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Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence

Abstract

We found that optogenetic burst stimulation of hippocampal dopaminergic fibers from midbrain neurons in mice exploring novel environments enhanced the reactivation of pyramidal cell assemblies during subsequent sleep/rest. When applied during spatial learning of new goal locations, dopaminergic photostimulation improved the later recall of neural representations of space and stabilized memory performance. These findings reveal that midbrain dopaminergic neurons promote hippocampal network dynamics associated with memory persistence.

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Figure 1: Midbrain dopaminergic neurons increase their discharge in novel environments.
Figure 2: Burst-mode photostimulation of dopaminergic neurons during exploration enhances reactivation of new hippocampal assemblies.
Figure 3: Burst-mode photostimulation of dCA1 dopaminergic axons during spatial learning on the crossword maze stabilizes new hippocampal maps and memory of new goal locations.

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Acknowledgements

We thank J. Csicsvari, P. Somogyi and P.J. Magill for their comments on a previous version of the manuscript, C. Etienne for her assistance with axon reconstruction, S. Cuell for his initial contribution with the crossword maze, S. Threfell and L. Norman for their assistance with the DAT-IRES-Cre mice, and K. Deisseroth (Stanford University) for sharing the DIO-ChR2-eYFP and DIO-eYFP constructs. C.G.M. is funded by a Medical Research Council Doctoral Training Award. This work was supported by the Medical Research Council UK (award MC_UU_12020/7) and a Mid-Career Researchers Equipment Grant from the Medical Research Foundation (award C0443) to D.D.

Author information

Authors and Affiliations

Authors

Contributions

C.G.M., Á.T.-C. and D.D. designed the experiments. C.G.M., N.C.-U. and S.T. carried out the experiments. C.G.M. and D.D. analyzed the data and wrote the manuscript. Á.T.-C. and S.T. edited the manuscript. D.D. conceived and supervised the project. All of the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Colin G McNamara or David Dupret.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Examples of two VTA dopaminergic neurons increasing their firing rate in response to spatial novelty.

(a, e) Raster plots showing the spike times of the two neurons recorded from a DATVTA::ChR2-eYFP mouse implanted with tetrodes and an optic fiber in the VTA. The mouse explored a familiar and a novel open field for 30 minutes each environment in the absence of photostimulation (VTA-OFF condition). No food reward was provided in these sessions. Ticks represent spike times (30 seconds exploration per row). Note the strong increase in rate during exploration of the novel environment associated with an increased ratio of bursts of action potentials (defined as at least two spikes within 50 ms; see Methods; gray ticks: single spikes; black ticks: burst spikes). (b, f) Spatial distribution of the individual burst action potentials (black dots) discharged by neurons in (a) and (e) superimposed on the animal’s path (gray traces) during the respective exploration sessions. (c, g) Cross-correlograms of the spike trains of these two neurons to laser pulse onsets subsequently recorded in an additional session while 473 nm light pulses (10 ms pulse) were delivered in the VTA (VTA-ON condition). The onset of light pulses was used as a reference to calculate the probability of spike discharge (1 ms bins). Note the presence of a sharp peak at short latency (< 3 ms) that optogenetically identified these neurons as dopaminergic. (d, h) Spike waveforms (gray traces) and superimposed mean waveform (black trace) for these two neurons from VTA-OFF exploration (left) and detected within 3 ms of laser pulse onset in subsequent VTA-ON exploration (right). All four channels of the tetrode are shown (one per row). Note that for each neuron the spike waveforms locked to the laser pulses were similar to those from the earlier exploration.

Supplementary Figure 2 Photostimulation of dCA1 dopaminergic axons in DATVTA::ChR2-eYFP mice did not alter the waking firing activity and cross-environment remapping of hippocampal pyramidal cells.

