Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

MacDonald, Penny A.

2nd Supervisor

Khan, Ali R.

Co-Supervisor

3rd Supervisor

Owen, Adrian M.

Co-Supervisor

Abstract

We investigated the connectivity of dopamine (DA) neurons emerging from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) and targeting the dorsal striatum (DS), ventral striatum (VS), and prefrontal cortex (PFC). We used diffusion magnetic resonance imaging (dMRI) probabilistic tractography on human connectome project MRI data. We found that unlike conventional descriptions of DA pathways (i.e., nigrostriatal, mesolimbic, mesocortical), connectivity from both SNc and VTA each targeted DS, VS, and PFC. We also found that from the DS, VS, and PFC, a greater proportion of connections targeted the SNc as compared to the VTA. These findings suggest that DA pathways are more complex than conventionally described. In a follow-up dMRI experiment, we found reduced connectivity from the SNc/VTA complex to the caudal motor region of the striatum in patients with Parkinson's disease, indicating a potential role of dMRI to measure DA connectivity changes in patients with DA-mediated diseases.

Summary for Lay Audience

Dopamine (DA) is a neurotransmitter in the brain that binds to brain cells (neurons) and which is responsible for a plethora of behaviours like movement, decision-making, reward-processing, learning, and memory. When DA transmission goes awry, it can lead to the development of various DA-mediated disorders like Parkinson's disease, schizophrenia, substance use disorder, and obsessive-compulsive disorder.

There are two primary brain regions in which DA is produced: the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). DA from these two areas project to the striatum, which itself can be divided into the dorsal striatum (DS) and ventral striatum (VS), and the prefrontal cortex (PFC). Classically, DA connectivity from the SNc and VTA to the DS, VS, and PFC has been described according to three different pathways. In the nigrostriatal pathway, SNc projects DA to the DS. In the mesolimbic pathway, VTA projects DA to the VS. In the mesocortical pathway, VTA projects DA to the PFC. This convention, while providing a convenient model to understand DA function and DA-mediated diseases, does not take into account a body of evidence that suggests that DA projections to the DS, VS, and PFC are far more complex.

To test this in living adults, we obtained magnetic resonance imaging (MRI) data from the Human Connectome Project, a consortium that has amassed high-resolution MRI data. We used an MRI technique called probabilistic tractography to measure SNc and VTA connectivity to the DS, VS, and PFC. At odds with conventional descriptions of DA pathways, we found evidence suggesting a VTA to DS pathway, an SNc to VS pathway, and an SNc to PFC pathway. Our findings add further evidence to suggest that conventional descriptions of DA pathways oversimplify the true underlying complexity.

Finally, as a validation for this method and as a demonstration of probabilistic tractography as a means to measure DA pathway changes in disease, we performed probabilistic tractography on a population of recently-diagnosed patients with Parkinson’s disease and on age-matched controls. We found that, as predicted, the connectivity from the SNc/VTA to a certain area of the striatum was reduced.

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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