Anatomic resolution of neurotransmitter-specific projections to the VTA reveals diversity of GABAergic inputs

Abstract

The ventral tegmental area (VTA) is important for reward processing and motivation. The anatomic organization of neurotransmitter-specific inputs to the VTA remains poorly resolved. In the present study, we mapped the major neurotransmitter projections to the VTA through cell-type-specific retrograde and anterograde tracing. We found that glutamatergic inputs arose from a variety of sources and displayed some connectivity biases toward specific VTA cell types. The sources of GABAergic projections were more widespread, displayed a high degree of differential innervation of subregions in the VTA and were largely biased toward synaptic contact with local GABA neurons. Inactivation of GABA release from the two major sources, locally derived versus distally derived, revealed distinct roles for these projections in behavioral regulation. Optogenetic manipulation of individual distal GABAergic inputs also revealed differential behavioral effects. These results demonstrate that GABAergic projections to the VTA are a major contributor to the regulation and diversification of the structure.

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Fig. 1: Retrograde mapping of neurotransmitter-specific inputs to the VTA.
Fig. 2: Glutamatergic and GABAergic innervation of VTA subregions.
Fig. 3: Connectivity of glutamatergic inputs to the VTA.
Fig. 4: Connectivity of GABAergic inputs to the VTA.
Fig. 5: Vgat knockout from local and distal sources differentially affects reward behaviors.
Fig. 6: Optogenetic activation and inhibition of specific distal GABAergic inputs differentially affect dopamine neuron activation and dopamine-dependent behaviors.

Data availability

Datasets supporting the findings in the present study are available from the corresponding author upon reasonable request. All viral vectors used in this manuscript are available from the corresponding author upon reasonable request.

Code availability

Code used for behavioral analysis is available from the corresponding author upon reasonable request.

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Acknowledgements

We thank members of the Zweifel lab for scientific discussion on the design and implementation of experiments. We also thank J. Allen for assistance in the production of AAV viral vectors. This work was funded by the US National Institutes of Health (grant nos. P50MH10642, R01-MH104450 and R01-DA044315 to L.S.Z).

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Authors

Contributions

M.E.S., A.S.C., J.M.R. and L.S.Z. designed the experiments, and collected and analyzed the data. M.E.S., A.S.C. and J.M.R. performed the viral injection surgery. M.E.S. and B.C. performed the behavioral analysis. M.E.S. performed the slice electrophysiology. M.E.S., A.S.C., B.C., J.M.R. and L.S.Z. performed the histology and cell counts. L.S.Z. generated CAV2-FLEX-ZsGreen. L.S.Z. and M.E.S purified all viral vectors. R.A. provided the ThFlpO mouse line. M.E.S. and L.S.Z. wrote the manuscript.

Corresponding author

Correspondence to Larry S. Zweifel.

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The authors declare no competing interests.

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Peer review information Nature Neuroscience thanks Alexxai Kravitz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Distribution of CAV2-FLEX-zsGreen retrogradely labeled neurons.

Cell counts of retrogradely labeled cells in indicated Cre lines across the rostral-caudal axis. Note that cells from different Cre lines in the same region are plotted on different axes. (Vgat n = 11 mice, Vglut1 n = 4; Vglut2 n = 10; Vglut3 n = 5, 5-HT n = 13, Chat n = 4.) Final panel depicts counts of infected cells in the VTA and neighboring substantia nigra (SN) region (Vgat n = 11 mice, Vglut2 n = 10 mice, One way ANOVA F(3,38)=112.3 p < 0.0001, Tukey’s Multiple Comparison ***p < 0.001). Error bars represent s.e.m.

Extended Data Fig. 2 Retrobead labeling of cholinergic neurons in the PPTg and LDTg.

(a) Representative image of CAV2-FLEX-zsGreen retrogradely labeled cells in the PPTg and LDTg of a Chat Cre mouse. (b) Total cells labeled in the PPTg and LDTg in different Cre driver lines (Vglut2 n = 10, Vgat n = 11, Chat n = 4; PPTg, One-way ANOVA, F(2,28)=7.740, P = 0.0023, *P < 0.05, **P < 0.01; LDTg, One-way ANOVA, F(2,28)=17.41, P < 0.0001, ***P < 0.01, ****P < 0.0001). (c, d) Representative images of Chat Cre:Tomato cells (red) and RetroBeads from the VTA (cyan) in the PPTg and LDTg, and quantification of cell counts and overlap across the rostral-caudal axis (n = 3/group). Error bars represent s.e.m. Scale bars = 50μm.