(a) Hippocampal representations, as quantified by pyramidal cell co-firing associations (waking theta co-firing similarity), reorganized from the familiar to the novel environments. Waking theta co-firing similarity was measured by correlating the tendency of pyramidal cell pairs to co-fire during cycles of theta-band oscillations in a given exploratory period with such a tendency in another exploratory period. The extent of the novelty-associated hippocampal remapping was unaltered by photostimulation (Z = 0.46, P = 0.65 for Familiar versus Novel OFF compared to Familiar versus Novel ON). The hippocampal co-firing associations within environments (first versus second half of exploration) were calculated as a reference (all P < 0.0001 for each within environment value compared to each across environment value). (b) Example of spatial rate maps for a set of dCA1 pyramidal cells from the same recording day followed across different environments and conditions. The peak firing rate (Hz) for each cell is shown. Note the changes in the spatially-selective discharge (i.e., firing field) and/or peak firing rate between environments. (c) The distribution of spatial tuning measures was unaltered by photostimulation (sparsity: P = 0.15, coherence: P = 0.80, Kolmogorov-Smirnov test, Novel OFF versus Novel ON). (d) The mean firing rate of dCA1 pyramidal cells was similar across conditions (F2, 1666 = 0.48, P = 0.62, ANOVA).

Supplementary Figure 3 Exploratory behavior in the open field environments and pyramidal cell population activity in the theta bins used to calculate waking co-firing.

(a) Example instantaneous speed plots (820 ms bins) of a DATVTA::ChR2-eYFP mouse implanted with tetrodes and optic fiber in the dCA1 showing similar movement speed across exploration in the familiar open field and two novel open fields (without photostimulation and with dCA1-ON photostimulation). (b,c) The mean speed and mean distance traveled across animals during exploration in the Familiar, Novel and Novel VTA/dCA1-ON conditions were not different (means ± s.e.m.; speed: F3, 143 = 0.44, P = 0.72; distance: F3, 143 = 0.58, P = 0.62; ANOVA). (d) Distribution of the instantaneous speed (means ± s.e.m.) in the theta bins used to measure pyramidal cell co-firing in the Familiar, Novel and Novel VTA/dCA1-ON conditions. The distributions are similar and show that theta/waking cofiring measure was confined to epochs of active exploration. (e) Distributions of the preferred theta phase for dCA1 pyramidal cells. (f) Average firing probability theta-phase histograms of dCA1 pyramidal cells (means ± s.e.m.). Dashed lines represent ideal theta waves. (g) Average autocorrelation histograms of dCA1 pyramidal cells (10 ms bins). These data indicate that the waking firing-phase coupling of pyramidal cells to theta oscillations was similar across conditions and that the theta co-firing measure was confined to epochs of theta-paced hippocampal activity.

Supplementary Figure 4 Behavioral and electrophysiological estimates of arousal states were similar in the rest sessions preceding and following exploration.

(a) Example instantaneous speed plots (820 ms bins) of a DATVTA::ChR2-eYFP mouse implanted with tetrodes and optic fiber in the dCA1 during rest in the sleep box before open field explorations, after exploration of a novel open field and after exploration of a novel open field with dCA1-ON photostimulation. Note that the animal spent most of its time immobile (instantaneous speed < 2cm/s; dashed line) in all conditions. (b) The distributions of the instantaneous speed (means ± s.e.m.) across animals. The proportion of time spent immobile (left of the 2 cm/s dashed line) was similar during the sleep/immobility rest sessions before exploration and after exploration across conditions. (c) The number of SWRs per second was similar in rest before exploration and after exploration across conditions (means ± s.e.m.; F3, 143 = 0.24, P = 0.86, ANOVA). (d) The theta/delta band power ratio (means ± s.e.m.; F3, 143 = 2.10, P = 0.10, ANOVA; see Methods) was not significantly different in rest before exploration and after exploration across conditions. Note that the slight non-significant decrease of theta/delta ratio during rest after the VTA-ON condition was not observed in the dCA1-ON condition and thus cannot account for the photostimulation-enhanced reactivation.

Supplementary Figure 5 Sharp-wave/ripple firing responses of dCA1 pyramidal cells during rest.

