State of the Art in Sub-Phenotyping Midbrain Dopamine Neurons

Simple Summary This review delves into the differences between two important groups of dopamine-producing brain cells, found in regions called the ventral tegmental area and the substantia nigra. While these cells are located close to each other, they play different roles in the brain and are affected differently by diseases like Parkinson's. Understanding these differences is key to developing better treatments and more selective, without causing unwanted effects on other brain functions. This review discusses how these cells are structured, how they connect to other parts of the brain, how they function, and the differences during development. The goal is to provide insights that could lead to more precise therapies, targeting specific groups of cells without harming others. This research is important for advancing treatments for brain disorders and improving our understanding of the brain's complex wiring.Abstract Dopaminergic neurons in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNpc) comprise around 75% of all dopaminergic neurons in the human brain. While both groups of dopaminergic neurons are in close proximity in the midbrain and partially overlap, development, function, and impairments in these two classes of neurons are highly diverse. The molecular and cellular mechanisms underlying these differences are not yet fully understood, but research over the past decade has highlighted the need to differentiate between these two classes of dopaminergic neurons during their development and in the mature brain. This differentiation is crucial not only for understanding fundamental circuitry formation in the brain but also for developing therapies targeted to specific dopaminergic neuron classes without affecting others. In this review, we summarize the state of the art in our understanding of the differences between the dopaminergic neurons of the VTA and the SNpc, such as anatomy, structure, morphology, output and input, electrophysiology, development, and disorders, and discuss the current technologies and methods available for studying these two classes of dopaminergic neurons, highlighting their advantages, limitations, and the necessary improvements required to achieve more-precise therapeutic interventions.