Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity1,2 and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here we show that high-frequency activity induces LTP at hippocampus–NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. We conclude that hippocampus–NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.
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We thank B. Mathur for D1–tdtomato mice; K. Deisseroth for permission to use the viral optogenetic constructs; the University of Maryland School of Medicine Center for Innovative Biomedical Resources, Confocal Microscopy Core for use of the confocal microscopes; the NIMH Chemical Synthesis and Drug Supply Program for supplying fluoxetine, and T. Gould, T. Blanpied, and T. Bale for suggestions and advice. This work was supported by R01MH086828 (S.M.T.), T32 NS007375 (T.A.L.), a NARSAD Young Investigator Award (T.A.L.), the Whitehall Foundation 2017-12-54 (M.C.C. and J.R.T.), and R01MH106500 (M.K.L. and T.C.F.).
Nature thanks J. Dani, C. McClung and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
a, HFS alters coefficient of variation. Friedman test and Dunn’s post hoc test; Q = 19.95, P = 0.0028, n = 18 cells. Centre values represent mean and error bars represent s.e.m. b, HFS stimulation decreases failure rate. Two-tailed paired t-test: t = 3.123, P = 0.0066, n = 17 cells. ***P < 0.001, **P < 0.01, *P < 0.05.
a, Low-magnification image of YFP fluorescence in ventral hippocampus. b, Blue inset from a. c, Low-magnification image showing YFP fluorescence in the NAc. Insets show overlap in labelling of D1R expression and YFP. This was repeated in mice used for optogenetic experiments. Scale bar, 100 μm.
Extended Data Fig. 3 LTP at hippocampus–NAc synapses is not associated with preferential insertion of GluA2-lacking AMPA receptors.
a, Wash-in of NASPM after LTP induction does not alter EPSC amplitude. Centre values represent mean and error bars represent s.e.m. b, Summary data from the last 5 min of recording. Two-tailed Mann–Whitney U-test: U = 24, P > 0.9999, n = 7, 7 mice; two-tailed paired t-test baseline EPSC amplitude/30 min post HFS: control: t = 2.508, P = 0.046, n = 7 cells; NASPM: t = 2.747, P = 0.0226, n = 10 cells. c, HFS does not alter rectification at positive holding potentials. Two-tailed Mann–Whitney U-test: U = 12, P = 0.7879, n = 7, 4 mice. Centre values represent mean and error bars represent s.e.m. #Significant increase in EPSC amplitude above baseline revealed by paired t-test. For box plots, the line in the middle of the box is plotted at the median. The box extends from the 25th to the 75th percentiles. Whiskers represent minimum and maximum.
Extended Data Fig. 4 D1 receptor signalling is required for LTP induction at non-specific NAc synapses.
a, Pre-incubation with D1 receptor antagonist SCH23390 blocks LTP induction in response to HFS. b, Summary data from the last 5 min of recording. Two-tailed Mann–Whitney U-test: U = 2, P = 0.0317, n = 5 mice per group. #Two-tailed paired t-test baseline EPSC amplitude/30 min post HFS: control: t = 3.017, P = 0.0393, n = 5 cells; SCH: t = 0.5016, P = 0.6372, n = 6 cells. LTP kinetic data are plotted in 1-min bins. Centre values represent mean and error bars represent s.e.m. For box plots, the line in the middle of the box is plotted at the median. The box extends from the 25th to 75th percentiles. Whiskers represent minimum and maximum.
a, Pre-incubation with the D2-receptor antagonist sulpiride does not affect the ability to elicit LTP in response to HFS in D2R-MSNs. b, Summary data from the last 5 min of recording. Two-tailed Mann–Whitney U-test: U = 20, P = 0.9452, n = 6, 7 mice. #Two-tailed paired t-test baseline EPSC amplitude/30 min post HFS: control: t = 3.840, P = 0.0121, n = 6 cells; sulpiride: t = 4.246, P = 0.0022, n = 10 cells. c, Representative traces of EPSCs from control and sulpiride-treated D2R-MSNs. #Significant increase in EPSC amplitude above baseline revealed by paired t-test. LTP kinetic data are plotted in 1-min bins. Centre values represent mean and error bars represent s.e.m. For box plots, the line in the middle of the box is plotted at the median. The box extends from the 25th to 75th percentiles. Whiskers represent minimum and maximum. Scale bar for representative traces, 10 pA/10 ms.
