The development of the dopaminergic midbrain: importance in health and disease.

Abstract

The dopaminergic midbrain consists of the substantia nigra, ventral tegmental area (VTA)and retrorubral field. These structures project to other brain areas via three dopaminergic pathways. These three pathways have different functions concerning voluntary movements, emotions and motivation. Several diseases are known to involve the dopaminergic system. These are Parkinson’s disease (PD), schizophrenia, attention deficit hyperactivity disorder , autism spectrum disorders, substance use disorders and Lesch-Nyhan disease. In this thesis it is researched if these diseases have a origin in the development of the dopaminergic midbrain. Therefore the normal development of the dopaminergic midbrain is discussed. This development is highly regulated in a spatiotemporal manner by a high number of genes. When the molecular borders are formed the dopaminergic neurons are born in the ventricular zone, anterior from the isthmus. After that they start migrating towards the ventral midbrain, during this migration they also start to differentiate from precursor cells to immature dopaminergic neurons. When these cells reach the ventral midbrain they start to make connections to other brain parts, making them mature dopaminergic neurons. For all six diseases or disorders there is a relationship with the dopaminergic system. However it is not clear for all of these diseases or disorders if the origin lies in the developmental phase. Especially for PD and schizophrenia, who arise later in life, more research should be done about the development and maintenance of the brain after birth, during life. From genetic studies there are susceptibility genes found for a few diseases. But it is known that also environmental factors play a role in some diseases. It could be that they have an effect on dopaminergic development if exposed during pregnancy or childhood. Or maybe it alters the dopaminergic midbrain later in life. In conclusion, more research must be done to find more genes and mechanisms who are involved in de development of the dopaminergic midbrain. Moreover research about the developing brain must be expanded till adolescence. When more is known about the development, diseases involved in the dopaminergic midbrain will be better understood so the origination can be found. Moreover, potential new therapies can be developed.