Extended Data Fig. 3 Retrobead and in situ labeling of VTA inputs.

(a–c) Representative images of indicated regions containing RetroBeads transported from the VTA and RNAscope in situ against Slc32a1 (Vgat) or Slc17a6 (Vglut2) and quantification of the percent of RetroBead labeled cells that colabel with in situ probes for BNST(a), LPO(b), and PAG(c). Arrows identify RetroBead-labeled Vglut-positive neurons, while arrowheads identify RetroBead-labeled Vgat-positive neurons (n = 3 mice, cells counted in 3–5 sections per region per mouse. One-way ANOVA, BNST: F(3,8)=2140, P < 0.0001, LPO: F(3,8)=441.3, P < 0.0001, PAG: F(3,8)=48.31, P < 0.0001, Tukey’s Multiple Comparisons *P < 0.05, **P < 0.01, ***P < 0.001). (d) Representative CAV2-FLEX-ZsGreen labeling in DR of ePet1-Cre mice (scale bar = 100 μm) and cell counts in DR for ePet1, Vglut2, Vglut3, and Vgat Cre mice (ePet n = 13, Vglut2 n = 10, Vglut3 n = 5, Vgat n = 11 mice; One-way ANOVA, F(3,35)=12.10, P = 0.0001, Tukey’s Multiple Comparisons *P < 0.05, **P < 0.01). (e, f) Representative images for DR RetroBeads transported from the VTA and RNAscope in situ against Slc32a1 (Vgat), Slc17a6 (Vglut2), or Slc17a8 (Vglut3), and quantification of the percent of RetroBead labeled cells that colabel with in situ probes. Arrows identify RetroBead-labeled Vglut-positive neurons, while arrowheads identify RetroBead-labeled Vgat-positive neurons (n = 3 mice, cells counted in 3–5 sections per mouse. One-way ANOVA, Vglut2: F(3,8)=161.9, P < 0.0001, Vglut3: F(3,8)=28.94, P = 0.0001, Tukey’s Multiple Comparisons *P < 0.05, **P < 0.01, ***P < 0.001). Error bars represent s.e.m. Scale bars = 50μm.

Extended Data Fig. 4 Density of inputs to the VTA.

(a) Integrated density (arbitrary units) of GFP fluoresence in the VTA following injection of synaptophysinGFP into the indicated region. Red bars: Vgat Cre, blue bars: Vglut 1 or 2 Cre (n = 3 mice/group for all regions except n = 4 mice for LS, NAc core, and BNST). (b) Correlation between average total integrated fluoresence density in the VTA and the average number of cells retrogradely labeled by CAV-FLEX-ZsGreen in each region. Black line = linear regression of all points excluding PFC (n = 3 mice/group for all regions except n = 4 mice for LS, NAc core, and BNST; Pearson r = 0.6570, Spearman two-tailed P = 0.0078). (c) Representative images of synaptophysinGFP injection into the dorsal striatum of a Vgat Cre mouse, and terminals in the SNr, adjacent to the VTA. Scale bars = 500 µm (left) and 200 µm (right). (d) Representative images of synaptophysinGFP injection into the PFC and terminals in the VTA-paranigral region and the adjacent pontine nucleus. Error bars represent s.e.m.

Extended Data Fig. 5 Connectivity of VTA inputs.

