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Publicaciones científicas más recientes (desde 2010)

Autores:  Zamarbide, M.; et al.
Revista: JOURNAL OF NEUROINFLAMMATION
ISSN 1742-2094  Vol. 16  Nº 1  2019 
Background Inflammation is a critical process for the progression of neuronal death in neurodegenerative disorders. Microglia play a central role in neuroinflammation and may affect neuron vulnerability. Next generation sequencing has shown the molecular heterogeneity of microglial cells; however, the variability in their response to pathological inputs remains unknown. Methods To determine the effect of an inflammatory stimulus on microglial cells, lipopolysaccharide (LPS) was administered peripherally to mice and the inflammatory status of the cortex, hippocampus, midbrain, and striatum was assessed. Microglial activation and interaction with the immune system were analyzed in single cell suspensions obtained from the different brain regions by fluorescence-activated cell sorting, next generation RNA sequencing, real-time PCR, and immunohistochemical techniques. Antigen-presenting properties of microglia were evaluated by the ability of isolated cells to induce a clonal expansion of CD4(+) T cells purified from OT-II transgenic mice. Results Under steady-state conditions, the midbrain presented a high immune-alert state characterized by the presence of two unique microglial subpopulations, one expressing the major histocompatibility complex class II (MHC-II) and acting as antigen-presenting cells and another expressing the toll-like receptor 4 (TLR4), and by the presence of a higher proportion of infiltrating CD4(+) T cells. This state was not detected in the cortex, hippocampus, or striatum. Systemic LPS administration induced a general increase in classic pro-inflammatory cytokines, in co-inhibitory programmed death ligand 1 (PD-L1), and in cytotoxic T lymphocyte antigen 4 (CTLA-4) receptors, as well as a decrease in infiltrating effector T cells in all brain regions. Interestingly, a specific immune-suppressive response was observed in the midbrain which was characterized by the downregulation of MHC-II microglial expression, the upregulation of the anti-inflammatory cytokines IL10 and TGF beta, and the increase in infiltrating regulatory T cells. Conclusions These data show that the midbrain presents a high immune-alert state under steady-state conditions that elicits a specific immune-suppressive response when exposed to an inflammatory stimulus. This specific inflammatory tone and response may have an impact in neuronal viability.
Autores: Luquin, María Esther; Huerta, I.; Aymerich, MS; et al.
Revista: FRONTIERS IN NEUROANATOMY
ISSN 1662-5129  Vol. 12  2018  págs. 34
The pedunculopontine tegmental nucleus (PPN) and laterodorsal tegmental nucleus (LDT) are functionally associated brainstem structures implicated in behavioral state control and sensorimotor integration. The PPN is also involved in gait and posture, while the LDT plays a role in reward. Both nuclei comprise characteristic cholinergic neurons intermingled with glutamatergic and GABAergic cells whose absolute numbers in the rat have been only partly established. Here we sought to determine the complete phenotypical profile of each nucleus to investigate potential differences between them. Counts were obtained using stereological methods after the simultaneous visualization of cholinergic and either glutamatergic or GABAergic cells. The two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67, were separately analyzed. Dual in situ hybridization revealed coexpression of GAD65 and GAD67 mRNAs in ~90% of GAD-positive cells in both nuclei; thus, the estimated mean numbers of (1) cholinergic, (2) glutamatergic, and (3) GABAergic cells in PPN and LDT, respectively, were (1) 3,360 and 3,650; (2) 5,910 and 5,190; and (3) 4,439 and 7,599. These data reveal significant differences between PPN and LDT in their relative phenotypical composition, which may underlie some of the functional differences observed between them. The estimation of glutamatergic cells was significantly higher in the caudal PPN, supporting the reported functional rostrocaudal segregation in this nucleus. Fi
Autores: Mengual, Elisa;
Revista: BRAIN STRUCTURE AND FUNCTION
ISSN 1863-2653  Vol. 221  Nº 9  2016  págs. 4549 - 4573
We previously analyzed the arborization patterns of rat ventral pallidal (VP) axons that coursed caudally to innervate the thalamus and brainstem (Tripathi et al. in Brain Struct Funct 218:1133-1157, 2013). Here, we have reconstructed 16 previously undetected axons from the same tracer deposits that follow a more lateral trajectory. Virtually all 16 axons emanating from the different VP compartments collateralized in the extended amygdala system (EAS) and amygdaloid complex. The most frequent targets of axons from the lateral and medial (VPm) VP compartments were the rostral sublenticular extended amygdala, the extended amygdala (EA), the central nucleus of the amygdala and the posterior part of the basolateral amygdaloid nucleus. In contrast, axons from the rostral extension of the VP preferentially innervated the anterior amygdaloid area, the magnocellular preoptic nucleus, and the anterior part of the basomedial amygdaloid nucleus. We additionally found and reconstructed a single corticopetal axon arising from the VPm. The new results show that both direct and indirect projections from the basolateral complex and EAS to the ventral striatopallidal system are reciprocated by VP projections, and suggest that the systems can be activated simultaneously. The results additionally suggest that the amygdaloid complex and cortex are innervated separately from the VP. Finally, the combination of new and previous data indicate that approximately 84 % of VP axons (88/105) participate
Autores: Fernández-Seara, M. A.; Mengual, Elisa; Castellanos, G.; et al.
