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5-HT modulation of a medial septal circuit tunes social memory stability

Abstract

Social memory—the ability to recognize and remember familiar conspecifics—is critical for the survival of an animal in its social group1,2. The dorsal CA2 (dCA2)3,4,5 and ventral CA1 (vCA1)6 subregions of the hippocampus, and their projection targets6,7, have important roles in social memory. However, the relevant extrahippocampal input regions remain poorly defined. Here we identify the medial septum (MS) as a dCA2 input region that is critical for social memory and reveal that modulation of the MS by serotonin (5-HT) bidirectionally controls social memory formation, thereby affecting memory stability. Novel social interactions increase activity in dCA2-projecting MS neurons and induce plasticity at glutamatergic synapses from MS neurons onto dCA2 pyramidal neurons. The activity of dCA2-projecting MS cells is enhanced by the neuromodulator 5-HT acting on 5-HT1B receptors. Moreover, optogenetic manipulation of median raphe 5-HT terminals in the MS bidirectionally regulates social memory stability. This work expands our understanding of the neural mechanisms by which social interactions lead to social memory and provides evidence that 5-HT has a critical role in promoting not only prosocial behaviours8,9, but also social memory, by influencing distinct target structures.

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Fig. 1: Chemogenetic manipulation of the MS bidirectionally regulates social memory.
Fig. 2: Inhibition of MS to dorsal CA2 projection disrupts social memory.
Fig. 3: Glutamatergic inputs from the MS to dCA2 have a crucial role in social memory formation.
Fig. 4: Bidirectional modulation of social memory by MS 5-HT1B receptors.
Fig. 5: MR 5-HT release in the MS regulates social memory.

Data availability

The datasets generated and analysed during this study are included in this published article and its supplementary information files. Any additional data generated during and/or analysed during this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

Code used for data processing and analysis is available from the corresponding author upon reasonable request. The MATLAB code used for analyses of fibre photometry data is provided as a supplementary file.

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Acknowledgements

This work was supported by philanthropic funds donated to the Nancy Pritzker Laboratory at Stanford University. X.W. was supported by a NIH K99 Career Development Award (MH122697). K.T.B. was supported by NIH grant DP2 AG067666. B.D.H. was supported by a NIH K08 Career Development Award (MH110610). We thank B. S. Bentzley for providing assistance with the fear conditioning experiments; P. A. Neumann and S. R. Golf for providing mouse breeding pairs; and members of the Malenka laboratory for discussions. Extended Data Fig. 10 schematic by Sci Stories, LLC.

Author information

Affiliations

Authors

Contributions

X.W. conceived the study and performed the majority of experiments. X.W. and R.C.M. designed the experiments, interpreted the results and wrote the paper, which was edited by all authors. W.M. and X.W. performed the ex vivo electrophysiology experiments. K.T.B. prepared and provided Flp-expressing rabies virus. B.D.H. contributed to the design and analysis of fibre photometry experiments, including hardware configuration and creating analysis scripts in MATLAB.

Corresponding author

Correspondence to Robert C. Malenka.

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Competing interests

All protocols used during this study are freely available for non-profit use from the corresponding author upon reasonable request. R.C.M. is on the scientific advisory boards of MapLight Therapeutics and MindMed.

Additional information

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

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 MS cells show increased cFOS after a social experience.

