Doctoral theses defended

 

Current doctoral programme

Previous doctoral programmes

Doctoral theses defended

4 72

Extraordinary Doctoral Awards

- 1

PhDs in cotutelle

- -

International doctoral theses

2 23

Industrial doctorates

- -

 

Defended thesis of current programme

Pharmacological characterization of prostaglandin E2 EP receptors in the rodent brain: functional studies in locus coeruleus neurons and the preBötzinger complex.

NAZABAL GAZTAÑAGA, AMAIA
Director: MENDIGUREN ORDORICA, AITZIBER; PINEDA ORTIZ, JOSEBA GOTZON
Mentions: NAZABAL GAZTAÑAGA, AMAIA
Grade: Excellent Cum Laude
Year: 2019
Abstract:

This work focuses on the study of the neuropharmacological mechanisms underlying prostaglandin E2 (PGE2) receptor (EP) activation in locus coeruleus (LC) neurons and the preBötzinger complex (preBötC). PGE2 is an inflammatory mediator synthesized by the brain constitutive cyclooxygenase (COX) enzyme, whose activity is blocked by the nonsteroidal anti-inflammatory drugs (NSAIDs). PGE2 binds to G protein-coupled EP1-4 receptors (EP1 to Gq, EP2 and EP4 to Gs, and EP3 to Gi/o). Activation of EP receptors by PGE2 has been shown to modulate synaptic transmission and neuronal activity in various brain regions. The noradrenergic nucleus LC, which is involved in the regulation of the sleep-wake cycle, arousal, cognition, pain, and reward behavior, expresses EP2, EP3, and EP4 receptors, but their functional role remains unexplored. Therefore, we aimed to characterize the EP2, EP3, and EP4 receptors pharmacologically in the rat LC by extracellular electrophysiological recordings in acute slices. On the other hand, the inspiratory pattern is generated by the preBötC, whose inspiratory neurons express ¿-opioid receptors (MOR) and respond to PGE2. Thus, administration of opioids produces respiratory depression while PGE2 increases the frequency of sighs and induces gasps under hypoxic circumstances. However, the possible interaction between both systems to cause major respiratory disturbances remains to be elucidated. For this purpose, we also examined the interaction between opioids and PGE2 in the mice preBötC by live time-lapse calcium imaging in organotypic slice cultures.

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Characterization of an animal model of cognitive impairment associated with schizophrenia. Effets of alpha2-adrenoceptor compounds.

PEREZ DEL PALOMAR ASIN, BLANCA
Director: MEANA MARTINEZ, JOSE JAVIER; ORTEGA CALVO, JORGE
Mentions: PEREZ DEL PALOMAR ASIN, BLANCA
Grade: Excellent Cum Laude
Year: 2019
Abstract:

Schizophrenia is a multi multifaceted, heterogeneous, chronic and debilitating disorder triggered by a series of interacting genetic, developmental and environmental factors. Cognitive impairment is considered a core feature of this disorder and highly dependent on the correct functioning of the prefrontal cortex, however, current antipsychotics lack efficacy for treating this condition. Prenatal exposure to infection is contemplated as one the most significant environmental risk factors for developing schizophrenia in the offspring. In this context, maternal immune activation animal models produce neurochemical and behavioral alterations considered relevant for the study of schizophrenia dysfunctions. The first part of this thesis consists of a neurochemical and behavioral characterization of an animal model of cognitive impairment associated with schizophrenia by the administration of the immunostimulant agent Poly (I:C). The second part involves the study of the effects of ¿2-adrenoceptor compounds on cognitive performance in the offspring. Finally, selective targeting of the locus coeruleus-prefrontal cortex circuit by different optogenetic approaches was performed. The Poly (I:C) animal model shows a catecholaminergic hypofunction in the prefrontal cortex with marked cognitive deficits, which are reversed by the administration of ¿2A-adrenoceptor agonist guanfacine and the ¿2C-adrenoceptor antagonist MK-912. These results support the important role of the noradrenergic system in the prefrontal cortex-dependent cognitive functions and the Poly (I:C) animal model as a promising translational model of cognitive impairment associated with schizophrenia.

