Pathophysiological Study of ALDH1A1-negative Nigrostriatal Dopaminergic Neuron Subtypes in Parkinson's disease

National Institute On Aging

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Abstract

Various genetic, behavioral, and pharmacological studies have established a role of the nigrostriatal dopamine pathway in motor function, with reward largely associated with the mesolimbic dopamine pathway, which consists of dopaminergic connections that project from the ventral tegmental area (VTA) to the ventral striatum. However, research also supports the importance of the nigrostriatal dopamine pathway in reward, suggesting that both substantia nigra pars compacta (SNc) and VTA midbrain dopaminergic neurons (DANs) have altered firing in response to reward prediction and prediction errors. Studies show that reward-predicting stimuli result in SN activation, highlighting the fact that changes in midbrain DAN activity are not limited to the VTA. When considering SNc DANs specifically, there is again support for neuronal activation in response to reward or sensory stimuli that predict reward and inhibition by aversive stimuli. These DANs are located within the ventromedial part of the SNc adjacent to VTA, which raises the need to better define those two DAN subpopulations with more definitive genetic makers. On the other hand, there are also some SNc DANs that are activated by aversive stimuli or cues that predict aversive stimuli, which are located in the dorsolateral part of the SNc. The role of dopamine is expanding further to include response to novel, salient, and even aversive stimuli. However, molecular genetic makers are needed to better characterize different DAN subtypes, and their distinctive connectivity and functionality. By employing the newly available single cell RNA sequencing technology, recently multiple studies have been performed to reveal the diverse gene expression profiles of midbrain DNAs at single cell level. These high-resolution gene expression studies demonstrate more complex gene expression patterns in individual midbrain DANs, identify more DAN subtypes with additional genetic markers, and improve our understanding of the genetic diversity of midbrain DANs. Based on distinct gene expression patterns, the DANs in substantia nigra pars compacta may constitute at least three subtypes: Aldh1a1+/Sox6+, Aldh1a1-/Sox6+, and Aldh1a1-/Vglut2+. This study is particularly designed to characterize the connectivity and functionality of Aldh1a1-/Sox6+ and Aldh1a1-/Vglut2+ SNc DANs in motor control and Parkinson's disease.