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A circuit-based mechanism underlying familiarity signaling and the preference for novelty

Nature Neuroscience volume 20, pages 1260–1268 (2017)Cite this article

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Abstract

Novelty preference (NP) is an evolutionarily conserved, essential survival mechanism often dysregulated in neuropsychiatric disorders. NP is mediated by a motivational dopamine signal that increases in response to novel stimuli, thereby driving exploration. However, the mechanism by which once-novel stimuli transition to familiar stimuli is unknown. Here we describe a neuroanatomical substrate for familiarity signaling, the interpeduncular nucleus (IPN) of the midbrain, which is activated as novel stimuli become familiar with multiple exposures. In mice, optogenetic silencing of IPN neurons increases salience of and interaction with familiar stimuli without affecting novelty responses, whereas photoactivation of the same neurons reduces exploration of novel stimuli mimicking familiarity. Bidirectional control of NP by the IPN depends on familiarity signals and novelty signals arising from excitatory habenula and dopaminergic ventral tegmentum inputs, which activate and reduce IPN activity, respectively. These results demonstrate that familiarity signals through unique IPN circuitry that opposes novelty seeking to control NP.

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Figure 1: Familiar and novel social encounters differentially activate the IPN.
Figure 2: IPN GABAergic activity bidirectionally modulates social NP.
Figure 3: mHb cholinergic–glutamatergic input in IPN bidirectionally modulates social NP.
Figure 4: VTA sends functional DAergic input to the IPN to control social NP.
Figure 5: IPN D1 signaling drives DAergic VTA→IPN input, which modulates social NP.

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Acknowledgements

We thank K. Deisseroth for optogenetic plasmids and. G. Gao for viral plasmid packaging. We also thank A. Sacino for technical support. This work was supported by the National Institute on Drug Abuse award number DA041482 (to A.R.T.), DA035371 (to P.D.G. and A.R.T.) and by a NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation (to A.R.T.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Susanna Molas, Rubing Zhao-Shea, Liwang Liu, Steven R DeGroot, Paul D Gardner & Andrew R Tapper

  2. Graduate Program in Neuroscience, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Steven R DeGroot

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Contributions

S.M. and A.R.T. conceived of this study. S.M., R.Z.-S., L.L., S.R.D., P.D.G. and A.R.T. designed the experiments. S.M., R.Z.-S., L.L. and S.R.D. performed the experiments. S.M., R.Z.-S., L.L., S.R.D. and A.R.T. analyzed data. S.M., P.D.G. and A.R.T. wrote the manuscript.

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Correspondence to Andrew R Tapper.

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Integrated supplementary information

Supplementary Figure 1 IPN activation upon successive encounters to FS and FO stimuli.

(a) Schematic of experimental approach used for multiple exposures to FS stimuli. Mice were exposed to a novel juvenile mouse for one day (N1) or to the same juvenile mouse daily for 2-7 days (F1-F6) prior to brain processing for c-Fos expression analysis in the IPN. (b) Normalized number of c-Fos-immunopositive nuclei in the IPN increased with exposure to the same animal over consecutive days (one-way ANOVA F4,19 = 7.04, p = 0.0012; post-hoc test, *p < 0.05, **p < 0.01, ***p < 0.001; n = 4, 5, 4, 6, and 5 mice/group). Data were normalized to control mice (n = 4 mice) receiving no social interaction. (c) Schematic of experimental approach used to measure interactions with FO and NO stimuli. On day 1, mice were exposed to a novel object (N1) placed in the T-maze and exposed to the same object on day 2 (F1). On day 3, mice were split into two groups with half exposed to the same object as the prior days (F2) (n = 10 mice), and the other half exposed to a distinct novel object (N2) (n = 10 mice). (d) Representative heat maps showing locations of experimental animals on days 1-3 of the experiment in (c). (e) Time investigating the objects decreased across consecutive days (two-way RM ANOVA, day effect F2,36 = 7.17, p = 0.0024). Mice exposed to a novel object (N2) on day 3 (NO) displayed rebounded investigation (day x group interaction F2,36 = 8.34, p = 0.0011; post-hoc test, ***p < 0.0001). (f) Representative images of c-Fos-immunoreactivity (green signal) in the IPN from FO and NO groups. Nuclei were labeled with DAPI (blue signal). Scale bar 50 μm. (g) Normalized average number of c-Fos immunopositive nuclei in the IPN of mice presented to FO (n = 7 mice) was higher than NO (n = 6 mice) conditions (unpaired t-test, t11 = 3.38, **p = 0.0062). Data are expressed as mean ± s.e.m.

