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.

No abstract

Objective: Deep brain stimulation (DBS) has been used as a treatment of last resort for treatmentresistant depression (TRD) for more than a decade. Many DBS targets have been proposed and tested clinically, but the underlying circuit mechanisms remain unclear. Uncovering white matter tracts (WMT) activated by DBS targets may provide crucial information about the circuit substrates mediating DBS efficacy in ameliorating TRD. Methods: We performed probabilistic tractography using diffusion magnetic resonance imaging datas from 100 healthy volunteers in Human Connectome Project datasets to analyze the structural connectivity patterns of stimulation targeting currently-used DBS target for TRD. We generated mean and binary fiber distribution maps and calculated the numbers of WMT streamlines in the dataset. Results: Probabilistic tracking results revealed that activation of distinct DBS targets demonstrated modulation of overlapping but considerably distinct pathways. DBS targets were categorized into 4 groups: Cortical, Striatal, Thalamic, and Medial Forebrain Bundle according to their main modulated WMT and brain areas. Our data also revealed that Brodmann area 10 and amygdala are hub structures that are associated with all DBS targets. Conclusions: Our results together suggest that the distinct mechanism of DBS targets implies individualized target selection and formulation in the future of DBS treatment for TRD. The modulation of Brodmann area 10 and amygdala may be critical for the efficacy of DBS-mediated treatment of TRD.

While midbrain dopamine (DA) neuronal circuits are central to motivated behaviors, much remains unknown about our knowledge of how these circuits are modified over time by experience to facilitate selective aspects of experience-dependent plasticity. Most studies of the DA system in drug addiction focus on the role of the mesolimbic DA pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) in facilitating drug-associated reward. In contrast, less is known about how midbrain DA cells and associated circuits contribute to negative affective states including anxiety that emerge during protracted withdrawal from drug administration. Here, we demonstrate the selective role of a midbrain DA projection to the amygdala (VTADA→Amygdala) for anxiety that develops during protracted withdrawal from cocaine administration but does not participate in cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach revealed a persistent elevation in spontaneous and task-related activity of GABAergic cells from the bed nucleus of the stria terminals (BNST) and downstream VTADA→Amygdala cells that could be detected even after a single cocaine exposure. Activity in BNSTGABA cells was related to cocaine-induced anxiety but not reward or sensitization, and silencing the projection from these cells to the midbrain was sufficient to prevent the development of anxiety during protracted withdrawal following cocaine administration. We observed that VTADA→Amygdala cells, but not other midbrain DA cells, were strongly activated after a challenge exposure to cocaine, and found that activity in these cells was necessary for the expression of reinstatement of cocaine place preference. Lastly, the importance of activity in VTADA→Amygdala cells extends beyond cocaine, as these cells mediate the development of anxiety states triggered by morphine and a predator odor. Our results provide an exemplar for how to identify key circuit substrates that contribute to behavioral adaptations and reveal a critical role for BNSTGABA→VTADA→Amygdala pathway in anxiety states induced by drugs of abuse or natural experiences as well as cocaine-primed reinstatement of conditioned place preference.

Exposure to drugs of abuse causes long-lasting changes in connectivity to ventral tegmental area dopamine cells that contribute to drug-induced behavioral adaptations. However, it is not known which inputs are altered, largely due to technological limitations of previous methods. Here we used a rabies virus-based mapping strategy to quantify rabies-labeled inputs to ventral tegmental area cells after a single exposure to one of a variety of abused drugs, such as cocaine, amphetamine, methamphetamine, morphine, and nicotine, and compared the relative global input labeling across conditions using dimensionality reduction approaches. We observed that all tested drugs of abuse elicited input changes onto dopamine cells, in particular those projecting to the lateral shell of the nucleus accumbens and amygdala, and that these changes were common to all drugs tested. Interestingly, we also noticed that animals anesthetized with a ketamine/xylazine mixture exhibit a different brain-wide input pattern from those anesthetized with isoflurane, indicating that the method of anesthesia can influence rabies input labeling by inducing long-lasting changes in circuit connectivity. In addition, many input changes were common between animals anesthetized with ketamine/xylazine and those anesthetized with isoflurane but also given a single dose of a drug of abuse, suggesting that the ketamine/xylazine mixture can induce these long-lasting input changes. We found that many of the brain regions that exhibited changes in rabies input labeling in drug- vs. saline-treated mice were preferentially interconnected, and that select communities of brain regions showed similar changes for both drugs of abuse and ketamine/xylazine anesthesia. Lastly, the basal expression patterns of several gene classes were highly correlated with the extent of both addictive drug- or ketamine/xylazine-induced input changes, especially calcium channels. These results indicate that the expression of calcium channels is related to whether these inputs to dopamine cells are altered by drug exposure. Furthermore, ketamine/xylazine anesthesia induces a similar but different set of long-lasting input changes onto midbrain dopamine cells, indicating that caution should be taken when using ketamine/xylazine-based anesthesia in rodents when assessing motivated behaviors.