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Serotonin-mediated inhibition of ventral hippocampus is required for sustained goal-directed behavior

Abstract

The ability to sustain goal-directed action is essential for success in many domains, but little is known about the corresponding neural substrates. Using fiber photometry to monitor population neural activity, we demonstrate that engagement in sustained food- or punishment-motivated behavior is associated with suppression of ventral but not dorsal hippocampal activity. Using optogenetic stimulation, we demonstrate that this suppression is required for goal-directed behavior, whereas optogenetic suppression of the ventral hippocampus (vHP) enhances the ability to sustain goal-directed behavior. Suppression of vHP during sustained goal-directed behavior was accompanied by increased activity in median but not dorsal raphe, implicating serotonergic signaling through Htr3a as a mechanism of vHP suppression during successful goal-directed behavior. Sustainment of goal-directed action may require suppression of vHP because of the structure’s well-documented role in behavioral inhibition.

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Data availability

The data and code that support the findings of this study are available from the corresponding author upon reasonable request.

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Journal peer review information: Nature Neuroscience thanks Attila Losonczy and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Acknowledgements

This work was supported by a Grant for Research Fellow of the Japan Society for the Promotion of Science (18J12572) to K.Y., a Grant-in-Aid for Scientific Research (B) from MEXT (15H03123) to K.F.T., a Grant-in-Aid for Scientific Research on Innovative Area ‘Willdynamics’ (17H06062) from the MEXT to K.F.T. and a Grant-in-Aid for Program for the Advancement of Next Generation Research Projects from Keio University to K.F.T. Htr5B-tTA mice (RBRC05445), Tph2-tTA mice (RBRC05846), tetO-YCnano50 mice (RBRC09550), tetO-ChR2(C128S) mice (RBRC05454) and tetO-ArchT mice (RBRC05842) were provided by RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan.

Author information

K.Y. conducted all experiments and analyses. M.M. and K.F.T. designed the experiments. K.Y., M.R.D. and K.F.T. wrote the paper.

Competing interests

The authors declare no competing interests.

Correspondence to Kenji F. Tanaka.

Integrated supplementary information

  1. Supplementary Figure 1 Optical fiber placements for fiber photometry.

    a,b, Histological reconstruction of optical fiber tip placements in the vCA1 (a) and the dCA1 (b). Red dots indicate fiber tips.

  2. Supplementary Figure 2 Compound Ca2+ activity of vCA1 neurons increased during exploration of the anxiogenic open-arm compartment in the elevated plus maze (EPM).

    a, An overview of the maze. b, Representative trace of the YC ratio in vCA1 during exploration of the EPM. Upper: periods when the mouse was located in open and closed arms are represented in magenta and green lines, respectively. c, Mean Ca2+ amplitude in vCA1 was significantly higher in open arms compared with closed arms of the EPM (n = 7 mice, 14 sessions, *2-sided paired t-test: t(6) = −2.80, P = 0.031). Bars represent the mean and lines represent the s.e.m.

  3. Supplementary Figure 3 Compound Ca2+ activity in vCA1 during a lever press active-avoidance task.

    a,c,e, Experimental schedule for the active-avoidance task. FS, foot shock start; SP, safety period start. b,d,f, Trace of averaged Ca2+ signals in which the duration between trigger points was normalized (n = 8 mice, 30 sessions). Red, significant increase or decrease (2-sided permutation test: P < 0.05). The shaded areas represent s.e.m.

  4. Supplementary Figure 4 Effect of step-function-type ChR2 on electrophysiological responses in the vCA1 pyramidal cell layer.

    a, Schematic illustration of electrophysiological recording in vCA1 of Htr5B-ChR2(C128S) mice with a custom-made optrode. Scale bar, 1 mm. b, The position of electrode was identified with DiI fluorescence (red). Green shows ChR2(C128S)-EYFP expression in vCA1. Scale bar, 1 mm. c, Electrode placements (red dots) in the vCA1. d, A representative time course of high-pass-filtered LFP (>600 Hz). Vertical blue and yellow lines indicate 1-s illumination of each light color. ChR2 was activated by blue light and inactivated by yellow light. The red dashed line indicates threshold of MUA detection. e, Representative mean traces of MUA wave forms during a baseline period (−5–0 s, gray line), during the activation period (0–5 s, blue line) and after the activation period (5–10 s, black dashed line). f, Time course of normalized MUA counts recorded from the pyramidal cell layer of vCA1 during optogenetic activation (n = 8 traces from 5 mice). The bin size was 100 ms. Shaded areas represent mean ± s.e.m. g, Mean normalized MUA counts during the activation period (0–5 s; control, n = 8 traces from 5 mice; activation, n = 8 traces from 5 mice). Yellow light illumination was used in place of blue light in the control condition. Data are presented as mean ± s.e.m. *P = 9.14 × 10−4; 2-sided paired t-test compared with the control sessions, t(7) = 5.11.

