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. 2024 May 21;15(1):4100.
doi: 10.1038/s41467-024-47481-4.

Ventral tegmental area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning

Fares J P Sayegh  1 , Lionel Mouledous  2 , Catherine Macri  2 , Juliana Pi Macedo  2 , Camille Lejards  2 , Claire Rampon  2 , Laure Verret  2 , Lionel Dahan  3
Affiliations

Ventral tegmental area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning

Fares J P Sayegh et al. Nat Commun. .

Abstract

In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning.

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Conflict of interest statement

All authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Specific transfection of the VTA-hippocampus dopamine pathway.
a Transfected coronal sections by unilateral injection for electrophysiology recording stained for Tyrosine Hydroxylase (TH) and YFP. b quantification for unilaterally injected mice. Transfection and specificity (transfection, specificity) were (91.5 ± 2%, 83.4 ± 4%, n = 6 mice) for YFP and (70 ± 2%, 91.5 ± 2%, n = 57 mice) for ChETA injected mice. c Transfected coronal sections by bilateral injection for behavioral experiments stained for TH and YFP. d. Quantification for transfection and specificity (transfection, specificity) were (83.9 ± 2%, 94.7 ± 1%, n = 27 mice) for YFP, (65.9 ± 2%, 93.3 ± 2%, n = 34 mice) for ChETA and (70.8 ± 5%, 99.4%, n = 11 mice) for eNpHR3.0 bilaterally injected mice. For panels a & c, Dashed line represents midline; rectangle represents sampled area captured at x20 magnification. fr, fasciculus retroflexus; SNc, Substantia Nigra pars compacta; VTA, Ventral Tegmental Area. Scale bars, 100 µm. For panels b and d Quantification of Transfection (green) and Specificity (red) are represented as the number of double-stained cells divided by TH+ cells and YFP+ cells, respectively. In the box plots representations, whiskers show the minimum and maximum values, bounds of the box the 1st and 3rd quartile and center line indicate the median. e Representative image of confocal microscopy examination of coronal sections of the dorsal hippocampus of mice injected bilaterally with the YFP virus (n = 27) which revealed a sparse labeling in the CA1 region that was not restricted to a specific layer. Dopaminergic fibers originating from the VTA and expressing YFP are shown in green. TH containing fibers are in red, while cell nuclei labeled with Hoechst are in blue. SO, stratum oriens; SP, stratum pyramidale; SR, stratum radiatum. Scale bar, 20 µm. Source data are provided as a Source Data file.
Fig. 2
Fig. 2. Midbrain dopamine triggers a long-lasting, D1/5R-dependent, increase of synaptic transmission in CA1, which occludes TBS-triggered LTP in DAT::Cre mice.
a a schema representing the procedure. DAT::Cre mice were injected with either floxed YFP-coding vectors or ChETA and YFP-coding vectors in their Ventral Tegmental Area (VTA). Three weeks later, we performed anesthetized in vivo electrophysiology recording of CA1 response to Schaffer collaterals electric stimulation in the ventral hippocampal commissure (vHCom.) every 30 seconds. Optic stimulation was delivered through the glass recording pipette following paired or unpaired protocols (lightning represents electrical stimulations and blue rectangle represents one light burst of 4 ms pulses @50 Hz during 400 ms of laser stimulation). Illustration include an image created with BioRender.com. b Effect of 50 coupling optical stimulations and electrical stimulations of Schaffer Collaterals (blue shaded part of the timeline). When stimulations were simultaneously coupled in ChETA injected mice, an increase in fEPSP slopes was observed (Dark Blue, ChETA paired, t-test vs 100%: p = 0.0021, n = 12 mice). No such increase was observed in control vector injected mice (Orange, YFP paired, t-test vs 100%: p = 0.38, n = 5 mice) nor when electrical and optogenetic stimulations were separated by 15 seconds (Light Blue, ChETA Unpaired, t-test vs 100%: p = 0.70, n = 6 mice). The increase in the ChETA paired group is statistically different from other groups (Kruskal Wallis: p = 0.01, Mann-Whitney post hoc tests: p = 0.79 for ChETA unpaired vs. YFP, p = 0.0097 for ChETA paired vs. ChETA unpaired and p = 0.02 for ChETA paired vs. YFP). c SCH23390 injected 20 minutes prior to the coupling (dashed line); EPSP slope increase was no longer observed in the SCH23390 group (red, t-test vs 100%: p = 0.72, n = 5 mice) while significant in the control