Mechanisms and functions of dendritic dopamine release in the brain

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Neurons in the brain that use the chemical messenger dopamine (DA) play a key role in the control of movement, motivated behaviors and cognition. At present, we know very little about the basic mechanisms that control DA release in the brain. Although DA release from the neurons' nerve endings (axon terminals) is well characterized and known to occur through a form of regulated exocytosis, DA is also released from the cell body and dendrites of DA neurons (STD DA release) and very little is presently known about how this occurs and what roles it plays in brain function. This integrated research program may lead to a better understanding of the role of DA neurons in movement, motivation and cognition. It will also identify a mechanism that is likely to be relevant to explain the dendritic release of other chemical messengers of the brain such as serotonin and neuropeptides. The reason we know so little about the roles of STD DA release is mainly because at the present time, there is no way to selectively block or enhance STD DA release to examine the functional and behavioral consequences.The development of a mouse model in which STD DA release is strongly reduced or blocked would represent a major advance in the field. We plan to build on our recent in vitro discoveries to establish such a mouse model. We will address the following two specific aims: Specific aim #1 : Identification of the mechanism of STD DA release. We will build on our recent discovery using DA neurons maintained in culture showing that the calcium-sensing proteins synaptotagmin 4 and synaptotagmin 7 are critical determinants of STD DA. We will detect DA release in mouse brain sections to test the hypothesis that deletion of synaptotagmin 4 and/or synaptotagmin 7 in DA neurons will severely reduce STD DA release. Specific aim #2 : Identification of the functional and behavioral roles of STD DA release. We will build on our experiments from aim 1 to obtain the first insights into the roles of STD DA release in brain function and behavor. Due to a presumed negative feedback role of STD DA release, we hypothesize that in the absence of STD DA release, the electrical activity of DA neurons will be increased. We also hypothesize that the strength of connections onto DA neurons will be altered. Finally, we will perform a thorough behavioral evaluation of these mice in which STD DA release has been reduced to identify some of the major roles of STD DA release in regulating behavior. We hypothesize that movement, motivated behaviors and spatial working memory will be altered.