AbstractsMedical & Health Science

Millions of neurons are connected in a highly specific manner in the central nervous system. The majority of these connections are formed during embryonic and postnatal development. During development, axons are guided over long distances towards their targets where they make connections with appropriate partner neurons. Once laid out, these connections remain highly plastic to accommodate different aspects of behavior. Since the precise pattern of connectivity determines the functional properties of brain regions, studying how these connections are formed is crucial for understanding how the brain functions. In addition, emerging evidence suggests that wiring defects may contribute to various neurological and psychiatric disorders. Knowledge on the formation of affected circuits will be crucial for developing therapeutic strategies to prevent or restore these situations of perturbed connectivity. Studies into the development of neuronal connections have advanced our knowledge of the complex molecular and cellular mechanisms that control the formation of these connections. However, for many brain regions these mechanisms remain poorly understood. In this thesis, the mesodiencephalic dopamine (mdDA) system is studied within this context for two reasons: (1) it is a well described and accessible system, making it suitable for studying the development of neuronal connectivity in the CNS; (2) the mdDA system is (in)directly associated with many neurological and psychiatric diseases and advancing our knowledge of the development of this system is crucial for developing successful therapeutic strategies. The mdDA system, located within the ventral midbrain, consists of dopaminergic neurons essential for controlling voluntary movement and motivational behavior. The aim of this thesis is to investigate the molecular mechanisms that orchestrate the formation of mdDA neuronal circuitry and to develop new tools to support future studies into the molecular and cellular basis of dopaminergic pathway development. Overall, this thesis provides new insights into the mechanisms controlling the development and maintenance of mdDA connectivity. In particular, a novel role for LAMP-mediated axon-axon interactions in subdomain-targeting of mdDA axons was uncovered. We also revealed a new role for target-derived Netrin-1, which at early developmental stages controls target entry via the DCC receptor, and at adult stages plays a role in maintaining functional circuitry via the DCC/Unc5C receptor complex. In addition, we present newly developed genetic tools to facilitate future studies aimed at unraveling how mdDA circuitry is established. The findings and newly developed tools presented in this thesis will help to unravel how disturbances in the molecular mechanisms that control the formation of mdDA circuitry contribute to the symptomatology of various neurological and psychiatric diseases and help develop new therapeutic strategies aimed at restoring perturbed mdDA connectivity.