, Nuria; Morari, Michele; Meissner, Wassilios G.; Vila, Miquel; Obeso, Jose A.; Bezard, Erwan; Dehay, Benjamin; Herrero Ezquerro, María Trinidad; Anatomía Humana y Psicobiología
Synucleinopathies encompass several neurodegenerative diseases, which include Parkinson’s disease, dementiawith Lewy bodies and multiple system atrophy. These diseases are characterized by the deposit ofa-synucleinaggregates in intracellular inclusions in neurons and glial cells. Unlike Parkinson’s disease and dementia withLewy bodies, where aggregates are predominantly neuronal, multiple system atrophy is associated witha-synu-clein cytoplasmic inclusions in oligodendrocytes. Glial cytoplasmic inclusions are the pathological hallmark ofmultiple system atrophy and are associated with neuroinflammation, modest demyelination and, ultimately, neu-rodegeneration.To evaluate the possible pathogenic role of glial cytoplasmic inclusions, we inoculated glial cytoplasmic inclusion-containing brain fractions obtained from multiple system atrophy patients into the striatum of non-human pri-mates. After a 2-yearin vivophase, extensive histochemical and biochemical analyses were performed on thewhole brain.We found loss of both nigral dopamine neurons and striatal medium spiny neurons, as well as loss of oligodendro-cytes in the same regions, which are characteristics of multiple system atrophy. Furthermore, demyelination, neu-roinflammation anda-synuclein pathology were also observed. These results show that thea-synuclein species inmultiple system atrophy-derived glial cytoplasmic inclusions can induce a pathological process in non-human pri-mates, including nigrostriatal and striatofugal neurodegeneration, oligodendroglial cell loss, synucleinopathy andgliosis.The present data pave the way for using this experimental model for MSA research and therapeutic development
Open Access
Brn3a as a marker of retinal ganglion cells: qualitative and quantitative time course studies in naïve and optic nerve–injured retinas
(Association for Research in Vision and Ophthalmology, 2009-08) Jiménez López, Manuel; Sobrado Calvo, Paloma; Nieto López, Leticia; Cánovas Martínez, Isabel; Vidal Sanz, Manuel; Agudo, Marta; Salinas Navarro, Manuel Ángel; Nadal-Nicolás, Francisco Manuel; Anatomía Humana y Psicobiología
Purpose. To characterize Brn3a expression in adult albino rat retinal ganglion cells (RGCs) in naïve animals and in animals subjected to complete intraorbital optic nerve transection (IONT) or crush (IONC). methods. Rats were divided into three groups, naïve, IONT, and IONC. Two-, 5-, 9-, or 14-day postlesion (dpl) retinas were examined for immunoreactivity for Brn3a. Before the injury, the RGCs were labeled with Fluorogold (FG; Fluorochrome, Corp. Denver, CO). Brn3a retinal expression was also determined by Western blot analysis. The proportion of RGCs double labeled with Brn3a and FG was determined in radial sections. The temporal course of reduction in Brn3a+ RGCs and FG+ RGCs induced by IONC or IONT was assessed by quantifying, in the same wholemounts, the number of surviving FG-labeled RGCs and Brn3a+RGCs at the mentioned time points. The total number of FG+RGCs was automatically counted in naïve and injured retinas (2 and 5 dpl) or estimated by manual quantification in retinas processed at 9 and 14 dpl. All Brn3a immunopositive RGCs were counted using an automatic routine specifically developed for this purpose. This protocol allowed, as well, the investigation of the spatial distribution of these neurons. results. Brn3a+ cells were only present in the ganglion cell layer and showed a spatial distribution comparable to that of FG+ cells. In the naïve retinal wholemounts the mean (mean ± SEM; n = 14) total number of FG+RGCs and Brn3a+RGCs was 80,251 ± 2,210 and 83,449 ± 4,541, respectively. Whereas in the radial sections, 92.2% of the FG+RGCs were also Brn3a+, 4.4% of the RGCs were Brn3a+FG− and 3.4% were FG+Brn3a−. Brn3a expression pattern was maintained in injured RGCs. The temporal course of Brn3a+RGC and FG+RGC loss induced by IONC or IONT followed a similar trend, but Brn3a+RGCs loss was detected earlier than that of FG+RGCs. Independent of the marker used to detect the RGCs, it was observed that their loss was quicker and more severe after IONT than after IONC. conclusions. Brn3a can be used as a reliable, efficient ex vivo marker to identify and quantify RGCs in control and optic nerve–injured retinas.
Open Access
Cardiac Noradrenaline Turnover and Heat Shock Protein 27 Phosphorylation in Dyskinetic Monkeys.