Revista: HUMAN BRAIN MAPPING
ISSN 1065-9471  Vol. 36  Nº 5  2015  págs. 1937 - 1950
Neurophysiological changes within the cortico-basal ganglia-thalamocortical circuits appear to be a characteristic of Parkinson's disease (PD) pathophysiology. The subthalamic nucleus (STN) is one of the basal ganglia components showing pathological neural activity patterns in PD. In this study, perfusion imaging data, acquired noninvasively using arterial spin-labeled (ASL) perfusion MRI, were used to assess the resting state functional connectivity (FC) of the STN in 24 early-to-moderate PD patients and 34 age-matched healthy controls, to determine whether altered FC in the very low frequency range of the perfusion time signal occurs as a result of the disease. Our results showed that the healthy STN was functionally connected with other nuclei of the basal ganglia and the thalamus, as well as with discrete cortical areas including the insular cortex and the hippocampus. In PD patients, connectivity of the STN was increased with two cortical areas involved in motor and cognitive processes. These findings suggest that hyperconnectivity of the STN could underlie some of the motor and cognitive deficits often present even at early stages of the disease. The FC measures provided good discrimination between controls and patients, suggesting that ASL-derived FC metrics could be a putative PD biomarker.
Autores: Mengual, Elisa;
Revista: BRAIN STRUCTURE AND FUNCTION
ISSN 1863-2653  Vol. 218  Nº 5  2013  págs. 1133 - 1157
The ventral pallidum (VP) is a key component of the cortico-basal ganglia circuits that process motivational and emotional information, and also a crucial site for reward. Although the main targets of the two VP compartments, medial (VPm) and lateral (VPl) have already been established, the collateralization patterns of individual axons have not previously been investigated. Here we have fully traced eighty-four axons from VPm, VPl and the rostral extension of VP into the olfactory tubercle (VPr), using the anterograde tracer biotinylated dextran amine in the rat. Thirty to fifty percent of axons originating from VPm and VPr collateralized in the mediodorsal thalamic nucleus and lateral habenula, indicating a close association between the ventral basal ganglia-thalamo-cortical loop and the reward network at the single axon level. Additional collateralization of these axons in diverse components of the extended amygdala and corticopetal system supports a multisystem integration that may take place at the basal forebrain. Remarkably, we did not find evidence for a sharp segregation in the targets of axons arising from the two VP compartments, as VPl axons frequently collateralized in the caudal lateral hypothalamus and ventral tegmental area, the well-known targets of VPm, while VPm axons, in turn, also collateralized in typical VPl targets such as the subthalamic nucleus, substantia nigra pars compacta and reticulata, and retrorubral field. Nevertheless, VPl and VPm displayed
Autores: Fernández-Seara, M. A.; Mengual, Elisa; Aznárez-Sanado, Maite; et al.