a, Schematic of experimental timeline, 4-OHT was administered via intraperitoneal injection. b, Quantification of tdTomato-positive cells in the median raphe (MR: F2,12 = 4.681, P = 0.0314), paraventricular nucleus of the hypothalamus (PVH: F2,11 = 3.446, P = 0.0689), nucleus of the diagonal band (NDB: F2,12 = 4.423, P = 0.0364), medial septum (MS: F2,12 = 13.31, P = 0.0009), lateral septum (LS: F2,12 = 4.14, P = 0.0429) in the social (n = 7), object (n = 5) and control (n = 3) conditions. Representative images of MS expressing tdTomato. Scale bar, 200 μm (right). c, Quantification of tdTomato-positive cells in the ventral CA1 (vCA1: F2,8 = 1.478, P = 0.2842) in social (n = 5), object (n = 3) and control (n = 3) conditions. d, Quantification of tdTomato-positive cells in the dorsal CA2 (dCA2: F2,9 = 5.367, P = 0.0292) in social (n = 5), object (n = 4) and control (n = 3) conditions. Representative images of dCA2 expressing tdTomato. Scale bar, 200 μm (right). e, Schematic of monosynaptic tracing experiment. f, Representative images of injection site in the dorsal hippocampus and presynaptic labelling in the MS (left), injection site in the ventral hippocampus and presynaptic labelling in the MS (right). Scale bar, 200 μm, n = 3. g, Schematic of anterograde tracing experiment. h, Representative images of injection site in the MS (left) and axon terminals in the dorsal and ventral hippocampus (right). Statistical tests: bd, One-way ANOVA with Tukey’s post-hoc test, N.S. = not significant, *P < 0.05, **P < 0.01, ***P < 0.001 (left). Scale bar, 200 μm, n = 3. Error bars denote s.e.m.

Source data

Extended Data Fig. 2 Chemogenetic manipulation of the MS does not affect sociability and object memory.

a, Representative traces of subjects during three-chamber social memory test. b, Duration in chamber with novel object (no) or novel mouse (nm) (left) and discrimination scores (right) (F2,40 = 0.2875, P = 0.7517; mCh: n = 19, hM4Di: n = 12). c, Duration in chamber with familiar object (fo) or no (left) and discrimination scores (right) (F2,40 = 0.04521, P=0.9558; mCh: n = 19, hM4Di: n = 12). d, Schematic and representative image of MS injection site showing hM3Dq expression. n = 10. Scale bar, 500 μm. e, Duration in chamber with fm or nm (left) and discrimination scores (right) (F2,27 = 6.689, P = 0.0044, n = 10). f, Duration with no or nm (left) and discrimination scores (right) (t9 = 0.2358, P = 0.8189; n = 10). g, Duration with familiar object (fo) or no (left) and discrimination scores (right) (F2,27 = 0.3243, P = 0.9681; n = 10). h, Schematic and representative image of hM4Di expression in the MS. n = 8. Scale bar, 500 μm. i, Individual subjects from Fig. 1j. Statistical tests: b, c, e, f, g, duration: two-tailed paired Student’s t-test. b, c, e, g, Discrimination scores: one-way ANOVA with Tukey’s post-hoc test. f, Discrimination scores: two-tailed paired Student’s t-test. N.S. = not significant, *P < 0.05, **P < 0.01, ***P < 0.001. Error bars denote s.e.m.

Source data

Extended Data Fig. 3 Optogenetic MS cell body and chemogenetic terminal inhibition do not affect sociability and object memory.

a, Schematic of experimental set-up (left) and representative image of MS injection site showing NpHR expression (right). n = 10. Scale bar, 500 μm. b, Duration in chamber with no or nm (left) and discrimination scores (right) (t18 = 0.9531, P = 0.3532; n = 10). c, Duration in chamber with fo or no (left) and discrimination scores (right) (t18 = 0.1348, P = 0.8943; n = 10). d, Schematic of experimental set-up (left) and representative images of MS injection sites showing hM4Di expression and cannula implant sites (right). n = 13. Scale bar, 500 μm. e, Duration in chamber with no or nm (left) and discrimination scores (right) (t26 = 0.2453, P = 0.8081; mCh: n = 15, hM4Di: n = 13). f, Duration in chamber with fo or no (left) and discrimination scores (right) (t22 = 0.6383, P = 0.5298; n = 12). All data were assessed by two-tailed unpaired Student’s t-test. N.S. = not significant, *P < 0.05, ***P < 0.001. Error bars denote s.e.m.