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Impacto de la falta de adherencia terapéutica sobre la eficacia antimicrobiana de Amoxicilina, Levofloxacino y Moxifloxacino, como probabilidad de alcanzar un índice farmacocinético-farmacodinámico, en pacientes ambulatorios con neumonía adquirida en la comunidad, teniendo en cuenta su variabilidad interindividual

CARRAL TELLITU, NEREA
Director: SUAREZ GONZALEZ, MARIA ELENA
Mentions: CARRAL TELLITU, NEREA
Grade: Excellent Cum Laude
Year: 2017
Abstract:

El punto de partida para la realización de este trabajo ha sido la falta de estudios que permitan conocer las consecuencias de la falta de adherencia a la prescripción de la dosificación antimicrobiana sobre su eficacia en el tratamiento de neumonía adquirida en la comunidad en los pacientes ambulatorios. Ante la imposibilidad ética de plantear estudios clínicos controlados para evaluar este objetivo, el objetivo de nuestro trabajo ha sido evaluar las consecuencias de la falta de adherencia al tratamiento antimicrobiano empírico con Amoxicilina, Levofloxacino y Moxifloxacino, en pacientes con neumonía adquirida en la comunidad en tratamiento ambulatorio, sobre su eficacia clínica antimicrobiana, medida como probabilidad de alcanzar un determinado índice Fc-Fd basado en el análisis de sus propiedades farmacocinéticas-farmacodinámicas y teniendo en cuenta la variabilidad interindividual de los pacientes. Se han realizado estudios de simulación farmacocinética-farmacodinámica, como herramienta metodológica de trabajo, en diferentes escenarios de pacientes virtuales. Una de las consecuencia es que en zonas geográficas con baja incidencia de resistencia a S.Pneumoniae, la Amoxicilina, s, presenta clara ¿idoneidad¿ en estas poblaciones, , aun en situación de presentar baja adherencia al tratamiento.

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Learning and memory improvement mediated by CB1 cannabinoid receptors in animal models of cholinergic dysfunction

MORENO RODRIGUEZ, MARTA
Director: RODRIGUEZ PUERTAS, RAFAEL
Mentions: MORENO RODRIGUEZ, MARTA
Grade: Excellent Cum Laude
Year: 2018
Abstract:

The selective vulnerability of the basal forebrain cholinergic system (BFCS) is responsible for most of the clinical alterations in learning and memory processes that are characteristic of the Alzheimer¿s disease (AD). The loss of cholinergic neurons and muscarinic receptors (MR) in the nucleus basalis of Meynert has been reported in AD. The endocannabinoid system is a neuromodulator of the BFCS, but there are controversial reports regarding the cannabinoid effects in learning and memory processes. The animal models of cholinergic impairment mimick the main histopathological and behavioral effects observed in patients. The MR antagonism, e.g. using scopolamine (SCOP), is used as a model of amnesia in rodents. The intraparenchymal administration of 192-IgG-saporin (SAP) in the nucleus basalis magnocellularis eliminates cholinergic neurons leading to learning and memory deficits. Then, the present study evaluates the modulation of spatial and working memory with the Barnes Maze following a subchronic treatment with a low dose (0.5 mg/kg) of WIN55,212-2 (WIN) in both the SCOP and SAP models of learning and memory deficit. In the SCOP model, the administration of WIN protects learning and memory impairment during the probe trial, recorded as the time spent in the target quadrant (WIN + SCOP: 78 ± 13 sec vs VEH + SCOP: 45 ± 3 sec; p ¿ 0.001). A similar effect of the treatment was observed in the SAP model (SAP: 50 ± 3 sec vs SAP + WIN: 82 ± 7 sec; p ¿ 0.001). This effect was specifically mediated by CB1 receptors, since it was blocked by the co-administration of the specific CB1 antagonist, SR141716A (0.5 mg/kg) (SAP: 49 ± 3 sec vs SAP + WIN + SR: 48 ± 5 sec). However, higher doses of WIN (3 mg/kg) induced negative effects in learning and memory in control (C) rats, but positive and comparable to the lower dose in the SAP model (C: 89 ± 3 sec, C + WIN-3 mg/kg: 48 ± 3 sec; SAP: 49 ± 3; SAP + WIN-3 mg/kg: 80 ± 12 sec). The CB1 activation by low doses of the cannabinoid agonist WIN are able to block the amnesic effects induced by SCOP and also the learning and memory impairment produced by the BFCS pathway degeneration. CB1 agonists could contribute to improve the clinical symptoms of AD.