  5. Supplementary Figure 5 No behavioral effects of vCA1 optogenetic activation during TS-LP and ITI periods in the FR-5 task.

    a, Schematic illustration of optogenetic activation in bilateral vCA1 of Htr5B-ChR2(C128S) mice. We used same mice as in Fig. 2a–c. b, The timing of illumination in the FR-5 task. Optogenetic activation was performed during every TS-LP or ITI period. Blue and yellow illuminations were 1 s in duration. Yellow light illumination was used in place of blue light in the control condition. c,d, The effects of vCA1 activation during TS-LP (c, n = 7 mice, 23 sessions) and ITI (d, n = 7 mice, 20 sessions) periods on behavioral parameters in the FR-5 task. Optogenetic activation during TS-LP and ITI period did not affect behavioral parameters (c, accuracy: 2-sided paired t-test, t(6) = −1.16, P = 0.29; first active lever press latency: 2-sided Wilcoxon signed-rank test, z = −0.34, P = 0.74; time spent to complete the FR-5: 2-sided Wilcoxon signed-rank test, = −0.68, P = 0.49; time-out trial: 2-sided paired t-test, t(6) = −1.29, P = 0.24; d, accuracy: 2-sided paired t-test, t(6) = −0.32, P = 0.76; first active lever press latency: 2-sided Wilcoxon signed-rank test, z = 0.01, P = 0.99; time spent to complete the FR-5: 2-sided Wilcoxon signed-rank test, z = −0.51, P = 0.61; time-out trial: 2-sided paired t-test, t(6) = −0.34, P = 0.75). Bars represent the mean and lines represent the s.e.m. In box plots, the central mark indicates the median and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. Whiskers extend to the most extreme data points not considered outliers. e, Bilateral fiber placements in the vCA1. Red dots indicate fiber tips.

  6. Supplementary Figure 6 Effect of step-function-type ChR2 on electrophysiological responses in the dCA1 pyramidal cell layer.

    a, Schematic illustration of electrophysiological recording in dCA1 of Htr5B-ChR2(C128S) mice with a custom-made optrode. Scale bar, 1 mm. b, The position of electrode was identified with DiI fluorescence (red). Green shows ChR2(C128S)-EYFP expression in dCA1. Scale bar, 1 mm. c, Electrode placements (red dots) in the dCA1. d, A representative time course of high-pass-filtered LFP (>600 Hz). Vertical blue and yellow lines indicate 1-s illumination of each light color. ChR2 was activated by blue light and inactivated by yellow light. e, Representative mean traces of MUA wave forms during a baseline period (−5–0 s, gray line), during the activation period (0–5 s, blue line) and after the activation period (5–10 s, black dashed line). f, Time course of normalized MUA counts recorded from the pyramidal cell layer of dCA1 during optogenetic activation (n = 8 traces from 5 mice). The bin size was 100 ms. Shaded areas represent mean ± s.e.m. g, Mean normalized MUA counts during the activation period (0–5 s; control, n = 8 sessions from 5 mice; activation, n = 8 traces from 5 mice). Yellow light illumination was used in place of blue light in the control condition. Data are presented as mean ± s.e.m. *P = 2.15 × 10−9; 2-sided paired t-test compared with the control sessions, t(7) = 15.79