Source data

Extended Data Fig. 4 Inhibition of dCA2-projecting MS neurons has no effect on sociability, object memory, contextual fear memory and conditioned place preference.

a, Schematic of experimental set-up (left). Duration in chamber with fm or nm (middle) and discrimination scores (right) (hM4Di: P = 0.5135; female mCh: n = 11, hM4Di: n = 10, male mCh: n = 4, hM4Di: n = 5). b, Duration in chamber with no or nm (left) and discrimination scores (right) (F2,42 = 0.4013, P = 0.6721; n = 15, hM4Di+saline: n = 14). c, Duration with fo or no (left) and discrimination scores (right) (t27 = 0.1384, P = 0.891; mCh: n = 15, hM4Di: n = 14). d, Schematic of experimental set-up (top) and quantification of the percent freezing during shock and recall (bottom left) and fold increase in freezing time (bottom right) (P = 0.2671; n = 15). e, Schematic of experimental set-up (top), quantification of the percent time spent on each surface after CNO and saline pairing (bottom left) and discrimination scores (bottom right) (t28 = 0.2619, P = 0.7953; n = 15). f, Schematic of virus injection, left. Representative images of MS injection site as well as the labelled axon in the dCA2, ventral CA1 (vCA1) and supramammillary nucleus (SUM), right (n  =  3, scale bars  =  500 μm above and 200 μm below; arrows point to mRuby puncta. Statistical tests: a, two-tailed Mann-Whitney test. b, c, Duration: two-tailed paired Student’s t-test. b, Discrimination score: one-way ANOVA with Tukey’s post-hoc test c, e, Discrimination scores: two-tailed unpaired Student’s t-test. d, % freezing: Kruskal–Wallis with post-hoc Dunn’s test, fold-increase in freezing: two-tailed Mann-Whitney test. e, % time on one side: one-way ANOVA with Tukey’s post-hoc test. N.S. =  = not significant. *P < 0.05, **P < 0.01, ***P < 0.001. Error bars denote s.e.m.

Source data

Extended Data Fig. 5 dCA2-projecting MS cells are primarily cholinergic and glutamatergic.

a, Schematic of monosynaptic rabies tracing set-up in Amigo2-Cre mice (left) and representative images of injection site in the dCA2 as well as Gfp-positive cells in the MS (right). Scale bar, 200 μm, n = 3. b, Representative images of in-situ hybridization. Scale bar, 200 μm (upper left panel), 40 μm. c, Quantification of in-situ hybridization, n = 3 subjects. d, Quantification of same in-situ hybridization data for percent of Gfp-positive cells colocalizing with Chat only, Slc17a6 only, Gad2 only or double-positive for Slc17a6 and Chat, Gad2 and Chat (right), n = 3 subjects. e, Quantification of colocalization with GFP-positive cells via immunohistochemistry (IHC) using either CHAT or CaMKII antibodies (left) and representative images (right, scale bar, 40 μm, n = 3). f, Schematic of experimental set-up and representative image of dCA2 infusion site filled with ink. g, Duration in chamber with no or nm (left) and discrimination scores (right) (F2,36 = 1.702, P = 0.1967; n = 13). h, Duration in chamber with fo or no (left) and discrimination scores (right) (F2,36 = 3.259, P = 0.05; n = 13). Statistical tests: g, h, duration: two-tailed paired Student’s t-test; discrimination scores: one-way ANOVA with Tukey’s post-hoc test. N.S. = not significant, *P < 0.05, **P < 0.01, ***P < 0.001. Error bars denote s.e.m.

