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Title: Regulation of dopamine release by striatal GABA and acetylcholine in health and disease
Author: Lopes, Emanuel Ferreira
ISNI:       0000 0004 8507 9431
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Dopamine (DA) signalling plays a central role in the normal functions of the basal ganglia, by helping facilitate behavioural processes such as action selection and reinforcement learning. Dysregulation of DA signalling is implicated in a diversity of neurological and psychiatric disorders including Parkinson’s disease and addiction. Striatal DA release is subject to major local influences besides action potentials generated in the soma. Striatal mechanisms have been shown to drive and gate axonal DA release. Understanding how these factors regulate DA signalling, and how they may be dysfunctional in disease states, is crucial for identifying novel disease therapies. Firstly, this thesis will describe the role of striatal GABA in regulating DA release. The striatum is one of the most GABAergic nuclei in the brain, however, whether striatal GABA can modulate DA release is not understood. DA release, detected with fast-scan cyclic voltammetry from ex vivo striatal slices, was found to be inhibited by the activation of GABAA and GABAB receptors, independent of cholinergic input. GABA receptor antagonists enhanced DA release, indicating that DA release is under tonic inhibition by striatal GABA. Furthermore, ambient GABA manipulates short-term plasticity of DA release, and K⁺-mediated changes in short-term plasticity require activity on GABA receptors. I will then describe the implementation of several approaches to further our understanding of striatal ACh signalling. I will discuss the characterisation of a new mouse cross which will allow for the genetic targeting of striatal cholinergic interneurons (ChIs) within a parkinsonian disease state. These animals show normal parkinsonian deficits and are appropriate for the study of ChIs within the disease context. I will also describe the implementation and results of an immunohistochemical procedure for accessing ChI cell count and activity. This method reveals that parkinsonian mice have higher ChI counts but show less global activity. I also describe a method for detecting choline fluxes within striatal slices, as a proxy for ACh. Finally, I will discuss a collaborative, standalone set of experiments exploring the impact of conditionally knocking out midbrain DA neuron-derived insulin-like growth factor 1 in striatal DA release. No changes in DA release were found within these animals. The data presented in this thesis provide novel roles for GABA in the modulation of DA release. Furthermore, the implementation of several new methods for assessing changes in the cholinergic axis allow for further study of striatal ACh in both health and disease.
Supervisor: Cragg, Stephanie Sponsor: Fundação para a Ciência e a Tecnologia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available