Ana Guadaño - Academia.edu (original) (raw)

Papers by Ana Guadaño

Fluids and Barriers of the CNS, Nov 2, 2023

Resumen del poster presentado al 16th Congress of the Spanish Society for Neuroscience, celebrado... more Resumen del poster presentado al 16th Congress of the Spanish Society for Neuroscience, celebrado en Granada del 23 al 25 de septiembre de 2015.

Resumen del trabajo presentado al MCT8 Symposium: "Current Knowledge, Future Research on Tre... more Resumen del trabajo presentado al MCT8 Symposium: "Current Knowledge, Future Research on Treatment", celebrado en California (USA) del 12 al 14 de enero de 2016.

Endocrine Abstracts, Sep 2, 2022

Thyroid hormones (THs) play a crucial role orchestrating neurodevelopment, but also regulate adul... more Thyroid hormones (THs) play a crucial role orchestrating neurodevelopment, but also regulate adult brain function. Recently, the potent effects that THs exert in adult neurogenic niches have started to be uncovered in rodents. These include an important role in the modulation of progenitor generation, especially controlling whether a neural stem cell (NSC) determines to become a neuronal or an oligodendroglial progenitor in the adult subventricular zone (SVZ), the largest NSC niche in the mammalian brain. A complex network of regulators tightly modulates TH availability and action, including transmembrane transporters, deiodinases and receptors. Among the TH-transporters, there is only one that is TH-specific, the monocarboxylate transporter 8 (MCT8). Deficiency of MCT8 leads to an ultra-rare but devastating disease, the Allan-Herndon-Dudley Syndrome (AHDS). Patients exhibit a plethora of endocrine and severe neurological disturbances and so far, no effective treatment for their neurological symptoms exists. Its complexity, along with its low prevalence and severe symptomatology, makes animal models and biomarkers of the disease a crucial step in the research for potential strategies to alleviate the patients' severe conditions. Using a well-validated animal model of AHDS, the Mct8/Dio2 KO mice, we aimed to characterize how a reduced T3 availability structurally and functionally affected the neurogenic and gliogenic capacity of the adult SVZ-NSCs. To this end, we analysed the expression of cell markers by immunohistochemistry to study the balance between neurons and glia in the SVZ, both in-vivo and using ex-vivo neurosphere cultures. These studies revealed severe alterations in the neuroglial balance, with an increase of the neuron/glia ratio in the SVZ in adult Mct8/Dio2 KO mice. We also observed that MCT8/DIO2 deficiency reduced NSC proliferation twofold and hampered migrating of proliferating neuronal progenitors. Moreover, we tested the effects of administering exogenous THs and TH-analogues on neurospheres prepared from dissected SVZs. Neither the neuron/glia balance, nor proliferative activity responded to TH treatment in MCT8/DIO2 deficient neurospheres. Also, behaviour consequences of the observed NSCs alterations were studied using the olfactory memory and odour discrimination tests, as potential non-invasive biomarkers of the disease. These tests revealed that Mct8/Dio2 KO mice did not recognize new odours and failed to memorize them. Altogether, these results indicate that MCT8/DIO2 deficiency severely hampers TH-dependent regulation of adult SVZ-neurogliogenesis and suggest potential biomarkers for future preclinical studies.

Resumen del trabajo presentado al MCT8 Symposium, celebrado en Los Angeles (California-USA) del 4... more Resumen del trabajo presentado al MCT8 Symposium, celebrado en Los Angeles (California-USA) del 4 al 6 de enero de 2017.

PLOS ONE, Dec 6, 2019

Patients lacking the thyroid hormone (TH) transporter MCT8 present abnormal serum levels of TH: l... more Patients lacking the thyroid hormone (TH) transporter MCT8 present abnormal serum levels of TH: low thyroxine and high triiodothyronine. They also have severe neurodevelopmental defects resulting from cerebral hypothyroidism, most likely due to impaired TH transport across the brain barriers. The use of TH analogs, such as triiodothyroacetic acid (TRIAC), that can potentially access the brain in the absence of MCT8 and restore at least a subset of cerebral TH actions could improve the neurological defects in these patients. We hypothesized that direct administration of TRIAC into the brain by intracerebroventricular delivery to mice lacking MCT8 could bypass the restriction at the brain barriers and mediate TH action without causing hypermetabolism. We found that intracerebroventricular administration of therapeutic doses of TRIAC does not increase further plasma triiodothyronine or further decrease plasma thyroxine levels and does not alter TH content in the cerebral cortex. Although TRIAC content increased in the brain, it did not induce TH-mediated actions on selected target genes. Our data suggest that intracerebroventricular delivery of TRIAC has the ability to target the brain in the absence of MCT8 and should be further investigated to address its potential therapeutic use in MCT8 deficiency.

