Modulación de la neurogénesis y de la conducta por hormonas tiroideas en ratas adultas

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina. Departamento de Bioquímica. Fecha de lectura: 23 de Junio de 200

Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment

La Universidad Central durante la Segunda República: Las Ciencias Humanas y Sociales y la vida universitaria (1931–1939)

La Junta para Ampliación de Estudios y la Universidad Central.- La reforma de la Facultad de Filosofía y Letras y sus referentes internacionales.- La Fundación del Amo y las residencias de la Ciudad Universitaria.- El desarrollo científico de las humanidades: la Sección de Filología de la Facultad de Filosofía y Letras y del Centro de Estudios Históricos.- La modernización del discurso jurídico en la Universidad Central durante la Segunda República.- La inserción de la Universidad Central en las redes científicas y culturales americanas.- Entrecruzamientos hispano-americanos en la Universidad Central.- La politización de la vida universitaria madrileña durante los años veinte y treinta.- La Facultad de Derecho de la Universidad Central en sus actas .- Las tres vidas de la Universidad de Madrid durante la Guerra Civil

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.This work was supported by Grants BFU2011-28058 and BFU2014-53610P from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET from the Comunidad de Madrid; and RD12/0036/0030 from the Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER fund

Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

Objective: Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is demanding to find strategies to protect BAT against the effects of inflammation in energy balance. In this study we have explored the impact of moderate Sirtuin 1 (SIRT1) overexpression in insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods: The effect of inflammation in BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies in differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophagederived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), as well as norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results: BAT from db/db mice was susceptible to metabolic inflammation manifested by activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in lean WT mice upon LPS injection. By contrast, BAT from mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPSinduced activation of pro-inflammatory signaling, insulin resistance and defective thermogenicrelated responses upon cold exposure. Importantly, the drop of triiodothyronine (T3) levels both in circulation and intra-BAT after exposure of WT mice to LPS and cold was markedly attenuated in SIRT1Tg+ mice. In vitro experiments in BA from the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophagederived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. Conclusion: This study has unraveled the benefit of moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by inflammation in BAT. Our results have potential therapeutic value proposing combinatorial therapies of BATspecific thyromimetics and SIRT1 activators to combat metainflammation in this tissue

Effects of hypothyroidism on cell proliferation and neuroblasts in the hippocampal dentate gyrus in a rat model of type 2 diabetes

We observed how the hypothyroid state affects diabetic states and modifies cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus (DG). For this, 0.03% methimazole, an anti-thyroid drug, was administered to 7-week-old, pre-diabetic Zucker diabetic fatty (ZDF) rats by drinking water for 5 weeks, and the animals were sacrificed at 12 weeks of age. At this age, corticosterone levels were significantly increased in the ZDF rats compared to those in the control (Zucker lean control, ZLC) rats. Methimazole (methi) treatment in the ZDF rats (ZDF-methi rats) significantly decreased corticosterone levels and diabetes-induced hypertrophy of adrenal glands. In the DG, Ki67 (a marker for cell proliferation)- and doublecortin (DCX, a marker for neuronal progenitors)-immunoreactive cells were much lower in the ZDF rats than those in the ZLC rats. However, in ZDF-methi rats, numbers of Ki67- and DCX-immunoreactive cells were similar to those in the ZLC rats. These suggest that methi significantly reduces diabetes-induced hypertrophy of the adrenal gland and alleviates the diabetes-induced reduction of cell proliferation and neuronal progenitors in the DG

Hypothyroidism confers tolerance to cerebral malaria

The modulation of the host’s metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas.This work was funded by grants SAF2017-83289-R to S.A. and A.A., SAF2017-90604REDT to A.A. supported by the The European Regional Development Fund (FEDER) and BIO2016-77430-R to J.M.B. from the Ministerio de Economía y Competitividad; B2017/BMD-3724 to S.A. and A.A. from the Comunidad de Madrid; and CIBERONC CB/16/00228 to A.A. from the Instituto de Salud Carlos III

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3–10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5′-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27Kip1 and p57Kip2. In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans