Abstract
Decades of research have revealed the remarkable complexity of the midbrain dopamine (DA) system, which comprises cells principally located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Neither homogenous nor serving a singular function, the midbrain DA system is instead composed of distinct cell populations that (1) receive different sets of inputs, (2) project to separate forebrain sites, and (3) are characterized by unique transcriptional and physiological signatures. To appreciate how these differences relate to circuit function, we first need to understand the anatomical connectivity of unique DA pathways and how this connectivity relates to DA-dependent motivated behavior. We and others have provided detailed maps of the input-output relationships of several subpopulations of midbrain DA cells and explored the roles of these different cell populations in directing behavioral output. In this study, we analyze VTA inputs and outputs as a high dimensional dataset (10 outputs, 22 inputs), deploying computational techniques well-suited to finding interpretable patterns in such data. In addition to reinforcing our previous conclusion that the connectivity in the VTA is dependent on spatial organization, our analysis also uncovered a set of inputs elevated onto each projection-defined VTADA cell type. For example, VTADA→NAcLat cells receive preferential innervation from inputs in the basal ganglia, while VTADA→Amygdala cells preferentially receive inputs from populations sending a distributed input across the VTA, which happen to be regions associated with the brain’s stress circuitry. In addition, VTADA→NAcMed cells receive ventromedially biased inputs including from the preoptic area, ventral pallidum, and laterodorsal tegmentum, while VTADA→mPFC cells are defined by dominant inputs from the habenula and dorsal raphe. We also go on to show that the biased input logic to the VTADA cells can be recapitulated using projection architecture in the ventral midbrain, reinforcing our finding that most input differences identified using rabies-based (RABV) circuit mapping reflect projection archetypes within the VTA.
Highlights
The ventral tegmental area (VTA) plays a central role in a variety of both adaptive and pathological motivated behaviors, principally through cells that release the neurotransmitter DA (Morales and Margolis, 2017)
We used a more sensitive method that enabled brain-wide analysis of the entire axonal arbor of each DA cell subpopulation to show that each cell population does send collaterals to other brain sites, but that the collateralization patterns are largely unique for each subpopulation, and the overall projection pattern of each population is largely distinct (Beier et al, 2015, 2019)
Given that we have collected whole-brain quantitative datasets of the inputs and outputs of VTADA→NAcMed, VTADA→NAcLat, VTADA→medial prefrontal cortex (mPFC), and VTADA→Amygdala cells, we wanted to perform a more indepth analysis to identify factors that differentiated the inputs and outputs of different DA cell types
Summary
The VTA plays a central role in a variety of both adaptive and pathological motivated behaviors, principally through cells that release the neurotransmitter DA (Morales and Margolis, 2017). We know that the VTA is comprised of heterogenous cell types: DA cells comprise roughly 50% of VTA cells in the rat, fewer than the >70% previously estimated (Margolis et al, 2006); another ∼40% of cells in the VTA are GABAergic Many of these GABAergic cells inhibit VTADA neurons, and their activation has the opposite effect of DA cell stimulation (Bouarab et al, 2019). Many NAc-projecting midbrain DA cells co-transmit glutamate, and some can synthesize and transmit GABA through a non-canonical pathway (Tritsch et al, 2012; Kim et al, 2015) This complexity makes it difficult to definitively disentangle the roles that various cells play in adaptive and maladaptive behaviors
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