Journal of Biological Chemistry, Jun 1, 1995

Molecular Psychiatry, Jan 31, 2006

Hormonal imbalances are involved in many of the age-related pathologies, as neurodegenerative and... more Hormonal imbalances are involved in many of the age-related pathologies, as neurodegenerative and psychiatric diseases. Specifically, thyroid state alterations in the adult are related to psychological changes and mood disorders as depression. The dentate gyrus of the hippocampal formation undergoes neurogenesis in adult mammals including humans. Recent evidence suggests that depressive disorders and their treatment are tightly related to the number of newly born neurons in the dentate gyrus. We have studied the effect of thyroid hormones on hippocampal neurogenesis in adult rats in vivo. A short period of adult-onset hypothyroidism impaired normal neurogenesis in the subgranular zone of the dentate gyrus with a 30% reduction in the number of proliferating cells. Hypothyroidism also reduced the number of newborn neuroblasts and immature neurons (doublecortin immunopositive cells) which had a severely hypoplastic dendritic arborization. To correlate these changes with hippocampal function, we subjected the rats to the forced swimming and novel object recognition tests. Hypothyroid rats showed normal memory in object recognition, but displayed abnormal behavior in the forced swimming test, indicating a depressive-like disorder. Chronic treatment of hypothyroid rats with thyroid hormones not only normalized the abnormal behavior, but also restored the number of proliferative and doublecortin positive cells, and induced growth of their dendritic trees. Therefore, hypothyroidism induced a reversible depressive-like disorder which correlated to changes in neurogenesis. Our results indicate that thyroid hormones are essential for adult hippocampal neurogenesis and suggest that mood disorders related to adult-onset hypothyroidism in humans could be due, in part, to impaired neurogenesis.

Social Science Research Network, 2021

Neurobiology of Disease, Nov 1, 2022

Neurobiology of Disease, 2022

Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to profoun... more Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to profound brain alterations, including myelination impairments, in humans. We aimed to further explore the pathophysiological mechanisms underlying the MCT8 deficiency-associated myelination impairments to unravel new biomarkers and therapeutic targets. We have performed brain histological analysis on an MCT8-deficient subject and histological, ultrastructural, and magnetic resonance imaging (MRI) analysis in the brain of a mouse model of the syndrome, lacking MCT8 and enzyme deiodinase type 2 (DIO2, Mct8/Dio2 KO). We have found that the MCT8-deficient subject presents severely reduced myelin lipid and protein staining and increased proportion of small-caliber myelinated axons in detriment of large-caliber ones. Mct8/Dio2 KO mice present myelination impairments and abnormal oligodendroglial development. We conclude that the greater proportion of small-caliber axons and impairments in the oligodendroglia lineage progression arise as potential mechanisms underlying the permanent myelination defects in MCT8-deficiency. Moreover, we present the Mct8/Dio2 KO mouse model, and MRI as a non-invasive biomarker, as highly valuable tools for preclinical studies involving MCT8 deficiency. These findings contribute to the understanding of the pathological mechanisms in MCT8 deficiency and suggest new biomarkers and therapeutic targets to consider therapeutic options for the neurological defects in patients.

Humana Press eBooks, Nov 15, 2003

Neurobiology of Disease, 2021

Journal of Comparative Neurology, 2019

The cold‐ and menthol‐activated ion channel transient receptor potential channel subfamily M memb... more The cold‐ and menthol‐activated ion channel transient receptor potential channel subfamily M member 8 (TRPM8) is the principal detector of environmental cold in mammalian sensory nerve endings. Although it is mainly expressed in a subpopulation of peripheral sensory neurons, it has also been identified in non‐neuronal tissues. Here, we show, by in situ hybridization (ISH) and by the analysis of transgenic reporter expression in two different reporter mouse strains, that TRPM8 is also expressed in the central nervous system. Although it is present at much lower levels than in peripheral sensory neurons, we found cells expressing TRPM8 in restricted areas of the brain, especially in the hypothalamus, septum, thalamic reticular nucleus, certain cortices and other limbic structures, as well as in some specific nuclei in the brainstem. Interestingly, positive fibers were also found traveling through the major limbic tracts, suggesting a role of TRPM8‐expressing central neurons in multipl...

Thyroid Hormone Receptors

Journal of Molecular Endocrinology, 2004

We have generated transgenic reporter mice to analyze the spatio-temporal distribution of thyroid... more We have generated transgenic reporter mice to analyze the spatio-temporal distribution of thyroid hormone signaling during mouse brain development. The reporter system, utilizing a chimeric yeast Gal4 DNA-binding domain–thyroid hormone α ligand-binding domain fusion protein to drive lacZ expression, revealed that thyroid hormone signaling starts in the midbrain roof several days before the onset of thyroid gland function, and that it remains highly heterogeneous in the central nervous system throughout pre- and postnatal development. We speculate that this heterogeneity might provide neural cells with positional information during development.

Journal of Biological Chemistry, 1995