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 the involvement of the nigrostriatal dopamine pathway in motor function, while reward is predominantly associated with the mesolimbic dopamine pathway. The mesolimbic pathway comprises dopaminergic connections projecting from the ventral tegmental area (VTA) to the ventral striatum. However, research also supports the significance of the nigrostriatal dopamine pathway in reward processing, indicating that both the substantia nigra pars compacta (SNc) and VTA midbrain dopaminergic neurons (DANs) exhibit altered firing patterns in response to reward prediction and prediction errors. Studies have demonstrated that stimuli predicting rewards lead to activation in the SNc, highlighting that midbrain DAN activity changes are not solely confined to the VTA. Specifically, SNc DANs, particularly those located in the ventromedial part adjacent to the VTA, show neuronal activation in response to reward or sensory cues predicting reward, as well as inhibition in the presence of aversive stimuli. Conversely, there are also SNc DANs located in the dorsolateral part of the SNc that are activated by aversive stimuli or cues predicting aversive outcomes. This raises the need for more definitive genetic markers to better distinguish between these two DAN subpopulations. Moreover, the role of dopamine is continuously expanding to include responses to novel, salient, and even aversive stimuli. However, further characterization of different DAN subtypes and their distinctive connectivity and functionality requires the use of molecular genetic markers. Fortunately, the advent of single-cell RNA sequencing technology has enabled multiple studies to reveal diverse gene expression profiles of midbrain DANs at the single-cell level. These high-resolution gene expression studies have unveiled more complex gene expression patterns in individual midbrain DANs, identified additional DAN subtypes with unique genetic markers, and improved our understanding of the genetic diversity of midbrain DANs. Based on these distinct gene expression patterns, the DANs in the substantia nigra pars compacta may be categorized into at least three subtypes: Aldh1a1+/Sox6+, Aldh1a1-/Sox6+, and Aldh1a1-/Vglut2+. This study is specifically designed to explore the connectivity and functionality of Aldh1a1-/Sox6+ and Aldh1a1-/Vglut2+ SNc DANs in the context of motor control and PD.