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[eng] Huntington’s disease (HD) is a neurodegenerative disorder caused by an autosomic mutation on the Huntingtin (HTT) coding gene. HD is mainly characterized by the appearance of motor symptoms or choreas, which are associated to the selective degeneration of striatal neurons, and by the presence of cognitive disturbances, which are attributed to alterations in corticostriatal connectivity and to hippocampal dysfunction. For this reason, finding targets involved both on striatal vulnerability and cognitive disturbances, might result in therapeutic strategies able to act simultaneously on HD’s motor and cognitive symptoms. In this Thesis we have focused on Cyclin-dependent kinase 5 (Cdk5) as one of these putative targets. Cdk5 acts mainly in the central nervous system, where its activator p35 is expressed, and it plays a major role on synaptic plasticity regulation. In addition, altered Cdk5 activity has been described in several neurodegenerative disorders, including HD, where Cdk5 deregulation has been associated to increased striatal vulnerability to excitotoxicity. Moreover, alteration of Cdk5 activity and/or subcellular distribution has also been linked to neuronal cell cycle re-entry, which has been proposed as a possible mechanism leading to neuronal dysfunction and eventual death in several neurodegenerative conditions. Therefore, on one hand, we aimed to study Cdk5 involvement in cognitive deficits and synaptic plasticity alterations in HD. To this end, we generated a new double mutant mice model which expresses one copy of mutant HTT (mHTT) (knock-in or KI), and is conditionally heterozygous for Cdk5 (Cdk5+/). We described that double mutant mice (KI:Cdk5+/-) presented restored corticostriatal and hippocampal cognitive function when compared to their KI littermates. We also observed that preserved corticostriatal function correlated with recovery of corticostriatal NR2B surface levels, which were reduced in KI mice. Moreover, recovery of NR2B surface levels was associated to normalization of NR2B total levels and of the pSrc/pNR2B pathway in the cortex of KI:Cdk5+/- mice. On the other hand, preserved hippocampal cognitive function correlated with recovery of CA1 dendritic spine density, as well as, with increased Rac1 activity in KI:Cdk5+/- mice. Restoration of dendritic spine density was also observed in layer V cortical neurons, in a Rac1-independent manner. Finally, we described that KI mice showed reduced physiological p35 plasma membrane levels in the cortex, which was recovered in KI:Cdk5+/- mice, correlating with preferential alteration of Cdk5 substrates phosphorylation levels in this brain region. In sum, our results demonstrate Cdk5 complex and brain region-specific involvement in cognitive deficits appearance and in synaptic alterations in HD. On the other hand, we also assessed whether Cdk5 deregulation might cause cell cycle re-entry of striatal neurons in HD. Cdk5 forms a nuclear complex with p27 and E2F1 in differentiated neurons, thus preventing E2F1 from binding to its coactivator DP1 and from activating transcription of cell cycle progression genes. For this reason, we analysed nuclear levels of Cdk5 and p27, and we observed that KI mice showed reduced Cdk5 and p27 nuclear levels, which could induce neuronal cell cycle re-entry. In agreement, we also observed increased levels of CyclinD1 in the striatum of KI mice since early symptomatic stages, and increased Cdk4 levels at late disease stages. Finally, we observed that NMDA treatment of striatal primary cultures caused a general reduction of cell cycle proteins neuronal expression, and importantly, it altered their subcellular distribution, reducing nuclear localization of the cell cycle inhibitor p27 and inducing nuclear presence of cell cycle progression proteins, E2F1 and Cdk4. Our results also suggested that presence of mHTT might further potentiate NMDA-induced subcellular distribution alteration of cell cycle proteins. Therefore, we suggest that reduction of Cdk5 nuclear levels might induce cell cycle re-entry of striatal neurons, a process which could be favoured by alterations in NMDA receptors activation, present in HD., [cat] La malaltia de Huntington (MH) és un desordre neurodegeneratiu causat per una mutació al gen que codifica per la proteïna Huntingtina (HTT), i que consisteix principalment en l’aparició de dèficits motors, associats a la degeneració selectiva de l’estriat; i en l’aparició de dèficits cognitius, associats a una alteració en la connectivitat corticoestriatal i a una disfunció hipocampal. En aquesta Tesi, hem analitzat la implicació de la cinasa Cdk5, per una banda, en l’aparició dels dèficits cognitius; i per l’altre banda, en la reentrada neuronal al cicle cel·lular com a un possible mecanisme de