Pathophysiological Study of Mesolimbic and Mesocortical Dopaminergic Neurons in Parkinson's Disease

National Institute On Aging

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Abstract

VTA holds an intriguing and diverse population of DANs in the midbrain. The VTA neurons synthesize several major neurotransmitters, including dopamine, GABA, and glutamate. While most neurons in the VTA are dopaminergic, the exact percentage can vary between subregions. Overall, only around 50% exclusively secrete dopamine, while others co-secrete glutamate and GABA or do not secrete dopamine at all. In contrast to the SNc, which is greatly associated with movement, the VTA is more related to emotion and cognition. All of these functions are impaired in PD, making both regions of great translational interest. The anatomical separation of the VTA is not clear, hence its name ending in area, not nucleus. Its separation from the SNc is best described based on both its functional projections and molecular markers. While the SNc tends to project to the striatum via the nigrostriatal pathway, which is critical for motor movement, the VTA largely mediates dopamine secretion through limbic and cortical projections. These two, divergent VTA pathways are known as the mesolimbic and mesocortical, respectively. They are especially important for incentive-based behavior, motivation, and cognition. The mesocortical pathway projects to the prefrontal cortex and is related to the attention to reward experience, interpretation of motivation and the cognitive appraisal to seek out reward again. On the other hand, the mesolimbic pathway projects to limbic structures, such as the amygdala, nucleus accumbens and hippocampus. Different stimuli can lead to different degrees of dopamine secretion or firing patterns, helping to explain why some drugs may be more addictive than others. PD involves loss of both SNc and VTA DANs; however, the contribution of DAN loss in the VTA to PD symptoms remains controversial among scientists and physicians alike. Results from a series of studies comparing DAN counts in SNc and VTA across PD and healthy control brains stained with TH demonstrated the involvement of the VTA in PD. Although researchers observed significantly more degeneration of DANs within the SNc, the substantial neurodegeneration within the VTA may contribute to PD-related clinical symptoms, especially the non-motor syndrome. It needs to be pointed out that in the previous studies the boundary between SNc and VTA was often drawn arbitrarily based on a few anatomical landmarks. With the availability of increasing numbers of distinctive genetic markers, the function and survival of SNc and VTA DAN subtypes will be investigated in a more precise and molecularly defined way. In other words, future experiments are expected to pinpoint which DAN subtypes in the SNc and VTA DANs are involved, and the extent to which they are degenerated in PD. We suspect that the selective susceptibility of DAN subtypes during the progression of PD may contribute to the complex clinical manifestations of the disease. Our current research focuses on understanding the functional role of ALDH1A1-positive VTA DANs in motivational behaviors. We want to know whether the loss of this particular subtype of VTA DANs contributes to the PD-related motor and nom-motor phenotypes.