Topological Organization of Ventral Tegmental Area Connectivity Revealed by Viral-Genetic Dissection of Input-Output Relations

SUMMARY Viral-genetic tracing techniques have enabled mesoscale mapping of neuronal connectivity by teasing apart inputs to defined neuronal populations in regions with heterogeneous cell types. We previously observed input biases to output-defined ventral tegmental area dopamine (VTA-DA) neurons. Here, we further dissect connectivity in the VTA by defining input-output relations of neurochemically and output-defined neuronal populations. By expanding our analysis to include input patterns to subtypes of excitatory (vGluT2-expressing) or inhibitory (GAD2-expressing) populations, we find that the output site, rather than neurochemical phenotype, correlates with whole-brain inputs of each subpopulation. Lastly, we find that biases in input maps to different VTA neurons can be generated using publicly available whole-brain output mapping datasets. Our comprehensive dataset and detailed spatial analysis suggest that connection specificity in the VTA is largely a function of the spatial location of the cells within the VTA.

[1]  Karl Deisseroth,et al.  Rabies screen reveals GPe control of cocaine-triggered plasticity , 2017, Nature.

[2]  Liqun Luo,et al.  Viral-genetic tracing of the input–output organization of a central norepinephrine circuit , 2015, Nature.

[3]  R. Yuste,et al.  The Brain Activity Map Project and the Challenge of Functional Connectomics , 2012, Neuron.

[4]  Anatol C. Kreitzer,et al.  Differential Innervation of Direct- and Indirect-Pathway Striatal Projection Neurons , 2013, Neuron.

[5]  L. Schmued,et al.  Fluoro-gold: a new fluorescent retrograde axonal tracer with numerous unique properties , 1986, Brain Research.

[6]  B. Sabatini,et al.  Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis , 2014, eLife.

[7]  H. Fields,et al.  Ventral Tegmental Area Glutamate Neurons: Electrophysiological Properties and Projections , 2012, The Journal of Neuroscience.

[8]  S. Lammel,et al.  Unique Properties of Mesoprefrontal Neurons within a Dual Mesocorticolimbic Dopamine System , 2008, Neuron.

[9]  G. Silberberg,et al.  A Whole-Brain Atlas of Inputs to Serotonergic Neurons of the Dorsal and Median Raphe Nuclei , 2014, Neuron.

[10]  Liqun Luo,et al.  Connectivity of Mouse Somatosensory and Prefrontal Cortex Examined with Trans-synaptic Tracing , 2015, Nature Neuroscience.

[11]  David J. Barker,et al.  VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons , 2016, Nature Neuroscience.

[12]  K. Deisseroth,et al.  Input-specific control of reward and aversion in the ventral tegmental area , 2012, Nature.

[13]  Ian R. Wickersham,et al.  Monosynaptic Restriction of Transsynaptic Tracing from Single, Genetically Targeted Neurons , 2007, Neuron.

[14]  K. Kristensson,et al.  Retrograde axonal transport of protein. , 1971, Brain research.

[15]  Alexander B. Johnson,et al.  Afferent Inputs to Neurotransmitter-Defined Cell Types in the Ventral Tegmental Area. , 2016, Cell reports.

[16]  M. King,et al.  Biocytin: a versatile anterograde neuroanatomical tract-tracing alternative , 1989, Brain Research.

[17]  Liqun Luo,et al.  Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping , 2015, Cell.

[18]  Michihiro Kawano,et al.  Particular subpopulations of midbrain and hypothalamic dopamine neurons express vesicular glutamate transporter 2 in the rat brain , 2006, The Journal of comparative neurology.

[19]  Sachie K. Ogawa,et al.  Whole-Brain Mapping of Direct Inputs to Midbrain Dopamine Neurons , 2012, Neuron.

[20]  B. Hoffer,et al.  Characterization of a mouse strain expressing Cre recombinase from the 3′ untranslated region of the dopamine transporter locus , 2006, Genesis.

[21]  Allan R. Jones,et al.  A mesoscale connectome of the mouse brain , 2014, Nature.

[22]  Hidetoshi Shimodaira,et al.  Pvclust: an R package for assessing the uncertainty in hierarchical clustering , 2006, Bioinform..

[23]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[24]  A. Reiner,et al.  Biotinylated dextran amine as an anterograde tracer for single- and double-labeling studies , 1992, Journal of Neuroscience Methods.

[25]  Talia N. Lerner,et al.  Intact-Brain Analyses Reveal Distinct Information Carried by SNc Dopamine Subcircuits , 2015, Cell.

[26]  Liqun Luo,et al.  Monosynaptic Circuit Tracing with Glycoprotein-Deleted Rabies Viruses , 2015, The Journal of Neuroscience.

[27]  Ling Fu,et al.  Whole-Brain Mapping of Inputs to Projection Neurons and Cholinergic Interneurons in the Dorsal Striatum , 2015, PloS one.

[28]  E. Callaway,et al.  Previously Published Works Uc Irvine Title: Cell-type-specific Circuit Connectivity of Hippocampal Ca1 Revealed through Cre-dependent Rabies Tracing Cell-type Specific Circuit Connectivity of Hippocampal Ca1 Revealed through Cre-dependent Rabies Tracing Nih Public Access Author Manuscript , 2022 .

[29]  Jordan M. Sorokin,et al.  Brain-Wide Maps of Synaptic Input to Cortical Interneurons , 2016, The Journal of Neuroscience.

[30]  Liqun Luo,et al.  Presynaptic Partners of Dorsal Raphe Serotonergic and GABAergic Neurons , 2014, Neuron.

[31]  Sachie K. Ogawa,et al.  Dopamine neurons projecting to the posterior striatum form an anatomically distinct subclass , 2015, eLife.

[32]  D. H. Root,et al.  Single rodent mesohabenular axons release glutamate and GABA , 2014, Nature Neuroscience.

[33]  S. Nelson,et al.  A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex , 2011, Neuron.

[34]  J. Bolam,et al.  Structural correlates of heterogeneous in vivo activity of midbrain dopaminergic neurons , 2012, Nature Neuroscience.

[35]  Y. Agid,et al.  Labeled wheat germ agglutinin (WGA) as a new, highly sensitive retrograde tracer in the rat brain hippocampal system , 1978, Brain Research.

[36]  N. Uchida,et al.  Dopamine neurons projecting to the posterior striatum reinforce avoidance of threatening stimuli , 2018, Nature Neuroscience.

[37]  C. Gerfen,et al.  An anterograde neuroanatomical tracing method that shows the detailed morphology of neurons, their axons and terminals: Immunohistochemical localization of an axonally transported plant lectin,Phaseolus vulgaris leucoagglutinin (PHA-L) , 1984, Brain Research.

[38]  Linh Vong,et al.  Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons , 2011, Neuron.