susceptibilitat a la vulnerabilitat estriatal en la MH. Els nostres resultats han mostrat que la reducció genètica de Cdk5 en un model murí de la MH (KI), prevé l’aparició dels dèficits cognitius corticoestriatal i hipocampals. Aquesta millora cognitiva està associada a la recuperació dels nivells de membrana de NR2B a nivell corticoestriatal, i a la restauració de la densitat d’espines dendrítiques a l’hipocamp i a l’escorça, indicant una implicació de Cdk5, complexa i específica de regió cerebral, en les alteracions sinàptiques i l’aparició dels dèficits cognitius en la MH. D’altre banda, hem observat que els nivells nuclears de Cdk5 estan disminuïts a l’estriat dels ratolins KI, cosa que podria alterar la seva funció com a inhibidor de la progressió del cicle cel·lular en neurones diferenciades. En concordança amb aquesta hipòtesi, diferents proteïnes del cicle cel·lular presenten una alteració en els seus nivells proteics, tant en ratolins KI, com en mostres de pacients humans. A més, l’activació dels receptors NMDA en neurones estriatals porta a una alteració de la distribució subcel·lular de les proteïnes del cicle cel·lular prèviament analitzades, un efecte que podria ser potenciat per la presència de la HTT mutada. En conclusió, els resultats d’aquesta Tesi, mostren la complexa implicació de Cdk5 en l’aparició dels dèficits cognitius en la MH, i suggereixen que l’alteració de la localització nuclear de Cdk5 podria portar a la desregulació de diferents proteïnes del cicle cel·lular, un mecanisme que es podria veure afavorit per alteracions en l’activació dels receptors NMDA, presents en la MH.

[eng] Endogenous Cushing’s syndrome is a rare disease due to an excess of circulating cortisol. Chronic cortisol excess can lead to different comorbidities which may persist after biochemical cure, including brain volume decrease, neuropsychological impairment, mood disorders and high cardiovascular risk. This PhD thesis aims to study some of the effects of Cushing’s syndrome on the brain, and its relationship to other clinical parameters. More specifically, the aims of this thesis include analyzing cerebellar volume in patients with Cushing’s syndrome and establishing associations with neuropsychological performance, cortisol levels and other clinical parameters. On the other hand, it pretends to analyse brain white matter lesions in patients with Cushing’s syndrome and the relationship between cardiovascular risk, white matter lesions, neuropsychological performance and brain volume. Our results showed smaller cerebellar cortex volumes in active patients, but not in patients in remission, in comparison to controls. Cerebellar cortex positively correlated with visual memory performance and quality of life, and negatively correlated with age at diagnosis and triglyceride levels. Active patients had worse memory performance than controls. Both patient groups had higher anxiety and depression levels than controls. Patients in remission (but not active patients) had a higher degree of white matter lesions than controls. White matter lesions where correlated to diastolic blood pressure and duration of hypertension. Patients in remission on hydrocortisone replacement had higher level of white matter lesions than patients in remission not taking hydrocortisone. Finally, both patient groups (active and in remission) had higher cardiovascular risk than controls. Cardiovascular risk negatively correlated with cognitive function and cerebellar volume in patients in remission. In conclusion, Cushing’s syndrome leads to different comorbidities in the two phases of the disease (active and in remission). Some of the alterations found in active patients may be, at least, partially reversible, although the cardiovascular risk associated with Cushing’s syndrome may lead to further comorbidities in the future if it is not controlled. These data highlight the importance of providing psychological support to the patients if necessary and controlling cardiovascular risk in order to prevent brain damage and to reduce the risk of stroke or heart attack., [spa] El síndrome de Cushing endógeno es una enfermedad rara debida a un exceso de cortisol circulante. El exceso crónico de cortisol puede provocar una serie de alteraciones que no en todos los casos revierten tras la curación hormonal, y que incluyen disminución del volumen cerebral, alteraciones neuropsicológicas y del estado de ánimo y riesgo cardiovascular elevado. Esta tesis pretende estudiar algunos de los efectos que provoca el síndrome de Cushing a nivel cerebral, analizando su relación con otros parámetros clínicos. Concretamente, los objetivos de la tesis incluyen por un lado analizar el volumen cerebelar en los pacientes con síndrome de Cushing, así como establecer su relación con el rendimiento neuropsicológico, los niveles de