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A prefrontal–paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice

Nature Neuroscience volume 23, pages 1240–1252 (2020)Cite this article

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Abstract

Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.

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Fig. 1: jSI impairs activation of mPFC→pPVT projection neurons upon social exposure in adulthood.
Fig. 2: Chemogenetic suppression of mPFC→pPVT projection neuron activity reduces sociability in adult GH mice.
Fig. 3: Optogenetic suppression of mPFC→pPVT projection terminal activity reduces sociability in adult GH mice.
Fig. 4: Optogenetic activation of mPFC→pPVT projection terminals biases sociability in adult GH mice.
Fig. 5: jSI leads to reduced intrinsic excitability and increased inhibitory input drive of mPFC→PVT neurons in adulthood.
Fig. 6: jSI leads to increased intrinsic excitability of mPFC LTS-SST interneurons and impaired LTS-SST to mPFC→pPVT synaptic transmission in adulthood.
Fig. 7: Chemogenetic activation of mPFC→pPVT projection neurons rescues sociability deficits in adult jSI mice.
Fig. 8: Optogenetic activation of mPFC→pPVT projection terminals rescues sociability deficits in adult jSI mice.

Data availability

Source data are provided with this paper. The remaining relevant data are available from the corresponding author on reasonable request.

Code availability

Codes for fiber photometry analysis are available from the authors upon reasonable request.

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Acknowledgements

We thank M. Janis for assisting with histological analysis and R. Clem, P. Rudebeck, M. Baxter and members of the Morishita laboratory for helpful feedback. This work was supported by the Naito Foundation; the Uehara Memorial Foundation; the Mochida Memorial Foundation; JSPS to K.Y.; NIH grant no. T32MH966785 to L.K.B.; and NIH grant no. R01MH118297, grant no. R01MH119523 and the Simons Foundation/SFARI (grant no. 610850) to H.M.

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Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA

    Kazuhiko Yamamuro, Lucy K. Bicks, Michael B. Leventhal, Daisuke Kato, Susanna Im, Yury Garkun, Kevin J. Norman, Keaven Caro, Masato Sadahiro, Schahram Akbarian & Hirofumi Morishita

  2. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA

    Kazuhiko Yamamuro, Lucy K. Bicks, Michael B. Leventhal, Daisuke Kato, Susanna Im, Meghan E. Flanigan, Yury Garkun, Kevin J. Norman, Keaven Caro, Masato Sadahiro, Schahram Akbarian, Scott J. Russo & Hirofumi Morishita

  3. Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA

    Kazuhiko Yamamuro, Lucy K. Bicks, Michael B. Leventhal, Daisuke Kato, Susanna Im, Yury Garkun, Kevin J. Norman, Keaven Caro, Masato Sadahiro & Hirofumi Morishita

  4. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA

    Kazuhiko Yamamuro, Lucy K. Bicks, Michael B. Leventhal, Daisuke Kato, Susanna Im, Yury Garkun, Kevin J. Norman, Keaven Caro, Masato Sadahiro & Hirofumi Morishita

  5. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA

    Kazuhiko Yamamuro, Lucy K. Bicks, Michael B. Leventhal, Daisuke Kato, Susanna Im, Meghan E. Flanigan, Yury Garkun, Kevin J. Norman, Keaven Caro, Masato Sadahiro, Schahram Akbarian, Scott J. Russo & Hirofumi Morishita

  6. Department of Psychiatry, Nara Medical University, Kashihara, Nara, Japan

    Kazuhiko Yamamuro

  7. Unit of Developmental Genetics, Department of Neuroscience, Uppsala University, Uppsala, Sweden

    Klas Kullander

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  1. Kazuhiko Yamamuro
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Contributions

K.Y. and H.M. designed and analyzed experiments and wrote the manuscript with inputs from all authors. K.Y. performed most experiments, including surgeries, slice electrophysiology and behavior experiments, in part assisted by L.K.B., Y.G., K.J.N. and M.S. M.B.L. performed a part of behavioral experiments. D.K. performed the in vivo electrophysiology experiment. M.E.F. and S.J.R. assisted with fiber photometry experiments and analysis. S.I. and K.C. assisted with viral validation and immunohistochemistry. S.A. supervised L.K.B. K.K. contributed to experiments and analysis with Chrna2-Cre mice.

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Correspondence to Hirofumi Morishita.

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The authors declare no competing interests.

