PROJECT 4 - Monoamine regulation of basal ganglia output

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A group of brain nuclei collectively known as the basal ganglia are involved in learning to perform complex behavioral tasks. A major instructive signal for learning these tasks is the brain chemical dopamine, which is thought to signal important environmental cues related to rewards or positive outcomes, thereby allowing the brain to more effectively learn how to perform tasks that lead to reward. Unfortunately, addictive drugs hijack this system by directly causing the release of dopamine, thereby signaling a false "reward" signal, and leading to reinforcement ofthe behaviors associated with drug administration itself. By understanding how dopamine causes plastic changes in the brain that lead to addictive behaviors, we hope to be able to develop treatments for this devastating neurological condition. This project takes a unique and novel approach to this problem. In Aim 1, we apply new tools and methods that allow for highly selective stimulation of defined cell populations. We will perform electrophysiological recordings in brain slices taken from one ofthe least understood parts ofthe basal ganglia: the substantia nigra pars reticulata (SNr). The SNr is one ofthe two major output regions ofthe basal ganglia, and is therefore in a privileged position to control the signals that leave the basal ganglia and regulate cortical and subcortical motor control systems. Although early studies demonstrated its sensitivity to dopamine signaling and its importance in animal paradigms of addiction, little progress has been made, due to technical difficulties in disentangling the function ofthe complex brain circuits that are integrated in this region. In Aim 2, we will develop and exploit a new paradigm for addiction that involves optogenetic self-stimulation ofthe direct pathway circuit. This behavior is highly reinforcing and increases in frequency over many days, and may share key mechanistic features with psychostimulant addiction. We will dissect the mechanisms ofthis behavioral reinforcement in the SNr, and then in Aim 3, we will perform in vivo recordings to determine how direct pathway strength is modified during the acquisition of a highly-reinforced behavior involving direct pathway activation. RELEVANCE (See instructions): Drug addiction and other compulsive behaviors represent major public health problems that impact not only those addicted, but society as a whole. Here, we utilize cutting edge technology to dissect the function of brain areas involved in addiction, with the goal of developing new therapies to treat these maladaptive behaviors.