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This doctoral thesis is the first to propose a causative working model for the cerebellum's role in drug-induced memories. We managed to explore the role of the cerebellum in cocaine-induced conditioned preference and its functional and anatomical relationships with the medial prefrontal cortex (mPFC). In the first chapter we investigated the role that specific regions of the cerebellum and mPFC play in the acquisition of cocaine-induced preference conditioning after brain deactivations. The second chapter addressed a cFos and PNN analysis in the cerebellum and other cerebral regions after mPFC deactivations. Importantly, cerebellar activity and PNN expression increased only after infralimbic deactivation. The third chapter explored the activity and plasticity in the striatum and mPFC after the cerebellar impairment. Finally, we accomplished a tracing study using anterograde and retrograde tracers in order to build a working neuroanatomical model to explain the facilitative effect of the cerebellar lesion on cocaine-induced conditioned memory. Esta tesis doctoral propone un modelo de trabajo causal sobre el papel del cerebelo en los recuerdos inducidos por drogas. Exploramos el papel del cerebelo en la preferencia condicionada inducida por cocaína y sus relaciones funcionales y anatómicas con la corteza prefrontal medial (CPFm). En el primer capítulo investigamos el papel que desempeñan el cerebelo y la CPFm en la adquisición del condicionamiento de preferencia inducido por cocaína después de las desactivaciones cerebrales. El segundo capítulo abordó un análisis de cFos y PNN en el cerebelo y otras regiones cerebrales después de desactivar la CPFm. Observamos que la actividad cerebelosa y la expresión de PNN aumentaron solo después de la desactivación infralímbica. El tercer capítulo exploró la actividad y la plasticidad en el estriado y la CPFm después de la desactivación del cerebelo. Finalmente, realizamos un estudio de rastreo utilizando trazadores anterógrados y retrógrados para construir un modelo neuroanatómico. Programa de Doctorat en Psicologia

Treball Final de Grau en Psicologia. Codi: PS1048. Curs: 2017/2018 Bibliographic review whose purpose is to try to demonstrate the mechanism of action of Ethanol . The studies focus on some molecular targets that seem to be affected by the consumption of Ethanol . Protein kinase A is possibly, one of those targets and Calcium seems to play a decisive role as an intermediary in the effects produced by Ethanol . In addition, Calcium itself seems to be also a target of the influence of Ethanol producing certain effects in the Central Nervous System

Treball Final de Màster Universitari en Investigació en Cervell i Conducta. Codi: SBM024. Curs 2016/2017 The c erebellum plays an important role in addiction. It has been suggested that there is a functional netw ork between the cerebellum and i nfralimbic cortex that could play a fundamental role in the inhibition of drug - induced behavioural patterns. Using olfactory stimuli paired with cocaine in a preference conditioning procedure, our previous research has shown that conditioned preference is promot ed when either of these regions are deactivated. Moreover, in cerebellum deactivated animals (dorsal lobule VIII) two infralimbic hallmarks signatures of cocaine - induced preference conditioning were found: increased c - Fos expression (used as a neuronal act ivity marker), and an upregulation of Perineuronal Nets, indicating a stabilization of drug - related memory. Due to this functional relationship, our hypothesis is that several thalamic regions would act as a relay for the cerebellum - infralimbic network. Other of the regions we were interested is a highly involved nucleus in the drug - seeking behaviour, the basolateral amygdala , will be affected .

