Wiring up diversity: subset-specific development of midbrain dopaminergic neurons

Abstract

The dopamine system of the ventral midbrain (mDA system) can be subdivided into three main nuclei: substantia nigra pars compacta (SNc, A9), ventral tegmental area (VTA, A10), and retrorubral field (RRF, A8). Dopaminergic neurons of the mDA system are characterized by the synthesis and release of the neurotransmitter dopamine, and the expression of tyrosine hydroxylase (TH) and the dopamine transporter (DAT). SNc mDA neurons contribute to the control of voluntary movement and their selective degeneration is a pathological hallmark of Parkinson’s disease. VTA mDA neurons play a role in positive and negative reinforcement, decision making, working memory, and aversion. Dopamine imbalance in VTA mDA neurons has been implicated in schizophrenia, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), addiction, and depression. Their important physiological functions and implication in human disease has triggered an enormous interest in understanding the development and function of mDA neurons. It is becoming clear that neurons within the anatomically defined SNc and VTA nuclei are not homogeneous. Rather multiple distinct mDA neuron subsets exist within and across the boundaries of the SNc and VTA. For example, subsets that differ by specific molecular markers, by afferent inputs, and by the brain structures they innervate. To understand how these differences arise, the developmental origin and molecular programs in mDA neuron subsets are studied intensively. It is likely, and in part known, that different mDA neuron subsets express specific molecular cues that allow subset-specific differentiation, migration and axon guidance. This thesis aims at investigating the development of subsets of mDA neurons. New genetic tools to distinguish mDA neuron-clusters in vivo are generated and applied to understand the cellular and molecular mechanisms orchestrating the migration and axon guidance of mDA neuron subtypes.