(a) Numbers of connected and not connected Th+ and Th- cells patched in the VTA with ChR2 expressed in the indicated region. Connected cells were those with a visible EPSC detectable across an average of 10 traces. Connected cells in the PFC include those cells that had no visible Li-EPSC until after high frequency stimulation. (b) Percent change in Li-EPSCs amplitude during the first five pulses of a 20 Hz train of light pulses activating PFC or PPTg inputs relative to the first pulse (Two-way RM ANOVA, F(4,60)=3.280, P = 0.0178, Bonferroni multiple comparisons *P < 0.05, ***P < 0.001; PFC n = 8 cells, PPTg n = 9 cells). (c) Percent change in amplitude of Li-EPSCs before and after high frequency stimulation of PFC or PPTg inputs relative to pre-stimulus train amplitude. PFC inputs were stimulated in the presence or absence of AP5 (100 µM), which remained in the bath for the duration of the experiment. (Two-way RM ANOVA, F(14,154)=2.40, P = 0.0046, Bonferroni multiple comparisons vs PPTg *P < 0.05, **P < 0.01; PFC n = 8 cells, PFC + AP5 = 7 cells, PPTg n = 9 cells). (d) Percent of baseline Li-EPSC amplitude following 3×1 s stimulus trains at the indicated frequencies (One-way RM ANOVA, F(3,8)=13.13, P < 0.0001, Tukey’s Multiple Comparisons ***P < 0.001 vs Pre, n = 9 cells). (e) Numbers of connected and not connected Vgat- and Vgat+ cells patched in the VTA with ChR2 expressed in the indicated region. Connected cells were those with a visible IPSC detectable across an average of 10 traces. Error bars represent s.e.m.

Extended Data Fig. 6 Local and distal Vgat knockout.

(a) Example images of RNAscope in situ labeling Cre and Slc32a1 (Vgat) in the VTA following injection of indicated viruses (red=Cre, cyan=Vgat), and quantification of Vgat+ cells/section (n = 3 mice/group, One way ANOVA F(2,6)=77.97 p < 0.0001, Tukey’s multiple comparisons *p < 0.05, ***p < 0.001, scale bar = 100 µm). (b) Locomotor activity (measured as infrared beam breaks) measured in 15 min bins (line) with s.e.m. (shading). (c) Locomotor activity summed over three nights (7 pm to 7 am) and two days (7 am to 7 pm) (Control n = 13 mice, VTA KO n = 11, Distal KO n = 15; Two-way RM ANOVA F(8,144)=6.33, p < 0.0001; Bonferroni multiple comparisons *p < 0.05, ****p < 0.0001). (d) Total head entries during each day of Pavlovian training (n = 23 mice/group control, 21 VTA KO, 27 distal KO; 2-way RM ANOVA F(12,402)=1.9, p = 0.032; Bonferroni multiple comparisons did not achieve significance). (e) Total lever presses during each day of FR1 instrumental conditioning (1 h session/day) (Control n = 21 mice, VTA KO n = 14 mice, Distal KO n = 27 mice; Two-way RM ANOVA F(4,118)=5.35, p = 0.0005; Bonferroni multiple comparisons **p < 0.01). (f) Lever presses on the preferred and non-preferred levers during 3 days of FR1 instrumental conditioning (Control n = 15 mice, VTA KO n = 11 mice, Distal KO n = 15 mice). (g) Percent of time spent freezing during delivery of the CS + or CS- tone during a baseline pretest or following two days of fear conditioning (n = 8 for Control and Distal KO, n = 7 for Local KO; Probe: 2-way RM ANOVA significant effect of CS F(1,20)=19.79 p = 0.0002, Bonferroni multiple comparisons *p < 0.05, **p < 0.01). Error bars represent s.e.m.

Extended Data Fig. 7 Fos induction in TH- cells and Jaws RTPA.

(a) Number of Fos+ TH- cells in each VTA subregion in Vgat-Cre mice expressing YFP or ChR2-YFP in the indicated brain region. (n = 3 mice/group, For IF: One-way ANOVA F(4,10)=9.207, p = 0.002; *p < 0.05, **p < 0.01 vs. YFP.) (b) Real-time place aversion assay comparing percent of time spent in the light paired chamber during the pretest (baseline) period and during the light stimulation period for Vgat-Cre mice expressing YFP or Jaws-GFP in the indicated regions (n = 8 for all groups except n = 10 for LH). Error bars represent s.e.m.

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Soden, M.E., Chung, A.S., Cuevas, B. et al. Anatomic resolution of neurotransmitter-specific projections to the VTA reveals diversity of GABAergic inputs. Nat Neurosci 23, 968–980 (2020). https://doi.org/10.1038/s41593-020-0657-z

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