Source data

Extended Data Fig. 6 MS synapses onto dCA2 pyramidal neurons are primarily glutamatergic and can express long-term depression ex vivo.

a, Top, pie charts of percentage of cells, in which the ChETA (n = 20/9) and ChR2 (n = 22/6) induced PSCs were >60% reduced by NBQX (10 μM), picrotoxin (50 μM) or Mecamylamine (5 μM). Below, summary time course of ChETA-evoked PSCs from tdTomato-positive dCA2 pyramidal neurons, which were completely blocked (>90%) by bath-application of NBQX (n = 13). b, Representative traces of PSCs evoked by paired-pulse MS input activation in slices prepared from Amigo2-Cre mice exposed to a novel object or novel mouse (social). Scale bars, 50 pA, 100 ms. Quantification of paired-pulse ratios for mice (below) interacting with a novel object (n = 17/3, cells/mice) or novel mouse (n = 24/4) (t39 = 1.589, P = 0.1201), two-tailed unpaired Student’s t-test. N.S. = not significant. c, Representative EPSCs from tdTomato-positive dCA2 pyramidal neurons before and after LTD induction protocol. Scale bars, 25 pA, 100 ms. Summary time-course of EPSCs with and without listed receptor antagonists in bath. With inhibitors: n = 8/4, without inhibitors: n = 6/3. d, Representative image of MS ChR2 injection site (above) and optical fibre implant site in the dCA2 (below). n = 10. Scale bars, 500 μm. Error bars denote s.e.m.

Source data

Extended Data Fig. 7 Effects of in vivo optogenetic low frequency stimulation to induce LTD at MS to dCA2 synapses on sociability, social memory and object memory.

a, b, Duration in chambers with fm or nm (left) and discrimination scores (right), LTD stimulation (1 Hz for 10 min) was performed prior to sociability test, (a: t13 = 2.898, P = 0.0125; off: n = 15, 1 Hz: n = 14. b: t9 = 0.9806, P = 0.3524; n = 10). c, d, Duration in chamber with no or nm, left and discrimination scores (right) in ChR2 and eYFP mice, LTD stimulation (1 Hz for 5 min) was performed after sociability test (c: t9 = 0.3201, P = 0.7563; n = 10, d: t9 = 0.6328, P = 0.5426; n = 10). e, Duration with fo or no (left) and discrimination scores (right) (t9 = 0.09968, P = 0.9228; n = 10) in ChR2 mice. f, g, Duration in chamber with no or nm, left and discrimination scores (right) in ChR2 and eYFP mice (f: t13 = 0.7717, P = 0.4540; n = 14, g: t9 = 1.208, P = 0.2577; n = 10). h, Duration with fo or no (left) and discrimination scores (right) (t13 = 0.6186, P = 0.5469; n = 14) in ChR2 mice. Two-tailed paired Student’s t-test was performed on all data. N.S. = not significant, *P < 0.05, **P < 0.01, ***P < 0.001. Error bars denote s.e.m.

Source data

Extended Data Fig. 8 Effects of CP93129 on dCA2-projecting MS neurons.

a, Sociability is not affected by MS infusion of indicated drugs. Duration in chamber with no or nm (left) and discrimination scores (right) (F5,78 = 0.3144, P = 0.9029; n = 14). b, Pie chart summarizing postsynaptic responses of EGFP-positive cells in CP93129 (2 or 5 μM, n = 42). c, Pie chart illustrating action potential (AP) firing changes in CP93129 (left, n = 15). Representative traces -/+ CP93129 (right). Vm refers to unclamped resting membrane potential. Scale bars, 25 mV, 100 ms. d, Effects of CP93129 on MS neurons projecting to dCA2. Number of cells per current are indicated in parentheses (t25 = 3.461, P = 0.002; n = 26) (NOCHG, no change). e, Quantification of action potential firing as function of current injection for dCA2-projecting MS neurons with increased firing in CP93129 (P = 0.001; n = 10). f, Summary time course of IPSC responses in D-AP5 and NBQX with a pipette solution comprising CsMeSO4+CsCl. Representative traces above shown at indicated time points. Scale bars, 100 pA, 50 ms, n = 5/2. g, Summary time course of EPSC responses in picrotoxin while recording with a pipette solution comprising CsMeSO4. Representative traces above shown at indicated time points. Scale bars, 50 pA, 10 ms, n = 5/3. h, Amplitudes of IPSCs (t4 = 0.0285, P = 0.979, n = 5) and EPSCs (t4 = 0.593, P = 0.585, n = 5) averaged over the last 5 min of recording as a percentage of the first 3 min of baseline recording. i, j, Corresponding input resistance measurements for cells shown in f and g. k, RN of IPSC (t4 = 0.058, P = 0.957, n = 5) and EPSC (t4 = −1.409, P = 0.232, n = 5) recordings averaged over the last 5 min of recording as a percentage of the first 3 min of baseline recording. l, Recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from EGFP-positive cells before and after bath-application of CP93129 (CP). Cumulative probability plot of sIPSC amplitudes with representative traces (above, scale bars, 15 pA, 15 ms, n = 9/6 (cells/mice)). Bar graph shows effect of CP93129 on mean IPSC amplitude. m, Cumulative probability plot of sIPSC inter-event intervals with representative traces (above, scale bars, 50 pA, 0.5 s, n = 9/6). Bar graph shows effect of CP93129 on mean IPSC frequency. Statistical tests: a, duration: two-tailed paired Student’s t-test; discrimination scores: one-way ANOVA with Tukey’s post-hoc test. d, h, k, Two-tailed paired Student’s t-test. e, Repeated measures two-way ANOVA with Sidak’s multiple comparison post-hoc test. l, m, tTwo-tailed Wilcoxon signed rank test. N.S. = not significant, *P < 0.05, **P < 0.01, ***P < 0.001. Error bars and shading denote s.e.m.