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

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Extended data

Extended Data Fig. 1 c-Fos mapping of cortical and sub-cortical regions upon social exposure.

a, (left) Mice were exposed in a 3-chamber apparatus for 10 min to either a novel mouse (social:S) under a wire corral, a novel object (object:O) under a wire corral, or kept in their home cage (HC), and then perfused 90 min after the end of the exposure. Brains were then stained for c-Fos, a marker of neuronal activity. (middle) Among many brain areas, including several areas that are known to be involved in social behavior, the posterior PVT (pPVT) showed significant c-Fos induction in social groups compared with both object and homecage groups. (one-way ANOVA, F2,9 = 34.020, P = 0.636 × 10-4 followed by a Tukey’s post hoc test: pPVT:, social vs object: **P = 0.003, social vs home cage: ****P = 0.468 × 10–4, n = 4 biologically independent mice each) *P<0.05, **P<0.01, ***P<0.001. (right) Representative c-Fos staining images from pPVT. Scale bar: 200um. Experimental images were obtained from each 12 mice, a few images per mouse, with similar results obtained. b, (upper left) mPFC→pPVT projection neurons were labeled by retrobeads injected into the pPVT. Representative images showing (right) beads in layer 5/6 mPFC→pPVT neurons (scale bar: 100um), and (bottom left) beads at injection site in pPVT (scale bar: 200um). Experimental images were obtained from 16 mice, a few images per mice, with similar results obtained. c, (left) Representative images showing preferential c-Fos induction in mPFC→pPVT neurons by social exposure (Scale bar: 50um, experimental images were obtained from 16 mice, a few images per mice, with similar results obtained), and (right) quantification (one-way ANOVA, F2,13 = 19.750, P = 0.115 × 10-3, followed by a Tukey’s post hoc test, Social vs object P = 0.056, Object vs home cage **P = 0.009, Social vs home cage ****P = 0.789 × 10-4: n = 6 biologically independent social exposed mice, n = 5 biologically independent object exposed mice, n = 5 biologically independent home caged mice). PL: prelimbic cortex, IL: infralimbic cortex, cg1/2: cingulate cortex1/2, Pir: Piriform cortex, aPVT: anterior paraventricular thalamus, pPVT: posterior paraventricular thalamus, MD: medial dorsal thalamus, Nac: nucleus accumbens, BLA: basolateral amygdala, LA: lateral amygdala, CeA: central amygdala, dPAG: dorsal periaqueductal gray, PVN: paraventricular nucleus of hypothalamus. Data in a, c are presented as mean ± s.e.m.

Source data

Extended Data Fig. 2 Juvenile social isolation leads to long lasting reduction of sociability in adult mice.

a, Timeline showing weaning at p21 and subsequent 2 weeks of juvenile social isolation (jSI), followed by re-housing or control group housing (GH). b, jSI mice showed reduced sociability scores vs GH mice in a 3 chamber sociability test, in which a mouse chooses between a social target and an object, and time spent investigating both is measured and compared (two tailed t-test, t36 = 2.154, *P = 0.038, n = 20 biologically independent GH mice, n = 18 biologically independent jSI mice) and reduced social interaction (two-way RM ANOVA, housing (GH/jSI) × stimulus (social/object) interaction F1,36 = 7.042, *P = 0.012, effect of housing F1,36 = 1.117, P = 0.298, effect of stimulus F1,36 = 14.860, P = 0.460 × 10-3, n = 20 biologically independent GH mice, n = 18 biologically independent jSI mice) c, jSI mice showed no difference in distance traveled during the open field test (two tailed t-test, t36 = 0.939, P = 0.354, n = 20 biologically independent GH mice, n = 18 biologically independent jSI mice), suggesting normal motor activity. While jSI mice showed reduced time in center during open field test (two tailed t-test, t36 = 2.054, *P = 0.047, n = 20 biologically independent GH mice, n = 18 biologically independent jSI mice), they showed no difference in an independent anxiety task (elevated plus maze (EPM)) two tailed t-test, t38 = 0.926, P = 0.360, n = 20 biologically independent GH mice, n = 18 biologically independent jSI mice). Data in b, c are presented as mean ± s.e.m.