Because of its role in drug-seeking, consumption and addictive behavior, there is a growing interest in identifying the neural circuits and molecular mechanisms underlying the formation, maintenance and retrieval of drug-induced memories. However, very few studies have focused on brain areas beyond the corticostriatal-limbic circuitry. Despite the growing evidence confirming the involvement of the cerebellum in drug-induced alterations, this structure has been traditionally disregarded in the addiction field (Miquel et al, 2009; Miquel et al, 2016). The general aim of the present research is to address wether the cerebellum is part of the neuronal systems that sustains the plasticity mechanisms underlying drug-induced conditioned memories. We have focused our research in an attempt to clarify if the cerebellum is involved in the acquisition and storage of drug memories. The present doctoral thesis contains three different chapters. In the first chapter, Involving the cerebellum in cocaine induced memory: pattern of cFos expression in mice trained to acquire conditioned preference for cocaine, we explored the pattern of neuronal activation as revealed by cFos immunoreactivity of mice trained to develop conditioned preference for an olfactory stimulus paired with cocaine. In the second one, entitled Cerebellar hallmarks of conditioned preference for cocaine, we used the same behavioral task of the first study in order to further extend the description of cFos expression patterns in cerebellar circuitry, including now the major inputs and one of the output nuclei of the cerebellum. In the last chapter, Cerebellar perineuronal nets in cocaine-induced Pavlovian memory: site does matter, we accomplished a broad analysis of perineuronal nets (PNNs) expression of cerebellar vermis. First, we analysed an outbred mouse strain trained to acquire preference for olfactory stimuli associated with cocaine. Second, α6Cre- Cacna1a mice (Galliano et al, 2013) were used to test if a reduction in the glutamate release of parallel fibres to Purkinje dendrites would alter the acquisition of cocainepreference conditioning and the expression of PNNs in the cerebellum., Debido a su papel en la búsqueda de drogas, el consumo y la conducta adictiva, hay un creciente interés en la identificación de los circuitos neuronales y mecanismos moleculares subyacentes en la formación, el mantenimiento y la recuperación de las memorias inducidas por drogas. Sin embargo, muy pocos estudios se han centrado en áreas cerebrales más allá de los circuitos corticoestriatal-límbicos. A pesar de la creciente evidencia que confirma la participación del cerebelo en las alteraciones inducidas por drogas, esta estructura ha sido tradicionalmente descartada en el campo de la adicción (Miquel et al, 2009; Miquel et al, 2016). El objetivo general de la presente investigación es abordar si el cerebelo forma parte de los sistemas neuronales que sostienen los mecanismos de plasticidad subyacentes a las memorias condicionadas inducidas por drogas. Hemos centrado nuestra investigación en un intento de aclarar si el cerebelo está involucrado en la adquisición y almacenamiento de memorias asociadas a drogas. La presente tesis doctoral contiene tres capítulos diferentes. En el primer capítulo: Involving the cerebellum in cocaine-induced memory: pattern of cFos expression in mice trained to acquire conditioned preference for cocaine, exploramos el patrón de activación neuronal revelado por inmunorreactividad de cFos en ratones entrenados para desarrollar preferencia condicionada por un estimulo olfatorio asociado a la cocaína. En el artículo, titulado Cerebellar hallmarks of conditioned preference for cocaine, se utilizó la misma tarea comportamental del primer estudio con el fin de ampliar la descripción del patrón deexpresión de cFos en la circuitrería cerebelar, incluyendo ahora los principales aferentes y uno de los núcleos de salida del cerebelo. En el último capítulo, Cerebellar perineuronal nets in cocaine-induced Pavlovian memory: site does matter, se realizó un amplio análisis de la expresión de PNNs en el vermis cerebeloso. En primer lugar, se realizó el análisis en ratones entrenados para adquirir preferencia por un estímulo olfatorio asociado con la cocaína. En segundo lugar, se utilizaron ratones modificados genéticamente de la cepa α6Cre-Cacna1a (Galliano et al, 2013) para probar si una reducción en la liberación de glutamato de las células granulares a las dendritas de Purkinje alteraría la adquisición de preferencia por estímulos asociados con la cocaína y la expresión de PNNs en el cerebelo.

Treball final de Màster Universitari en Investigació en Cervell i Conducta. Codi: SBM024. Curs acadèmic 2015-2016 Addiction could be considered the result of pathological learning. Drug-associated cues become strong conditioned stimuli that create drug-related memories which promote drug seeking leading to relapse. Both, the striatumcortico-limbic circuitry and the cerebellum store information about reinforcing stimuli and their related cues, sharing widespread connections. Previous studies from the lab showed that both, the IL and the cerebellum exhibit hallmark signatures of drug-induced memories, changes in c- Fos expression and in PNNs. Moreover, the deactivation of the infralimbic cortex (IL) promote preference towards cocaine-associated cues, and expressed increased c-Fos+ neurons, and stronger PNNs in Golgi neurons in the apex of lobule VIII of the cerebellum. In the present study, we managed the effect of a permanent lesion of the lobule VIII vermis of the cerebellum on cocaine-induced odour preference conditioning and plasticity changes in the IL. We aimed to elucidate whether the plasticity changes of drug-induced memories observed in the cerebellum can also be found in the IL. Our results showed that a permanent lesion of the lobule VIII in the vermis promotes preference towards cocaine-associated cues, an increased number of c-Fos+ neurons, and a reduction in the number of infralimbic neurons that expressed a PNN, but no differences were found between groups related to average intensity of the matrix expression. It seems that the IL cortex and vermis are part of a functional and structural network for inhibitory effects on the acquisition of these drug-dependent preference memories.

Treball Final de Grau en Psicologia. Codi: PS1048. Curs: 2013/2014 Craving has been considered one of the core features of addiction. It can be defined as the urge or desire to use a drug that can be elicited by the drug itself, drug-associated cues or stressors, and many authors hypothesize that it accomplishes a major role in relapse even after prolonged abstinence periods and also in the maintenance of drug seeking and taking behaviors in non-abstinent addicts. The cerebellum is a subcortical structure that has traditionally been linked to motor functions, but an increasing number of evidences show that this part of the brain is also involved in function related to cognition, such as learning and memory. Moreover, this structure shows a number of reciprocal connections with the areas in the encephalon that have been traditionally related to addiction, like the striatal-cortico-limbic system. In addition, the functional neuroimaging studies that study craving in humans systematically show cerebellar activations when this part of the brain is analyzed. Therefore, the goal of this study is to provide a quick conceptualization of craving, its assessment and the traditional neural basis of this phenomenon, and then the cerebellar activations related to craving and its underlying processes will be discussed together with the possible functions of these activations.