Supplementary Figure 2 IPN photoinhibition enhances investigation of FS but not NS stimuli during single encounters over consecutive days, without affecting locomotion.

(a) Total distance travelled during the social choice test in GAD2Cre::NpHRIPN mice was similar between light-OFF (n = 8 mice) and light-ON conditions (n = 10 mice) (unpaired t-test, t16 = 1.12, p = 0.2808). (b) Schematic of experimental approach used for FS and NS single interactions. GAD2Cre::NpHRIPN mice were exposed to a novel juvenile stimulus (N1) on day 1 and the same juvenile on day 2 (F1) without light stimulation. On day 3, mice were exposed to the same juvenile (F2) with half of the mice receiving light OFF/control (n = 8 mice) while the other half received light ON conditions (n = 8 mice). On day 4, mice were re-exposed to the same juvenile (F3) in the absence of photo-inhibition. On day 5, mice were exposed to a novel mouse (N2) during photo-inhibition or control conditions. Shaded columns represent optogenetic stimulation. (c) Average time spent investigating the social stimulus decreased across consecutive days (two-way RM ANOVA, day effect F3,42 = 41.79, p < 0.0001). Mice receiving photo-inhibition on day 3 displayed enhanced social investigation (day x light interaction F3,42 = 3.33, p = 0.0284). (d) Average time spent investigating the non-social stimulus was not affected by photo-inhibition (two-way RM ANOVA, day x light interaction F3,42 = 0.42, p = 0.7424), (e) Preference ratio for social stimuli decreased across consecutive days (two-way RM ANOVA, day effect F3,42 = 6.71, p = 0.0008). Light-induced photo-inhibition enhanced social preference (day x light interaction F3,42 = 3.21, p = 0.0323; post-hoc test, *p = 0.0160). (f) Total investigation time decreased across consecutive days (two-way RM ANOVA, day effect F3,42 = 28.02, p < 0.0001) but was unaffected by light stimulation (day x light interaction F3,42 = 1.69, p = 0.1827). Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 3 IPN GABAergic neuron inhibition increases the motivational reward component of FS but not NS interactions.

(a) Social novelty CPP schematic. On day 1, GAD2Cre::NpHRIPN mice were allowed to explore an empty CPP chamber for 20 min and 5-6 h later were presented to a novel social stimulus (N1) in a neutral arena. On days 2-4, mice were restricted to one of two CPP chambers that were paired with either the same familiar juvenile mouse or a distinct novel juvenile mouse. IPN photo-inhibition was paired with the FS stimulus during days 3 and 4 with control mice receiving no light illumination. On day 5, mice were allowed to freely explore both empty chambers with no light-stimulation. (b) Individual duration of time spent in the NS-paired context for control GAD2Cre::NpHRIPN mice (light off) was higher in the test vs. pre-test session (left, unpaired t-test, t14 = 2.35, *p = 0.0338, n = 8 mice). Mice receiving paired-photo-stimulation did not develop preference for the NS context (right, unpaired t-test, t16 = 1.05, p = 0.3101, n = 10 mice). (c) Individual duration of time spent in the FS-paired context did not change in control animals (left, unpaired t-test, t14 = 1.48, p = 0.1621) but increased in mice receiving paired photo-stimulation (right, unpaired t-test, t16 = 3.02, **p = 0.0081). (d) Subtracted CPP score indicating the time spent in the NS-paired chamber minus the time spent in the FS-paired chamber during the test session was reduced in mice receiving photo-inhibition paired with the FS stimuli (unpaired t-test, t16 = 2.17, *p = 0.0456). (e) During the real-time place-preference test, time spent in the left (L) and right (R) chambers in animals without light delivery and time spent in the unconditioned (CS-) or conditioned (CS+) chambers in mice receiving photo-inhibition. Light-induced photo-inhibition did not affect the time spent in the conditioned (CS+) chamber (two-way ANOVA, interaction F1,18 = 0.02, p = 0.8876). Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 4 IPN GABAergic photoinhibition increases exploration to FO stimuli but not NO stimuli.