  7. Supplementary Figure 7 No behavioral effects of optogenetic activation of dCA1 in the FR-5 task.

    a, Schematic illustration of optogenetic activation in bilateral dCA1 of Htr5B-ChR2(C128S) mice. Scale bar, 1 mm. b, The timing of illumination in the FR-5 task. Blue and yellow illuminations were 1 s in duration. Yellow light illumination was used in place of blue light in the control condition. ce, The effects of dCA1 activation during TS-LP (c, n = 5 mice, 16 sessions), LP-RW (d, n = 5 mice, 16 sessions) and ITI (e, n = 5 mice, 15 sessions) periods on behavioral parameters in the FR-5 task. Optogenetic activation during TS-LP, LP-RW and ITI periods did not affect behavioral parameters (c, accuracy: 2-sided paired t-test, t(4) = −0.99, P = 0.38; first active lever press latency: 2-sided Wilcoxon signed-rank test, z = −0.67, P = 0.50; time spent to complete the FR-5: 2-sided Wilcoxon signed-rank test, z = −0.14, P = 0.89; time-out trial: 2-sided paired t-test, t(4) = 1.98, P = 0.12; d, accuracy: 2-sided paired t-test, t(4) = −0.69, P = 0.53; first active lever press latency: 2-sided Wilcoxon signed-rank test, z = −0.41, P = 0.67; time spent to complete the FR-5: 2-sided Wilcoxon signed-rank test, z = −0.67, P = 0.50; time-out trial: 2-sided paired t-test, t(4) = 0.69, P = 0.53; e, accuracy: 2-sided paired t-test, t(4) = −0.19, P = 0.86; first active lever press latency: 2-sided Wilcoxon signed-rank test, z = −0.41, P = 0.69; time spent to complete the FR-5: 2-sided Wilcoxon signed-rank test, z = −0.16, P = 0.89; time-out trial: 2-sided paired t-test, t(4) = 0.98, P = 0.38). Bars represent the mean and lines represent the s.e.m. In box plots, the central mark indicates the median and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. Whiskers extend to the most extreme data points not considered outliers. f, Bilateral fiber placements in the dCA1. Red dots indicate fiber tips.

  8. Supplementary Figure 8 No effect of vCA1 activation on locomotor activity.

    a, Stimulation paradigm. Blue and yellow light illumination trains were delivered (1-s illumination at 1-min interval, 5 pulses) to bilateral vCA1 of Htr5B-ChR2(C128S) mice. The order of the light train blocks was counterbalanced between mice. b, Representative position tracking during the blue and yellow light trains. c, Distance traveled during the 10 min of blue or yellow light illumination (n = 8 mice, 2-sided paired t-test, t(7) = 1.65, P = 0.14). We used same mice as in Fig. 2a–c. Bars represent the mean and lines represent the s.e.m.

  9. Supplementary Figure 9 Effect of ArchT on electrophysiological responses in the vCA1 pyramidal cell layer.

    a, Schematic illustration of electrophysiological recording in vCA1 of Htr5B-ArchT mice with a custom-made optorode. Scale bar, 1 mm. b, The position of electrode was identified with DiI fluorescence (red). Green shows ArchT-EGFP expression in vCA1. Scale bar, 1 mm. c, Electrode placements (red dots) in the vCA1. d, A representative time course of high-pass-filtered LFP (>600 Hz). Vertical yellow line indicates 5-s illumination. The red dashed line indicates threshold of MUA detection. e, Representative mean traces of MUA wave forms during a baseline period (−5–0 s, gray line) and after the activation period (5–10 s, black dash line). f, Time course of normalized MUA counts recorded from the pyramidal cell layer of vCA1 during optogenetic inhibition (n = 8 traces from 4 mice). The bin size was 100 ms. Shaded areas represent mean ± s.e.m. g, Mean normalized MUA counts during the inhibition period (0–5 s; control, n = 8 traces from 4 mice; inhibition, n = 8 traces from 4 mice). Blue light illumination instead of yellow light in the control condition. Data are presented as mean ± s.e.m. *P = 4.10 × 10−5; 2-sided paired t-test compared with the control sessions, t(7) = −6.27.

  10. Supplementary Figure 10 No behavioral effects of vCA1 optogenetic inhibition during the TS-LP and ITI periods in the FR-5 task.

    a, Schematic illustration of optogenetic inhibition in bilateral vCA1 of Htr5B-ArchT mice. We used the same mice as in Fig. 2d–f. Scale bar, 1 mm. b, The timing of illumination in the FR-5 task. An optogenetic inhibition was performed during every TS-LP or ITI period. Blue light illumination was used instead of yellow light in the control condition. c,d, The effects of the vCA1 inhibition during TS-LP (c, n = 7 mice, 20 sessions) and ITI (d, n = 7 mice, 16 sessions) periods on behavioral parameters in the FR-5 task. Optogenetic inhibition during TS-LP and ITI periods did not affect behavioral parameters (c, accuracy: 2-sided paired t-test, t(6) = −0.13, P = 0.89; first active lever press latency: 2-sided Wilcoxon signed-rank test, z = −1.01, P = 0.31; time spent to complete the FR-5: 2-sided Wilcoxon signed-rank test, z = −1.01, P = 0.31; time-out trial: 2-sided paired t-test, t(6) = −1.53, P = 0.18; d, accuracy: 2-sided paired t-test, t(6) = −0.39, P = 0.73; first active lever press latency: 2-sided Wilcoxon signed-rank test, z = −1.01, P = 0.31; time spent to complete the FR-5: 2-sided Wilcoxon signed-rank test, z = −0.17, P = 0.87; time-out trial: 2-sided paired t-test, t(6) = −0.12, P = 0.91). Bars represent the mean and lines represent the s.e.m. In box plots, the central mark indicates the median and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. Whiskers extend to the most extreme data points not considered outliers. e, Bilateral fiber placements in the vCA1. Red dots indicate fiber tips.

