Unravelling the role of the cerebellum in drug addiction. Cerebellum-prefrontal networks in drug-induced preference memory Author: Isis Gil Miravet Directed by: Dra. Marta Miquel Salgado-Araujo May 2019 Programa de Doctorat en Psicologia Escola de Doctorat de la Universitat Jaume I Unravelling the role of the cerebellum in drug addiction. Cerebellum-prefrontal networks in drug-induced preference memory Memòria presentada per Isis Gil Miravet per a optar al grau de doctora per la Universitat Jaume I Isis Gil Miravet Marta Miquel Salgado-Araujo Castelló de la Plana, maig de 2019 Finançament rebut Aquesta recerca ha comptat amb el suport de les següents beques i subvencions publiques: • Universitat Jaume I (PREDOC2014/11) • Universitat Jaume I (E-2016-44) • Universitat Jaume I (14I307.01/1) • Ministerio de Educación Cultura y Deporte (FPU12/04059) • Ministerio de Economía y Competitividad (MINECO) (PSI2015-68600-P) • Plan Nacional de Drogas 2017 (PND-132400) A la meua família TABLE OF CONTENTS PREFACE ___________________________________________________________________________ 1 GENERAL INTRODUCTION __________________________________________________________ 5 Addiction and drug reward _________________________________________________________ 5 The addiction circuitry _____________________________________________________________ 6 Cerebellum: “the little brain” _______________________________________________________ 9 Cerebellum anatomy ______________________________________________________________ 9 Cerebellum-cerebro reciprocal loops _________________________________________________ 11 The cerebellum in addiction ________________________________________________________ 12 Drug-induced plasticity changes in the cerebellum ______________________________________ 14 AIMS AND HYPOTHESIS____________________________________________________________ 17 EXPERIMENTAL STUDIES ___________________________________________________________ 19 Chapter 1: The role of the cerebellum in drug-cue associative memory: functional interactions with the medial prefrontal cortex ______________________________________ 19 Chapter 2: Changes in neural activity and perineuronal net expression in the cerebellum after deactivation of the medial prefrontal cortex ___________________________________ 29 Chapter 3: From back to front: A functional model for the cerebellar modulation in the establishment of conditioned preferences for cocaine-related cues ___________________ 57 GENERAL DISCUSSION _____________________________________________________________ 83 STRENGTHS AND PITFALLS _________________________________________________________ 87 Strengths ________________________________________________________________________ 87 Pitfalls, weaknesses, and future directions __________________________________________ 87 REFERENCES _______________________________________________________________________ 89 ACKNOWLEDGEMENTS ____________________________________________________________ 99
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