Representative images of labelled hippocampal fibres. Hippocampal cells projecting to the NAc were labelled by injecting a retrograde virus expressing Cre recombinase into the shell of the NAc and a Cre-dependent virus containing YFP into the ventral hippocampus. Some collaterals are visible in the amygdala as well as the prelimibic and infralimbic regions of the PFC. Right: 100× image showing labelling of fibres. Scale bars, 50 μm. AC, anterior commissure; fmi, forceps minor of the corpus callosum. This was replicated in one other mouse.
Distance travelled during the conditioning segment of the CPP paradigm. Data were normalized to the distance the mouse travelled during the ‘no stimulation’ portion of the test. Two-tailed Mann–Whitney U-test: U = 43, P = 0.8773, n = 13, 7 mice. The line in the middle of the box is plotted at the median. The box extends from the 25th to 75th percentiles. Whiskers represent minimum and maximum.
a, Stimulation at 4 Hz does not potentiate EPSCs. Data are plotted in 1-min bins. Centre values represent mean and error bars represent s.e.m. b, Summary data from the last 5 min of recording. Two-tailed paired t-test: t = 1.171, d.f. = 2, P = 0.3621, n = 3 cells. The line in the middle of the box is plotted at the median. The box extends from the 25th to 75th percentiles. Whiskers represent minimum and maximum. Scale bar for representative traces, 10 pA/10 ms.
a, Representative images from NAc core and shell. Black/grey dots represent c-Fos-positive cells. Scale bar, 50 μm. b, Stimulation at 100 Hz but not 4 Hz increases c-Fos expression in the NAc shell. Two-way ANOVA: F2,36 = 5.262, P = 0.0099, n = 9, 5, 7 mice.
Extended Data Fig. 10 Chronic stress leads to preferential insertion of GluA2-lacking AMPA receptors in D2R-MSNs.
a, Chronic stress does not alter subunit composition in D1R-MSNs. Two-tailed Mann–Whitney U-test of amplitude at +40 mV: U = 35, P = 0.6665, n = 6, 7 mice. b, D2R-MSNs from mice exposed to chronic stress show inward rectification at positive membrane potentials. Two-tailed Mann–Whitney U-test of amplitude at +40 mV: U = 0, P = 0.0006, n = 6, 7 mice. c, NASPM decreases EPSC amplitude in D2R-MSNs from mice exposed to chronic stress. Kruskal–Wallis test: H = 7.423, P = 0.0132, n = 4 mice per group. d, Current–voltage relationships in D1R-MSNs remain unaffected by chronic stress or fluoxetine treatment. Kruskal–Wallis test with Dunn’s post hoc test: H = 0.9436, P = 0.8149, n = 5, 5, 5, 4 mice. e, D2R-MSNs from mice exposed to chronic stress treated with chronic fluoxetine show a linear current–voltage relationship, similar to unstressed controls. Inward rectification is observed in D2R-MSNs from mice exposed to chronic stress alone or chronic stress with acute fluoxetine treatment. Kruskal–Wallis test with Dunn’s post hoc test: H = 31.42, P < 0.0001, n = 5, 5, 5, 8 mice. The line in the middle of the box is plotted at the median. The box extends from the 25th to 75th percentiles. Whiskers represent minimum and maximum. Centre values represent mean and error bars represent s.e.m. ****P < 0.0001, **P < 0.01, *P < 0.05.
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