Project 461714

Neurons that use the chemical dopamine as a neurotransmitter have as a distinguishing characteristic a very long and elaborate axon with multiple branches and neurotransmitter release sites. Our recent work suggests that such morphological characteristics place them at risk in brain diseases. Dopamine neurons are critical for multiple normal brain functions such as the control of movement and learning and are implicated in multiple diseases such as Parkinson's. However, we still know very little concerning the basic mechanism that underlie the release of dopamine and about how the connectivity of these neurons changes and adapts in parallel to the gradual loss of dopamine containing neurons in Parkinson's disease. Here we propose to continue building on our recent fundamental discoveries on the basic connectivity of dopamine neurons using a range of experimental approaches, including genetically modified mice, cell culture models, electrophysiology and imaging. In the first aim, we will use genetically modified mice to manipulate proteins that are essential for the axonal connectivity of dopamine neurons in order to determine how dopamine neurons connect to target cells in the brain and what roles activity-dependent and spontaneous dopamine release play in striatal circuit function. In the second aim, we will explore the mechanisms that control the exuberant axonal branching of dopamine neurons in the normal brain and in the context of compensations that accompany cell loss in Parkinson's disease. We will also determine whether an altered capacity of these neurons to release glutamate and GABA as additional co-transmitters is implicated in pathological circuit reorganization. This work could shed light on some fundamental features of the functioning of dopamine neurons both under normal conditions and in the context of brain diseases.