(a) Schematic of experimental approach used to measure interactions with FO and NO stimuli during the choice paradigm. (b) In GAD2Cre::NpHRIPN mice, representative heat maps showing the location of testing mice during control (light-OFF, top)(n = 11 mice) and light-ON conditions (bottom)(n = 7 mice). (c) Time of FO investigation each minute of the object NP test increased in mice receiving photo-inhibition. (Inset) Averaged total time of FO investigation (unpaired t-test, t16 = 3.03, **p = 0.0080). (d) Time of NO investigation each minute of the object NP test was unaffected by light illumination. (Inset) Averaged total time of NO investigation (unpaired t-test, t16 = 0.49, p = 0.6265). (e) Object NP ratio decreased in photo-inhibited mice (unpaired t-test, t16 = 3.04, **p = 0.0078) without affecting (f) total investigation time (unpaired t-test, t16 = 0.67, p = 0.5108). (g) Schematic of experimental approach used for single interactions with FO and NO stimuli. GAD2Cre::NpHRIPN mice were presented to an inanimate object for two consecutive days. On day 3, half of the mice encounter the same object (FO) for two more days while the other half were presented to novel objects (NO) and half of both groups received light-induced photo-inhibition. (h) Time of object investigation decreased across consecutive days in the FO groups (two-way RM ANOVA, day effect F3,51 = 8.20, p = 0.0001). Mice in the FO group receiving photo-inhibition (light-ON on day 3)(n = 8 mice) increased object investigation, as compared to control mice (light-OFF on day 3) (n = 11 mice)(day x light interaction, F3,51 = 5.83, p = 0.017; post-hoc test, *p = 0.0209). Shaded columns represent optogenetic stimulation. (i) Time of object investigation increased across consecutive days in the NO groups (two-way RM ANOVA, day effect F3,42 = 10.98, p < 0.0001). Photo-inhibited mice (n = 8 mice) in the NO group had similar NO investigation as control mice (n = 8 mice)(day x light interaction, F3,42 = 1.16, p = 0.3373). Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 5 Opsin-specific effects of IPN GABAergic neuronal photoactivation in the reduction of NS stimuli investigation.

During the social NP task in GAD2Cre::ChR2IPN mice under light-OFF (n = 8 mice) or light-ON conditions (n = 14 mice) and in GAD2Cre::eYFPIPN non-opsin injected control mice under light stimulation (n = 16 mice): (a) Time of FS investigation each minute of the social NP task did not differ among conditions. (Inset) Average total time of FS investigation (one-way ANOVA, F2,35 = 0.65, p = 0.5276). (b) Time of NS investigation each minute of the social NP task decreased in ChR2-injected mice receiving photo-stimulation as compared to control ChR2-injected mice without light delivery or eYFP-injected mice receiving light-stimulation. (Inset) Average total time of NS investigation (one-way ANOVA, F2,35 = 5.29, p = 0.0099; post-hoc test, *p = 0.0205 and *p = 0.0377). (c) Preference ratio decreased in the ChR2-injected light-ON group (one-way ANOVA, F2,35 = 5.31, p = 0.0096; post-hoc test, *p = 0.0395 and *p = 0.0191) without affecting (d) total investigation time (one-way ANOVA, F2,35 = 2.95, p = 0.0644). Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 6 Photoactivation of IPN GABAergic neurons decreases investigation of NO stimuli.

In GAD2Cre::ChR2IPN mice: (a) representative heat maps showing the location of testing mice during control (light-OFF, top)(n = 7 mice) and light-ON conditions (bottom) (n = 8 mice) in the FO and NO choice paradigm. (b) Time of FO investigation each minute of the object NP test remained intact during photo-stimulation. (Inset) Averaged total time of FO investigation (unpaired t-test, t13 = 0.64, p = 0.5436). (c) Time of NO investigation each minute of the object NP test decreased in mice receiving photo-stimulation. (Inset) Averaged total time of NO investigation (unpaired t-test, t13 = 2.36, *p = 0.0348). (d) Object NP ratio decreased in photo-stimulated animals (unpaired t-test, t13 = 2.54, *p = 0.0246) without interfering with (e) total investigation time (unpaired t-test, t13 = 1.44, p = 0.1725). Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 7 Photoinhibition or photoactivation of IPN GAD2+ neurons does not affect anxiety-like behavior.