cortisol y otros parámetros clínicos. Por otro lado, se pretende analizar la presencia de lesiones de sustancia blanca cerebral en los pacientes con síndrome de Cushing y la relación entre riesgo cardiovascular, lesiones de sustancia blanca, rendimiento neuropsicológico y volumen cerebral. Se encontraron menores volúmenes del córtex cerebelar bilateral en los pacientes activos, pero no en los pacientes curados, en comparación con los controles. El córtex cerebelar correlacionó positivamente con el rendimiento en memoria visual y la calidad de vida y negativamente con la edad en el momento del diagnóstico y el nivel de triglicéridos circulantes. Los pacientes activos presentaban peor rendimiento a nivel de memoria, y ambos grupos de pacientes presentaban mayores niveles de ansiedad y depresión que los controles sanos. Por otro lado, los pacientes en remisión, pero no los pacientes activos presentaron mayor nivel de lesiones de sustancia blanca cerebral que los controles sanos. Estas lesiones estaban relacionadas con los niveles de tensión diastólica y la duración de la hipertensión. Los pacientes en remisión que tomaban hidrocortisona presentaban mayor nivel de lesiones que los pacientes en remisión que no tomaban el fármaco. Finalmente ambos grupos de pacientes (activos y en remisión) presentaban mayor riesgo cardiovascular que los controles sanos. El riesgo cardiovascular correlacionó negativamente con la función cognitiva y el volumen cerebral en los pacientes en remisión. En conclusión, el síndrome de Cushing determina diferentes comorbilidades en las distintas fases de la enfermedad. Algunas de las alteraciones halladas en los pacientes activos podrían ser al menos parcialmente reversibles, aunque el riesgo cardiovascular asociado a la enfermedad puede llevar a otras comorbilidades en el futuro si no se controla. Estos datos remarcan la importancia de proporcionar un soporte psicológico a los pacientes en caso necesario y de controlar el riesgo vascular para prevenir la posible afectación cerebral futura y reducir el riesgo de complicaciones cardiovasculares.

Continuous environmental stimulation induced by exposure to enriched environment (EE) has yielded cognitive benefits in different models of brain injury. Perinatal asphyxia results from a lack of oxygen supply to the fetus and is associated with long lasting neurological deficits. However, the effects of EE in middle aged rats suffering perinatal asphyxia are unknown. Therefore, the aim of the present study was to assess whether life long exposure to EE could counteract the cognitive and behavioral alterations in middle aged asphyctic rats. Experimental groups consisted of rats born vaginally (CTL), by cesarean section (C+), or by C+ following 19 min of asphyxia at birth (PA). At weaning, rats were assigned to standard (SE) or enriched environment (EE) for 18 months. During the last month of housing, animals were submitted to a behavioral test battery including Elevated Plus Maze, Open Field, Novel Object Recognition and Morris water maze (MWM). Results showed that middle aged asphyctic rats, reared in SE, exhibited an impaired performance in the spatial reference and working memory versions of the MWM. EE was able to counteract these cognitive impairments. Moreover, EE improved the spatial learning performance of middle aged CTL and C+ rats. On the other hand, all groups reared in SE did not differ in locomotor activity and anxiety levels, while EE reduced locomotion and anxiety, regardless of birth condition. Recognition memory was altered neither by birth condition nor by housing environment. These results support the importance of environmental stimulation across the lifespan to prevent cognitive deficits induced by perinatal asphyxia. Fil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina Fil: Blanco, Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Instituto de Investigaciones Bioquímicas de Málaga; España. Universidad de Malaga; España Fil: Logica Tornatore, Tamara Maite Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina Fil: Romero, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina Fil: Holubiec, Mariana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina Fil: Rodríguez de Fonseca, Fernando. Universidad de Malaga; España Fil: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina

Introduction: Breastfeeding effects on cognition are attributed to long-chain polyunsaturated fatty acids (LC-PUFAs), but controversy persists. Genetic variation in fatty acid desaturase (FADS) and elongase (ELOVL) enzymes has been overlooked when studying the effects of LC-PUFAs supply on cognition. We aimed to: 1) to determine whether maternal genetic variants in the FADS cluster and ELOVL genes contribute to differences in LC-PUFA levels in colostrum; 2) to analyze whether these maternal variants are related to child cognition; and 3) to assess whether children's variants modify breastfeeding effects on cognition. Methods: Data come from two population-based birth cohorts (n = 400 mother-child pairs from INMA-Sabadell; and n = 340 children from INMA-Menorca). LC-PUFAs were measured in 270 colostrum samples from INMA-Sabadell. Tag SNPs were genotyped both in mothers and children (13 in the FADS cluster, 6 in ELOVL2, and 7 in ELOVL5). Child cognition was assessed at 14 mo and 4 y using the Bayley Scales of Infant Development and the McCarthy Scales of Children's Abilities, respectively. Results: Children of mothers carrying genetic variants associated with lower FADS1 activity (regulating AA and EPA synthesis), higher FADS2 activity (regulating DHA synthesis), and with higher EPA/AA and DHA/AA ratios in colostrum showed a significant advantage in cognition at 14 mo (3.5 to 5.3 points). Not being breastfed conferred an 8- to 9-point disadvantage in cognition among children GG homozygote for rs174468 (low FADS1 activity) but not among those with the A allele. Moreover, not being breastfed resulted in a disadvantage in cognition (5 to 8 points) among children CC homozygote for rs2397142 (low ELOVL5 activity), but not among those carrying the G allele. Conclusion: Genetically determined maternal supplies of LC-PUFAs during pregnancy and lactation appear to be crucial for child cognition. Breastfeeding effects on cognition are modified by child genetic variation in fatty acid desaturase and elongase enzymes., This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041), Spanish Ministry of Health (FIS-PI041436, FIS-PI081151, 97/0588, 00/0021-2, PI061756 and PS0901958), Generalitat de Catalunya-CIRIT 1999SGR 00241, Beca de la IV convocatoria de Ayudas a la Investigacion en Enfermedades Neurodegenerativas de La Caixa, EC Contract No. QLK4-CT-2000-00263, Fundacion Roger Torne, and Fundacio La Marato de TV3 (Project No. 090430). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background: Cognitive dysfunction is common among depressed patients. However, the pattern and magnitude of impairment during episodes of major depressive disorder (MDD) through to clinical remission remains unclear. Heterogeneity of depressive patients and the lack of longitudinal studies may account for contradictory results in previous research. Methods/Design: This longitudinal study will analyze cognitive differences between CORE-defined melancholic depressed patients (n = 60) and non-melancholic depressed patients (n = 60). A comprehensive clinical and cognitive assessment will be performed at admission and after 6 months. Cognitive dysfunction in both groups will be longitudinally compared, and the persistence of cognitive impairment after clinical remission will be determined. Discussion: The study of neuropsychological dysfunction and the cognitive changes through the different phases of depression arise a wide variety of difficulties. Several confounding variables must be controlled to determine if the presence of depression could be considered the only factor accounting for group differences., The present study is being funded by a grant from the Instituto de Salud Carlos III of the Spanish Ministry of Health (FIS no PI08 1270); We thank the Research network on preventive activities and health promotion (Red de Investigacion en Actividades Preventivas y de Promocion de la Salud; RedIAPP) for its support in the development of this study.

La esquizofrenia, los trastornos de personalidad, el autismo y los disturbios del ánimo suelen acompañarse de alteraciones en el lenguaje, la memoria de trabajo, la función ejecutiva y la memoria episódica. Uno de los síntomas más llamativos es la irregularidad del pensamiento, que se deriva de modelos mentales ilógicos o confusos. En casos como la esquizofrenia, el lenguaje puede resultar absurdo y obstaculizar la comunicación. Presentamos en este ensayo académico dos asuntos críticos e interrelacionados: cómo y por qué ocurren estos disturbios y cuál es su naturaleza, intentando diferenciarlos como un desorden de pensamiento o un desorden en la producción del lenguaje. Psychopathological profiles, such as schizophrenia, personality disorders, autism and mood disorder are often accompanied by: language, working memory, executive function and episodic memory disorders. One of the most striking symptoms is the irregularity of thought, derived from illogical or confusing mental models. In cases such as schizophrenia, the absurd language may impeding communication. Two critical issues presented in this paper are related to how and why these disturbances occur and what is its nature, in terms of a semiological difference between a disorder of thought and language disorder. A perspective from cognitive neuroscience useful for answering these questions.