Source data

Extended Data Fig. 3 Chemogenetic suppression of pPVT neuron activity reduces sociability in adult group-housed mice.

a, (left) AAV8-DIO-iDREADD (or mCherry) was injected together with AAV1-CaMKII-Cre in the pPVT. (right) A representative image shows selective transduction at injection areas of pPVT. Scale bar: 300 μm. Experimental images were obtained from 12 mice, three images per mouse, with similar results obtained. b, Validation of iDREADD action in pPVT neurons by slice whole-cell patch clamp recording. (left) A representative trace shows that bath application of CNO significantly decreases membrane potential of pPVT neurons. Traces were recorded from 7 cells from 3 biologically independent mice, with similar results obtained. (Right) Quantification shows a reduction in membrane potential after CNO application (two tailed paired t-test, t6 = 4.177, **P = 0.006, n = 7cells from 3 biologically independent mice). c, Mice were treated with saline (SAL) or CNO (10 mg/kg) and then underwent the 3 chamber test of sociability. For CNO and SAL injections, order is counter-balanced. d, Viral spread validation at injection areas of pPVT from post-behavioral testing mice. Gray areas represent the minimum (lighter colour) and the maximum (darker colour) spread of iDREADD into the pPVT. e, (left) CNO-treated iDREADD+ mice showed reduced sociability, revealed by reduced sociability scores vs. SAL (two tailed paired t-test, t11 = 2.257, *P = 0.045, n = 12 biologically independent mice), and disrupted behavior in 3 chamber sociability task (two-way RM ANOVA, housing (GH/jSI) × stimulus (social/object) interaction F1,22 = 4.894, *P = 0.038, effect of drug F1,22 = 0.032, P = 0.859, effect of stimulus F1,22 = 0.109, P = 0.745, n = 12 biologically independent mice). (right) iDREADD+ mice showed no differences in motor activity or anxiety-related behaviors (Left; two tailed paired t-test, t11 = 0.688, P = 0.506, n = 12 biologically independent mice Middle; two tailed paired t-test, t11 = 1.604, P = 0.137, n = 12 biologically independent mice, Right; two tailed paired t-test, t10 = 1.096, P = 0.299, n = 11 biologically independent mice) as a result of CNO vs. SAL treatment. f, (left) Control mCherry+ mice showed no difference in sociability score (two tailed paired t-test, t7 = 1.459, P = 0.188, n = 8 biologically independent mice) or investigation time (two-way RM ANOVA, housing (GH/jSI) × stimulus (social/object) interaction F1,14 = 0.352, P = 0.563, effect of drug F1,14 = 0.024, P = 0.880, effect of stimulus F1,14 = 8.630, P = 0.011, n = 8 biologically independent mice) as a result of CNO vs. SAL treatment. (right) Control mCherry+ mice showed no difference in motor activity or anxiety-related behaviors (Left; two tailed paired t-test, t7 = 0.981, P = 0.359, n = 8 biologically independent mice, Middle; two tailed paired t-test, t7 = 0.317, P = 0.761, n = 8 biologically independent mice Right: two tailed paired t-test, t7 = 0.662, P = 0.529, n = 8 biologically independent mice). Data in b, e, f are presented as mean ± s.e.m.

Source data

Extended Data Fig. 4 Optogenetic suppression of mPFC→pPVT projection terminals does not change motor activity or anxiety-related behaviors in group-housed mice.