In GAD2Cre::NpHRIPN mice: (a) Average time in the center of the open field (unpaired t-test, t14 = 1.42, p = 0.1780, n = 8 mice per group), (b) total buried marbles (unpaired t-test, t14 = 0.16, p = 0.8776, n = 8 mice per group), (c) time in the open arms of the EPM (unpaired t-test, t22 = 0.49, p = 0.6269, n = 11 - 13 mice per group) and (d) total arm entries (unpaired t-test, t22 = 0.39, p = 0.7031) did not differ between light-OFF and light-ON conditions. In GAD2Cre::ChR2IPN mice photo-activation of IPN GAD2 neurons did not modify: (e) Average time in the center of the open field (unpaired t-test, t12 = 1.64, p = 0.1274, n = 6 - 8 mice per group), (f) total buried marbles (unpaired t-test, t12 = 0.17, p = 0.8691, n = 6 - 8 mice per group), (g) time in open arms of the EPM (unpaired t-test, t12 = 1.06, p = 0.3088, n = 6 - 8 mice per group) or (h) total arm entries (unpaired t-test, t12 = 0.49, p = 0.7016). Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 8 NP for inanimate objects controlled by mHb cholinergic–glutamatergic input in IPN.

In ChatCre::ChR2mHb→IPN mice: (a) representative heat maps showing the location of testing mice in control (light-OFF, top) (n = 7 mice) and light-ON conditions (bottom) (n = 8 mice) during the FO and NO choice paradigm. (b) Time of FO investigation each minute of the object NP test was not affected by light photo-stimulation. (Inset) Average total time of FO investigation (unpaired t-test, t13 = 1.01, p = 0.3322). (c) Time of NO investigation each minute of the object NP test decreased in mice receiving photo-stimulation. (Inset) Average total time of NO investigation (unpaired t-test, t13 = 2.69, *p = 0.0184). (d) Object NP ratio decreased in photo-illuminated mice (unpaired t-test, t13 = 2.45, *p = 0.0293). (e) Total investigation time (unpaired t-test, t13 = 1.63, p = 0.1264) and (f) total distance travelled (unpaired t-test, t13 = 0.34, p = 0.7367) were not affected by light exposure. In ChatCre::NpHRmHb→IPN mice: (g) representative heat maps showing the location of testing mice in control (light-OFF, top)(n = 13 mice) and light-ON conditions (bottom)(n = 12 mice). (h) Time of FO investigation each minute of the object NP test increased during photo-inhibition. (Inset) Average total time of FO investigation (unpaired t-test, t23 = 2.31, *p = 0.0305), (i) Time of NO investigation each minute of the object NP test was unaffected by light. (Inset) Average total time of NO investigation (unpaired t-test, t23 = 0.98, p = 0.3357). (j) Object NP ratio decreased in mice receiving photo-inhibition (unpaired t-test, t23 = 2.14, *p = 0.0432). (k) Total investigation time (unpaired t-test, t23 = 0.28, p = 0.7846) and (l) distance travelled (unpaired t-test, t14 = 1.976, p = 0.0682) were similar between light conditions. Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 9 Photoactivation of mHb terminals in the IPN reduces NS stimuli investigation in an opsin-dependent manner.

During the social NP task in ChatCre::ChR2mHb→IPN mice under light-OFF (n = 10 mice) or light-ON conditions (n = 11 mice) and in ChatCre::eYFPmHb→IPN non-opsin injected control mice under light stimulation (n = 8 mice): (a) Time of FS investigation each minute of the social NP task did not differ among conditions. (Inset) Average total time of FS investigation (one-way ANOVA, F2,26 = 1.13, p = 0.3381). (b) Time of NS investigation each minute of the social NP task decreased in ChR2-injected mice receiving photo-stimulation as compared to control ChR2-injected mice without light delivery or eYFP-injected mice receiving light-stimulation. (Inset) Average total time of NS investigation (one-way ANOVA, F2,26 = 6.25, p = 0.0061; post-hoc test, **p = 0.0092 and *p = 0.0383). (c) Preference ratio decreased in the ChR2-injected light-ON group (one-way ANOVA, F2,26 = 6.42, p = 0.0054; post-hoc test, *p = 0.0399 and **p = 0.0076) without affecting (d) total investigation time (one-way ANOVA, F2,26 = 1.4, p = 0.2647). Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 10 The IPN receives VTA DAergic projections.

