The neurotransmitter dopamine (DA), produced by midbrain DA neurons, influences a spectrum of behaviors including motor, reward, motivation, and cognition. In accordance with these functions, DA dysfunction is prominently implicated in a wide gamut of disorders affecting tens of millions of people, including Parkinson's disease, schizophrenia, ADHD, addiction and depression. Understanding how DA neurons control all of these distinct behaviors is important for understanding and treating these neuropsychiatric diseases. The literature is dominated by anatomical classification of DA neurons based on location within the Ventral Tegmental Area (VTA) or Substantia Nigra pars compacta (SNc). Guided by an emerging literature on DA neuron heterogeneity, we hypothesize that there must exist several molecularly and functionally distinct DA types, perhaps intermingled, that could underpin the myriad functions of DA. As a first step in classifying DA neurons, the Awatramani lab developed an approach to profile single midbrain DA neurons, each for the expression of 96 key genes, using a microfluidic dynamic RT-qPCR array. Hierarchical clustering indicated that DA neurons exhibited roughly six distinct molecular barcodes, presumably indicative of at least six molecularly and functionally distinct DA subtypes. The Dombeck laboratory has developed a robust data set demonstrating functional heterogeneity of DA neurons in behaving mice. Previous models postulated that slow variations in tonic firing rates bias the system toward or away from movement, whereas phasic signaling was linked to unpredicted rewards. Using imaging in behaving mice, we showed heterogeneous expression of phasic locomotion and reward signaling in DA axons projecting to the striatum. In the dorsal striatum we found that most DA fibers displayed a phasic signal locked to the animal's cyclic accelerations during locomotion. In the ventral striatum, axonal signaling to unpredicted rewards was more prevalent. These results indicate that striatum DA release is not simply homogenous and movement permissive, but is richly heterogeneous with respect to reward and locomotion signaling. Based on these complementary data sets- molecular heterogeneity and functional heterogeneity, our goal is to correlate molecular identity with anatomy and function.
In Specific Aim 1, we will define the diversity, transcriptomes, and projections of DA neuron subtypes, developing intersectional genetic tools to access DA neuron subtypes.
In Specific Aim 2, we will establish the behavioral signaling properties of the genetically identified DA subtypes that project to the striatum. Thus, using a collaborative approach between two laboratories each with distinct expertise, we aim to characterize DA neuron subtypes based on their molecular, anatomic and functional properties. These studies will be vital for designing targeted therapies for the DA system. Moreover these studies will provide genetic platforms for manipulations of DA subtypes towards understanding their role in mammalian behavior.
Midbrain dopamine (DA) neurons underpin a plethora of mammalian behaviors including movement control and reward based learning. The proposed aims seek to deconstruct the midbrain DA system into its constituent components, by identifying molecularly distinct DA neuron subtypes and then characterizing their anatomic projections and functional properties during behavior.
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