(Wiley Online Library, 2019-11) Almela, Pilar; Cuenca Bermejo, Lorena; Yuste, José E.; Estrada, Cristina; Pablos, Vicente de; Bautista Hernández, Víctor; Herrero Ezquerro, María Trinidad; Fernández Villalba, Emiliano; Laorden Carrasco, María Luisa; Anatomía Humana y Psicobiología; Medicina Interna
ABSTRACT: Background: Autonomic dysfunction is a well-known dominant symptom in the advanced stages of Parkinson’s disease. However, the role of cardiac sympathetic nerves still needs to be elucidated. Objectives: To evaluate cardiac sympathetic response in Parkinsonian and dyskinetic monkeys. Methods: Adult male monkeys were divided into 1 of the following 3 groups: controls, 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine–treated monkeys, and 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine+levodopa–treated animals. Noradrenaline, its metabolite normetanephrine, and phospho-Heat shock proten 27 (p-Hsp27) at erine 82 levels were analyzed in the left and right ventricles of the heart. Tyrosine hydroxylase immunohistochemistry was performed in the ventral mesencephalon. Results: The results were the following: (1) 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine intoxication significantly increased normetanephrine levels and decreased noradrenaline turnover in the right ventricle without changes in the left ventricle; however, (2) levodopa treatment decreased noradrenaline levels and enhanced the normetanephrine/noradrenaline ratio in parallel with a very significant increase of Hsp27 activity in both ventricles. Conclusions: Levodopa treatment could induce protective cardiac effects through the increased Hsp27 activity. © 2019 International Parkinson and Movement Disorder Society
Open Access
Characterizing microglia activation: a spatial statistics approach to maximize information extraction
(Nature Research, 2017) Salinas Navarro, Manuel Ángel; Cordeiro, M. Francesca; Moons, Lieve ; De Groef, Lies ; Davis, Benjamin M. ; Anatomía Humana y Psicobiología; Facultades de la UMU::Facultad de Medicina
Microglia play an important role in the pathology of CNS disorders, however, there remains significant uncertainty about the neuroprotective/degenerative role of these cells due to a lack of techniques to adequately assess their complex behaviour in response to injury. Advancing microscopy techniques, transgenic lines and well-characterized molecular markers, have made histological assessment of microglia populations more accessible. However, there is a distinct lack of tools to adequately extract information from these images to fully characterise microglia behaviour. This, combined with growing economic pressures and the ethical need to minimise the use of laboratory animals, led us to develop tools to maximise the amount of information obtained. This study describes a novel approach, combining image analysis with spatial statistical techniques. In addition to monitoring morphological parameters and global changes in microglia density, nearest neighbour distance, and regularity index, we used cluster analyses based on changes in soma size and roundness to yield novel insights into the behaviour of different microglia phenotypes in a murine optic nerve injury model. These methods should be considered a generic tool to quantitatively assess microglia activation, to profile phenotypic changes into microglia subpopulations, and to map spatial distributions in virtually every CNS region and disease state.
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Circadian phase asessment by ambulatory monitoring in humans: correlation with dim light melatonin onset
(Taylor and Francis Group, 2013-10-28) Middleton, Benita; Revell, Victoria L.; Skene, Debra J.; Rol, Maria-Angeles; Madrid, Juan Antonio; Bonmatí Carrión, María de los Ángeles; Anatomía Humana y Psicobiología
The increased prevalence of circadian disruptions due to abnormal coupling between internal and external time makes the detection of circadian phase in humans by ambulatory recordings a compelling need. Here, we propose an accurate practical procedure to estimate circadian phase with the least possible burden for the subject, that is, without the restraints of a constant routine protocol or laboratory techniques such as melatonin quantification, both of which are standard procedures. In this validation study, subjects (N = 13) wore ambulatory monitoring devices, kept daily sleep diaries and went about their daily routine for 10 days. The devices measured skin temperature at wrist level (WT), motor activity and body position on the arm, and light exposure by means of a sensor placed on the chest. Dim light melatonin onset (DLMO) was used to compare and evaluate the accuracy of the ambulatory variables in assessing circadian phase. An evening increase in WT: WTOnset (WTOn) and “WT increase onset” (WTiO) was found to anticipate the evening increase in melatonin, while decreases in motor activity (Activity Offset or AcOff), body position (Position Offset (POff)), integrative TAP (a combination of WT, activity and body position) (TAPOffset or TAPOff) and an increase in declared sleep propensity were phase delayed with respect to DLMO. The phase markers obtained from subjective sleep (R = 0.811), WT (R = 0.756) and the composite variable TAP (R = 0.720) were highly and significantly correlated with DLMO. The findings strongly support a new method to calculate circadian phase based on WT (WTiO) that accurately predicts and shows a temporal association with DLMO. WTiO is especially recommended due to its simplicity and applicability to clinical use under conditions where knowing endogenous circadian phase is important, such as in cancer chronotherapy and light therapy.

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