group (dark blue, t-test vs 100%: p = 0.015, n = 5 mice). The difference between the 2 groups is statistically significant (Mann-Whithney test: p = 0.0079). d Classic form of LTP was induced 90 minutes after the end of couplings using TBS. DA-LTP group (in blue) showed a rapid degradation of TBS induced LTP. Both groups show a significant LTP induced by TBS (t-test vs 100%: p = 0.0003 for NoDA-LTP (in grey) and p = 0.0032 for DA-LTP, n = 7 mice for each group). The difference between the 2 groups is statistically significant (Mann-Whithney test: p = 0.026). e DA-LTP was induced when optical stimulations were delivered 0 to 200 ms after the electrical stimulation (dark blue, t-test vs 100%: p = 0.048, n = 8 mice), but not when it was were delivered 200 to 0 ms before (dark green) nor 200 to 400 ms after (dark red) the electrical stimulation (t-test vs 100%: p = 0.29 and 0.79 and n = 5 and 6, respectively). The increase in the 0; + 200 ms group is statistically different from other groups (Kruskal Wallis: p: 0.0054, Mann-Whitney post hoc tests: p = 0.0016 for −200;0 vs. 0; + 200, p = 0.043 for 0; + 200 vs. +200; + 400 and p = 0.99 for −200;0 vs. +200; + 400). f 12 pairings of optical stimulations (0 to 200 ms in relation to SC electrical stimulations) were sufficient to induce DA-LTP (dark blue, t-test vs 100%: p = 0.044, n = 5 mice), but not 6 (light green, t-test vs 100%: p = 0.21, n = 5 mice). The difference between the 2 groups is statistically significant (Mann-Whithney test: p = 0.0079). For panels b to f, timelines of each group on the left, mean changes quantified by averaging the last 25 minutes of the recording for each mouse on the right. Data are presented as mean values +/- SEM. Sample size (n) indicates the number of mice included for each experimental group. * p < 0.05 Mann-Whitney, ** p < 0.01 Mann-Whitney (after significant Kruskal Wallis). # p < 0.05 t-test vs. 100%. ## p < 0.01 t-test vs. 100%. ### p < 0.001 t-test vs 100%. All statistical tests were two-sided. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Midbrain dopamine in the hippocampus contributes in learning a new context in DAT::Cre mice.
a Schema illustrating the behavioral procedure. DAT::Cre mice were used in a context pre-exposure facilitation effect paradigm. First, the effect of different pre-exposure durations was studied, and then the effect of optogenetic manipulation of midbrain dopamine afferents to the hippocampus was evaluated. On day 2, mice received an immediate shock, and on day 3 freezing was tested in the conditioned context and in an alternative one. b Preexposure had a significant effect on freezing to the conditioned context (ANOVA, p = 0.0008) in DAT::Cre mice. Animals pre-exposed for 30 seconds (n = 9 mice) did not freeze more than control non-pre-exposed group (n = 8 mice, Tukey post hoc test: p = 0,78). 2 min pre-exposure was sufficient to induce a significant increase (n = 9 mice, Tukey post hoc test: p = .0024) reaching levels comparable to those seen in the group with 8 min pre-exposure (n = 8 mice, Tukey post hoc test: p = 0.0041). c Mice were pre-exposed for 30 seconds on day one during which they received 90 bursts of blue light bilaterally in the dorsal hippocampus. Freezing in the conditioned context increased in the ChETA-injected mice (blue, n = 19 mice) compared the YFP-injected mice (orange, n = 16 mice, t-test: p = 0.0016). Freezing in the alternative context was considerably lower than in the conditioned context and was not significantly changed due to dopaminergic activation during pre-exposure (t-test: p = 0.23). d Mice were pre-exposed for 2 minutes on day one during which they received continuous green light. Freezing in the conditioned context levels observed during the test on day 3 were lower for eNpHR3.0 injected mice (green, n = 11 mice) in comparison to mice with control injection (orange, n = 7 mice, t-test: p = 0.0021). Freezing in the alternative context was considerably lower than in the conditioned context and was not significantly changed due to dopaminergic inhibition during pre-exposure (t-test: p = 0.60). Data are presented as mean values +/- SEM. Sample size (n) indicates the number of mice included for each experimental group. ## p < 0.01 Multiple comparisons following one-way ANOVA (p < 0.001). ** p < 0.01 t-test. All statistical tests were two-sided. Illustrations include an image created with BioRender.com. Source data are provided as a Source Data file.
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