(a) Top trace, wide band signal. Bottom trace, 135–250 Hz band pass filtered signal highlighting ripple frequency events. Raster plots, spike times of simultaneously recorded dCA1 pyramidal cells (one cell per row). Note the firing synchrony of pyramidal cells during ripple events. (b) Mean SWR-triggered waveforms from three separate tetrodes in a DATVTA::ChR2-eYFP mouse during rest before and after dCA1-ON photostimulation. Traces obtained from the same tetrode (one channel displayed) are superimposed. (c) SWR-triggered firing rate histograms (means ± s.e.m.) of dCA1 pyramidal cells from all DATVTA::ChR2-eYFP mice during rest sessions preceding and following exploratory sessions with or without photostimulation. SWR firing rate histograms were calculated using 20 ms bins in reference to the SWR peak (i.e., peak of ripple-band power). The mean peak SWR firing rate was unaltered by photostimulation (F2, 2892 = 0.86, P = 0.42, ANOVA). (d) The proportion of SWR-active pyramidal cells (i.e., for each SWR the proportion of cells discharging at least one spike) in rest sessions preceding and following exploratory sessions with or without photostimulation was similar (means ± s.e.m.; F2, 129 = 0.78, P = 0.46, ANOVA).

Supplementary Figure 6 Spatial learning on the crossword maze requires a functional hippocampal network.

(a) Isometric projection of the crossword maze showing an example configuration of barriers and reward location. On any given recording day only two of the start boxes were used. The shortest paths from the in use start boxes to the reward location are shown in red and green. (b) In order to disrupt locally the activity of dCA1 hippocampal pyramidal cells, the Cre-inducible viral construct coding for Channelrhodopsin-2 (ChR2-eYFP) was injected into the dCA1 of Parvalbumin PV-IRES-Cre+/+ mice. To control and monitor dCA1 pyramidal cell activity these PVdCA1::ChR2-eYFP mice were implanted in dCA1 for combined in vivo multichannel recordings with photostimulation. (c) Low magnification image showing the expression of ChR2-eYFP targeted to the dCA1 of a PVdCA1::ChR2-eYFP mouse. (d) High magnification confocal image of the dCA1 showing expression of ChR2-eYFP in PV-expressing interneurons (flattened 5 µm z-stack). Cell nuclei stained with DAPI. (e) Raster plot showing the spike times of one dCA1 interneuron recorded in a PVdCA1::ChR2-eYFP mouse in relation to the onset of 10 ms light pulses in the dCA1-ON condition. Note the increased spiking activity with short latency (< 3 ms) induced by the laser and confined to the duration of the stimulation pulse. (f) Photostimulation of dCA1 (dCA1-ON) in these PVdCA1::ChR2-eYFP mice led to a decrease in firing rate of dCA1 pyramidal cells (n = 224; t222 = 5.01, P = 1.1x10-6, t-test). (g) Left, learning performance, as measured by distance traveled to reward, was impaired in days when the PVdCA1::ChR2-eYFP mice received photostimulation (see Methods; group x trial interaction, F19, 354 = 2.08, P = 0.0054, ANOVA). Right, photostimulation applied during learning was associated with subsequent degraded performance during the probe test (t19 = 9.81, P = 7.1x10-9, t-test).

Supplementary Figure 7 Examples of dCA1 hippocampal maps recorded from a DATVTA::ChR2-eYFP mouse on the crossword maze.

Shown are the spatial rate maps for a set of dCA1 pyramidal cells from the same recording day followed across the Pre-learning, Learning and Probe stages. The peak firing rate (Hz) for each map is shown. The maze configuration for that day is depicted in the top left. Note that most cells established new firing fields in learning compared to pre-learning and many but not all reinstated the newly-established maps during the probe test.

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McNamara, C., Tejero-Cantero, Á., Trouche, S. et al. Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence. Nat Neurosci 17, 1658–1660 (2014). https://doi.org/10.1038/nn.3843

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