  11. Supplementary Figure 11 YCnano50 is specifically expressed in serotonin neurons in the transgenic mouse brain.

    ac, Upper panels: representative images of YCnano50 expression in DR nucleus and MR nucleus of Tph2-YC mice. Scale bar, 250 μm. Bottom panels: high-magnification view in the MR. Scale bar, 20 μm. a, Green represents GFP indirect fluorescence of YCnano50. b, Red represents tryptophan hydroxylase (TPH) staining. c, Merged image shows that YCnano50 was selectively expressed in serotonergic neurons; 97.8 ± 0.03% of TPH+ cells expressed YCnano50 (114 ± 1.4 of 117 ± 1.5 cells, n = 3 mice) and 98.5 ± 0.3% of YCnano50+ cells expressed TPH (113 ± 2.9 of 115 ± 2.8 cells, n = 3 mice).

  12. Supplementary Figure 12 Compound Ca2+ activity of dCA1 in FR-5 task with systemic granisetron administration.

    The effect of granisetron on Ca2+ activity in dCA1 in the FR-5 task (saline, n = 9 mice, 19 sessions; granisetron, n = 9 mice, 16 sessions). *P < 0.05 (2-sided permutation test, red line, significant increase or decrease points compared with saline treatment). Shaded areas represent s.e.m.

  13. Supplementary Figure 13 No behavioral effects of local Htr3a antagonist injection into dCA1 in FR-5 task.

    a, Htr3a messenger RNA expression in the dorsal hippocampus (n = 5 mice). Scale bar, 500 μm. b, Schematic illustration of injection sites into bilateral dCA1. Scale bar, 1 mm. c, Representative image of injection site. Asterisk indicates tip of injection canula. Scale bar, 1 mm. d, The effects of local injection of granisetron into dCA1 on behavioral parameters in the FR-5 task (saline, n = 7 mice, 19 sessions; granisetron, n = 7 mice, 20 sessions; 2-sided Wilcoxon signed-rank test, first active lever press latency: z = 0.51, P = 0.61; 2-sided Wilcoxon signed-rank test, time spent to complete the FR-5: z = −0.34, P = 0.74; 2-sided paired t-test, time-out trial: t(6) = −0.95, P = 0.38). Bars represent the mean and lines represent the s.e.m. In box plots, the central mark indicates the median and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. Whiskers extend to the most extreme data points not considered outliers.

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Fig. 1: Bulk Ca2+ monitoring reveals suppressed vCA1 activity during goal-directed lever pressing.
Fig. 2: Suppression of vCA1 activity is required for goal-directed lever pressing.
Fig. 3: Suppression of vCA1 activity promotes sustainment of goal-directed action.
Fig. 4: MR-5HT neurons are activated during lever pressing.
Fig. 5: Htr3a-mediated feedforward inhibition promotes ongoing lever pressing
Fig. 6: Htr3a-mediated feedforward inhibition in vCA1 is required for sustainment of goal-directed action.
Supplementary Figure 1: Optical fiber placements for fiber photometry.
Supplementary Figure 2: Compound Ca2+ activity of vCA1 neurons increased during exploration of the anxiogenic open-arm compartment in the elevated plus maze (EPM).
Supplementary Figure 3: Compound Ca2+ activity in vCA1 during a lever press active-avoidance task.
Supplementary Figure 4: Effect of step-function-type ChR2 on electrophysiological responses in the vCA1 pyramidal cell layer.
Supplementary Figure 5: No behavioral effects of vCA1 optogenetic activation during TS-LP and ITI periods in the FR-5 task.
Supplementary Figure 6: Effect of step-function-type ChR2 on electrophysiological responses in the dCA1 pyramidal cell layer.
Supplementary Figure 7: No behavioral effects of optogenetic activation of dCA1 in the FR-5 task.
Supplementary Figure 8: No effect of vCA1 activation on locomotor activity.
Supplementary Figure 9: Effect of ArchT on electrophysiological responses in the vCA1 pyramidal cell layer.
Supplementary Figure 10: No behavioral effects of vCA1 optogenetic inhibition during the TS-LP and ITI periods in the FR-5 task.
Supplementary Figure 11: YCnano50 is specifically expressed in serotonin neurons in the transgenic mouse brain.
Supplementary Figure 12: Compound Ca2+ activity of dCA1 in FR-5 task with systemic granisetron administration.
Supplementary Figure 13: No behavioral effects of local Htr3a antagonist injection into dCA1 in FR-5 task.