(a) Representative images of AAV2-DIO-ChR2-eYFP infections (yellow) in the VTA of DATCre mice colocalized with TH immunostaining (red) at different IPN Bregma coordinates. Nuclei were counterstained with DAPI (blue). Scale bars (50 μm lower magnification; 20 μm higher magnification). Arrowheads show eYFP+ axons in the central and lateral regions of the IPN. (b) Representative whole-cell voltage-clamp responses to ChR2 light stimulation in eYFP+ VTA DAergic neurons from midbrain slices of DATCre::ChR2VTA mice injected with AAV2-DIO-ChR2-eYFP in the VTA. (c) Representative images of c-Fos immunoreactivity (red) in the IPN of DATCre::ChR2VTA→IPN animals with (n = 6 mice) or without (n = 6 mice) IPN DAergic terminal photo-stimulation. Scale bar 50 μm. (d) Average number of c-Fos immunopositive nuclei in the IPN decreased in mice receiving photo-stimulation (unpaired t-test, t10 = 2.23, *p = 0.0499). During the social NP task in DATCre::ChR2VTA→IPN mice under light-OFF (n = 10 mice) or light-ON conditions (n = 11 mice) and in DATCre::eYFPVTA→IPN non-opsin injected control mice under light stimulation (n = 7 mice): (e) Time of FS investigation each minute of the social NP task was significantly higher in ChR2 photo-stimulated animals as compared to control ChR2-injected mice without light delivery or eYFP-injected mice receiving light-stimulation. (Inset) Average total time of FS investigation (one-way ANOVA, F2,25 = 5.87, p = 0.0081; post-hoc test, *p = 0.0450 and *p = 0.0134). (f) Time of NS investigation each minute of the social NP task did not differ among conditions. (Inset) Average total time of NS investigation (one-way ANOVA, F2,25 = 0.41, p = 0.6685). (g) Preference ratio decreased in the ChR2-injected light-ON group (one-way ANOVA, F2,25 = 6.84, p = 0.0043; post-hoc test, *p = 0.0118 and *p = 0.0150) without affecting (h) total investigation time (one-way ANOVA, F2,25 = 0.73, p = 0.4904). Data are expressed as mean ± s.e.m., n.s. not significant.

Supplementary Figure 11 DAergic VTA→IPN inputs do not modulate the expression of NP for inanimate objects.

(a) Schematic of experimental approach used to measure interactions with FO and NO stimuli during the choice paradigm. (b) Representative heat maps showing the location of testing mice in control (light-OFF, top)(n = 9 mice) and light-ON conditions (bottom) (n = 9 mice). (c) Time of FO investigation each minute of the object NP task was not affected by photo-stimulation. (Inset) Average total time of FO investigation (unpaired t-test, t16 = 0.94, p = 0.3612). (d) Time of NO investigation each minute of the object NP task was similar between groups. (Inset) Average total time of NO investigation (unpaired t-test, t16 = 0, p = 0.9999). (e) Object NP ratio (unpaired t-test, t16 = 0.58, p = 0.5672) and (f) total investigation time (unpaired t-test, t16 = 0.26, p = 0.8008) remained intact in mice receiving photo-stimulation. (g) Representative images of c-Fos immunoreactivity (green) in IPN and D1 DsRed fluorescence upon intra-IPN infusion of saline or D1 agonist (SKF82958) in Drd1atdTomato mice. Scale bars (50 μm lower magnification; 20 μm higher magnification). (h) Percentage of c-Fos nuclei colocalized with D1 DsRed fluorescence was higher after SKF82958 infusion (n = 4 mice) as compared to vehicle control conditions (n = 4 mice)(unpaired t-test, t6 = 22.49, ***p < 0.0001). Data are expressed as mean ± s.e.m., n.s. not significant.

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Molas, S., Zhao-Shea, R., Liu, L. et al. A circuit-based mechanism underlying familiarity signaling and the preference for novelty. Nat Neurosci 20, 1260–1268 (2017). https://doi.org/10.1038/nn.4607

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