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Extended Data Fig. 9 Optogenetic inhibition or excitation of 5-HT inputs in the MS does not alter sociability and object memory.

a, Schematic of virus injection (left) and representative images of the injection site in the median raphe (MR) on the left and the EGFP-positive axons in the MS (right). n  =  5. b, Schematic of virus injections to perform TRIO (left) and representative images of the injection site in the MS and the GFP-positive cells in the MR (right). n =  3. Scale bars  =  500 μm. c, d, Duration in chamber with no or nm (left) and discrimination scores (right) (c: t9 = 1.834; P = 0.0998; n = 10. d: P = 0.3750; n = 10). e, f, Duration in chamber with fo or no (left) and discrimination scores (right) (e: t9 = 0.2418, P = 0.8143; n = 10. f: t8 = 0.6029, P = 0.5632, n = 9). g, h, Duration in chamber with no or nm (left) and discrimination scores (right) (g: t10 = 0.9294, P = 0.3746; n = 11. h: t9 = 1.518, P = 0.1633; n = 10). i, Duration in chamber with no or nm (left) and discrimination scores (right) (t11 = 1.52, P = 0.152; saline: n = 12, CP93129: n = 14). Statistical tests: d, eYFP on duration and discrimination score: two-tailed Wilcoxon signed rank test. All other data in this figure were analysed by two-tailed paired Student’s t-test. N.S. = not significant, *P < 0.05, **P < 0.01, ***P < 0.001. Error bars denote s.e.m.

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Extended Data Fig. 10 Model illustrating 5-HT action on dCA2-projecting MS neurons.

During a novel social encounter, 5-HT diffuses away from its release sites to bind to 5-HT1BRs on the terminals of MS GABAergic interneurons thereby inhibiting GABA release onto the dCA2-projecting glutamatergic MS neurons. 5-HT also can bind to 5-HT1BRs on presynaptic glutamatergic terminals to inhibit glutamate release but a smaller proportion of glutamatergic inputs express 5-HT1BRs. The net effect of 5-HT is to reduce local inhibition of dCA2-projecting MS neurons to a greater extent than its reduction of excitatory drive, thereby resulting in increased activity in these neurons. The question mark indicates that there may also be a direct effect of 5-HT on dCA2-projecting MS neurons. The inset on the right depicts the circuitry investigated in this study from the median raphe (MR) to the medial septum (MS) to dorsal CA2 (dCA2).

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Wu, X., Morishita, W., Beier, K.T. et al. 5-HT modulation of a medial septal circuit tunes social memory stability. Nature 599, 96–101 (2021). https://doi.org/10.1038/s41586-021-03956-8

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