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In vivo functional role of the 5-HT2A/mGlu2 receptor heterocomplex in rodents

MOLLINEDO GAJATE, IRENE
Director: MEANA MARTINEZ, JOSE JAVIER
Mentions: MOLLINEDO GAJATE, IRENE
Grade: Excellent Cum Laude
Year: 2018
Abstract:

La esquizofrenia es una enfermedad prototípica humana de etiología aún desconocida. La investigación con modelos animales permite estudiar las causas y mecanismos afectados en dicha enfermedad. Así, fármacos como el DOI, actuando como agonista del receptor de serotonina 5-HT2A, induce sintomatología similar a la esquizofrenia de tipo paranoide. Existe un heterocomplejo formado entre los receptores 5-HT2A/mGlu2 en la corteza prefrontal de cerebros humanos y roedores, necesario para desencadenar dicha sintomatología positiva de esquizofrenia. Un número sustancial de artículos habían demostrado la interacción entre ambos receptores, incluyendo estudios celulares, genéticos, biofísicos y bioquímicos in vitro, pero la funcionalidad de este complejo in vivo permanecía aún poco conocida. La presente Tesis Doctoral evalúa la funcionalidad de este heterocomplejo in vivo, mediante el estudio de la liberación de catecolaminas en la corteza frontal de roedor tras la administración del alucinógeno DOI. Asimismo, se ha realizado un estudio de algunos circuitos noradrenérgicos modulados por la administración de este alucinógeno y se ha estudiado brevemente la señalización celular desencadenada por la activación del receptor 5-HT2A.

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Estudio de la expresión de micrornas y su modulacion como potencial diana terapéutica en la retinosis pigmentaria

ANASAGASTI VITERI, ANDER
Director: RUIZ EDERRA, JAVIER
Mentions: ANASAGASTI VITERI, ANDER
Grade: Excellent Cum Laude
Year: 2018
Abstract:

La retinosis pigmentaria (RP) es la principal causa genética de degeneración de la visión en todo el mundo con más de 1.5 millones de afectados, para la que aún no existe un tratamiento estandarizado y eficaz. Esta enfermedad se caracteriza por su gran heterogeneidad clínica y genética, con más de 70 genes relacionados en su desarrollo. Partimos de la hipótesis de que en la RP se ve alterado un conjunto de mecanismos moleculares comunes a distintas formas de la enfermedad, con independencia del gen mutado. Esta idea se apoya en distintos trabajos en los que se ha descrito un patrón común de expresión diferencial tanto de genes, como de microRNAs en distintos modelos animales de RP, causados por mutaciones en genes diferentes. El desarrollo de esta tesis se ha planteado alrededor de dos objetivos principales; por una parte el estudio de la expresión de microRNAs para la identificación de microRNAs diferencialmente expresados que sirvan como potencial diana terapéutica en la RP, y por otra parte la modulación in vivo de un grupo de microRNAs y el análisis del efecto de dicha modulación en un modelo animal de la enfermedad, el ratón rd10.

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RODILLA OJEDA, IRATI
Director: MENDIGUREN ORDORICA, AITZIBER; PINEDA ORTIZ, JOSEBA GOTZON
Mentions: RODILLA OJEDA, IRATI
Abstract:

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