- Title
- Dopaminergic pathway imbalance in the neurobiology of depression
- Creator
- Barreto, Rafael de Araújo
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2012
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- It is generally accepted that susceptibility to depression is influenced by a combination of biological and environmental factors such as genetics and stress. However, the molecular mechanisms underlying this disease remain incompletely defined. Moreover, it is not even unequivocally clear which part or parts of the brain is/are responsible for the manifestation of depression and its symptoms. However, recent studies have indicated that the midbrain dopamine system modulates depression-like behavior in stress-based animal models of depression. In the brain of mammals, dopamine neurons of the ventral tegmental area in the midbrain give rise to two major dopaminergic pathways, the mesocortical and mesolimbic pathways. These pathways innervate a number of brain regions, including the medial prefrontal cortex (mPFC; mesocortical or mesoprefrontal pathway) and the nucleus accumbens (NAc; mesolimbic or mesoaccumbal pathway). Importantly, molecular disturbances in both of these brain regions are believed to influence the development of psychiatric disorders such as schizophrenia, addiction and depression. The work presented in this thesis is based on the hypothesis that stress differentially induces molecular alterations in these dopaminergic pathways, creating a functional imbalance which, we propose, contributes to the pathogenesis of depression. The studies which comprise the first three research chapters sought to establish how stress alters the gene expression profile in the target areas of the two dopaminergic pathways. The stress paradigm used was based on previous work that had clearly demonstrated stress had to be administered in a repeated and chronic fashion to induce depression-like behaviours in animal models of depression. It was proposed that by using a sub-chronic stress paradigm, where depression-like behaviours are not observed, it might be possible to identify an early molecular signature for the pathogenesis of the disease. Firstly, by screening the whole rat genome using microarray technology it was revealed that a number of genes involved in neurotrophin signalling had altered expression in the infralimbic mPFC (IL mPFC). This finding is completely in accord with both the neurotrophic factor and neuroplasticity hypotheses of depression. Indeed, chronic pretreatment with a clinically used antidepressant (i.e., fluoxetine) prevented some of the changes observed, especially in regards to the expression of ntrk2, the gene that encodes for the receptor of the brain-derived neurotrophic factor (BDNF). These results add to the mounting evidence that neurotrophins may play a role on the pathophysiology of depression and the beneficial effects of antidepressants. In addition, it supports the notion that the mPFC is an important brain area involved in depression. Interestingly, the stress related effects on BDNF signalling seemed to be localized to the IL mPFC, as these alterations were not seen in the NAc. Therefore, at least as it applies to a pre-depressive state, these findings support our notion of dopaminergic pathway imbalance in the etiology of depression. The last chapter comprises a study whereby expression of genes involved in dopamine neurotransmission and neurotrophic factor signalling was evaluated specifically in VTA dopamine neurons obtained from sub-chronically stressed and control animals. Consistent with a role for neurotrophic factors in depression, the results showed that the expression of the gene that encodes for BDNF was increased by stress and, importantly, that antidepressant treatment could prevent this alteration. The findings presented in this thesis demonstrate that stress causes alteration in cellular neurotrophic mechanisms that might have consequences for neuroplastic phenomena and neuronal activity. Importantly, they reveal that these alterations can be observed after a relatively short period of exposure to stress, and that they occur only in a mesocortical dopaminergic pathway, as these changes were not observed in a mesolimbic pathway target region. The present findings support the mounting evidence that VTA dopamine neurons and the forebrain regions they target could play a crucial role in the pathogenesis of depression, perhaps by undergoing neuroplastic changes that differentially alter both dopaminergic pathways responsivity to stress, creating an imbalance that favours the development of depressive symptoms.
- Subject
- depression; dopaminergic pathways; brain regions; stress
- Identifier
- http://hdl.handle.net/1959.13/936186
- Identifier
- uon:12235
- Rights
- Copyright 2012 Rafael de Araújo Barreto
- Language
- eng
- Full Text
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