Revista: NEUROIMAGE
ISSN 1053-8119  Vol. 59  Nº 3  2012  págs. 2743-2750
Alterations in cerebral perfusion and metabolism in Parkinson's disease have been assessed in several studies, using nuclear imaging techniques and more recently magnetic resonance imaging. However, to date there is no consensus in the literature regarding the extent and the magnitude of these alterations. In this work, arterial spin labeled perfusion MRI was employed to quantify absolute cerebral blood flow in a group of early-to-moderate Parkinson's disease patients and age-matched healthy controls. Perfusion comparisons between the two groups showed that Parkinson's disease is characterized by wide-spread cortical hypoperfusion. Subcortically, hypoperfusion was also found in the caudate nucleus. This pattern of hypoperfusion could be related to cognitive dysfunctions that have been previously observed even at the disease early stages. The present results were obtained by means of whole brain voxel-wise comparisons of absolute perfusion values, using statistical parametric mapping, thus avoiding the potentially biased global mean normalization procedure. In addition, this work demonstrates that between-group comparison of relative perfusion values after global mean normalization, introduced artifactual relative perfusion increases, where absolute perfusion was in fact preserved. This has implications for perfusion studies of other brain disorders. (C) 2011 Elsevier Inc. All rights reserved.
Autores: Fernández-Seara, M. A.; Aznárez-Sanado, Maite; Mengual, Elisa; et al.
Revista: British Journal of Pharmacology
ISSN 0007-1188  Vol. 163   Nº 8  2011  págs. 1639 - 1652
Autores: Luquin, María Esther; Pérez, Eva ; Aymerich, MS; et al.
Revista: Journal of Histochemistry and Cytochemistry
ISSN 0022-1554  Vol. 58  Nº 4  2010  págs. 359 - 368
Acrolein is a potent fixative that provides both excellent preservation of ultrastructural morphology and retention of antigenicity, thus it is frequently used for immunocytochemical detection of antigens at the electron microscopic level. However, acrolein is not commonly used for fluorescence microscopy because of concerns about possible autofluorescence and destruction of the luminosity of fluorescent dyes. Here we describe a simple protocol that allows fine visualization of two fluorescent markers in 40-mu m sections from acrolein-perfused rat brain. Autofluorescence was removed by pretreatment with 1% sodium borohydride for 30 min, and subsequent incubation in a 50% ethanol solution containing 0.3% hydrogen peroxide enhanced fluorescence labeling. Thus, fluorescence labeling can be used for high-quality detection of markers in tissue perfused with acrolein. Furthermore, adjacent acrolein-fixed sections from a single experiment can be processed to produce high-quality results for electron microscopy or fluorescence labeling.
Autores: Prensa, Lucía; Mengual, Elisa;
Revista: Journal of Comparative Neurology
ISSN 0021-9967  Vol. 518  Nº 22  2010  págs. 4649 - 4673
The patterns of axonal collateralization of nucleus accumbens (Acb) projection neurons were investigated in the rat by means of single-axon tracing techniques using the anterograde tracer biotinylated dextran amine. Seventy-three axons were fully traced, originating from either the core (AcbC) or shell (AcbSh) compartment, as assessed by differential calbindin D28k-immunoreactivity. Axons from AcbC and AcbSh showed a substantial segregation in their targets; target areas were either exclusively or preferentially innervated from AcbC or AcbSh. Axon collaterals in the subthalamic nucleus were found at higher than expected frequencies; moreover, these originated exclusively in the dorsal AcbC. Intercompartmental collaterals were observed from ventral AcbC axons into AcbSh, and likewise, interconnections at pallidal and mesencephalic levels were also observed, although mostly from AcbC axons toward AcbSh targets, possibly supporting crosstalk between the two subcircuits at several levels. Cell somata giving rise to short-range accumbal axons, projecting to the ventral pallidum (VP), were spatially intermingled with others, giving rise to long-range axons that innervated VP and more caudal targets. This anatomical organization parallels that of the dorsal striatum and provides the basis for possible dual direct and indirect actions from a single axon on either individual or small sets of neurons.
Autores: Mengual, Elisa;
Libro:  Axons and brain architecture
2016  págs. 47 - 68
Axonal collateralization is a major organizational feature of basal ganglia circuits. Single-axon tracing techniques reveal the full collateralization patterns of individual axons, providing key connectional information about target diversity. Previous studies from our group have analyzed the axonal branching patterns of two output nuclei of the basal ganglia in the rat, the ventral pallidum (VP) and the substantia nigra pars reticulata (SNr). In this review we compare individual VP and SNr neurons, highlighting common features and unique characteristics, which may contribute to a deeper understanding of their respective connections and function. We additionally outline parallels with the entopeduncular nucleus and the globus pallidus that may help develop a more comprehensive understanding of basal ganglia organization.