a, (left) Halorhodopsin NpHR3.0 AAV under CamKII promotor was injected into mPFC and mPFC→pPVT projection terminals were illuminated at the pPVT using a wireless yellow LED system for behavioral testing. (middle/right) Validation of optogenetic suppression by patch-clamp recording from halorhodopsin NpHR3-expressing mPFC→pPVT projection neurons. (middle) Representative trace showing decreased action potentials of mPFC→pPVT projection neurons upon optogenetic stimulation (traces were recorded from 7 cells from 3 biologically independent mice, with similar results obtained), and (right) quantification (one-way RM ANOVA, F1.521,9.124 = 91.940, P = 0.167×10-5, Tukey’s multiple comparisons test: 1st OFF vs ON, ****P = 0.114×10-4, ON vs 2nd OFF, ****P = 0.328×10-3, n = 7 cells from 3 biologically independent mice,). b, c, In vivo validation of optogenetic suppression of mPFC→pPVT projection terminals. b, Representative in vivo recordings of pPVT neurons showing a significant decrease (top), increase (middle), or no change (bottom) in spike activity upon yellow light delivery over mPFC→pPVT projection terminals expressing halorhodopsin NpHR3 in pPVT. Experimental traces were obtained from 4 mice,13-16 cells per mouse, with similar results obtained. c, Distribution of pPVT neurons showing light-induced decreased firing (11 out of 57 cells from 4 biologically independent mice, 19%), increased firing (9 out of 57 cells from 4 biologically independent mice, 16%), or no change (37 out of 57 cells from 4 biologically independent mice, 65%). Effect of light stimulation for each unit was quantified by comparing the firing rates between light off period and light on period (5 s each) of 6 sessions per cell through paired t-test. d, Viral spread validation of NpHR3-expression from post-behavior testing mice at injection areas. Gray areas represent the minimum (lighter colour) and the maximum (darker colour) spread of NpHR3- expression in the mPFC. Experimental images were obtained from 14 mice, three images per mouse, with similar results obtained. e, Optic fiber location (yellow line circles) was validated in all mice. Experimental images were obtained from 14 mice, three images per mouse, with similar results obtained. f, Mice underwent open field testing, and elevated plus maze (EPM) with (ON) or without (OFF) light stimulation. ON and OFF session order was counter-balanced for each behavior test with a 24-hour interval between tests. Mice with optogenetic suppression showed no differences in motor activity or anxiety-related behaviors between ON and OFF sessions (Left; two tailed paired t-test, t13 = 0.747, P = 0.469, n = 14 biologically independent mice, Middle; two tailed paired t-test, t13 = 0.455, P = 0.657, n = 14 biologically independent mice, Right; two tailed paired t-test, t13 = 1.028, P = 0.323, n = 14 biologically independent mice). g, Control mCherry+ mice showed no difference in motor activity or anxiety-related behaviors between light ON and OFF sessions (Left; two tailed paired t-test, n = 9 biologically independent mice, t8 = 0.528, P = 0.612, Middle; two tailed paired t-test, t8 = 0.361, P = 0.727, n = 9 biologically independent mice, Right; two tailed paired t-test, t8 = 0.017, P = 0.987, n = 9 biologically independent mice,). Data in a, f, g are presented as mean ± s.e.m.

Source data

Extended Data Fig. 5 Juvenile social isolation does not change excitability, nor E/I input ratio of mPFC→NAc neurons, mPFC→cPFC neurons, or pPVT neurons in adulthood.

a–f, Whole-cell patch clamp recording from mPFC→NAc neurons in adult jSI or GH mice. b, c, Assessment of intrinsic excitability of PFC→NAc neurons in the presence of DNQX, D-AP5, and picrotoxin. b, (Left) Input-output curves showed no differences in spike frequency between jSI and GH mice (two-way RM ANOVA, housing (GH/jSI) × current step interaction F19,551 = 0.388, P = 0.992, effect of housing F1,29 = 1.103, P = 0.302, effect of current step F2.472, 71.70 = 161.200, P = 0.001×10-12, n = 15 cells from 8 biologically independent GH mice, n = 23 cells from 8 biologically independent jSI mice). (right) No significant differences in spike frequency at 200pA between jSI and GH (two tailed t-test, t36 = 0.399, P = 0.692, n = 15 cells from 8 biologically independent GH mice, n = 23 cells from 8 biologically independent jSI mice) (c) No significant differences in spike threshold between jSI and GH (two tailed t-test, t36 = -0.708, P = 0.484, n = 15 cells from 8 biologically independent GH mice, n = 23 cells from 8 biologically independent jSI mice). No significant differences in (d) sEPSC frequency (two tailed t-test, t48 = 0.308, P = 0.760, n = 23 cells from 8 biologically independent jSI mice), sEPSC amplitude (two tailed t-test, t48 = 0.305, P = 0.762, n = 27 cells from 8 biologically independent GH mice, n = 23 cells from 8 biologically independent jSI mice), e, sIPSC frequency (two tailed t-test, t48 = 0.879, P = 0.384, n = 27 cells from 8 biologically independent GH mice, n = 23 cells from 8 biologically independent jSI mice), sIPSC amplitude (two tailed t-test, t48 = 0.852, P = 0.398, n = 27 cells from 8 biologically independent GH mice, n = 23 cells, from 8 biologically independent jSI mice), or (f) sEPSC/sIPSC frequency ratio (two tailed t-test, t48 = 1.767, P = 0.084, n = 27 cells from 8 biologically independent GH mice, n = 23 cells from 8 biologically independent jSI mice) between jSI and GH. g–l, Whole-cell patch clamp recording from mPFC->contralateral PFC projection neurons (cPFC) in adult jSI or GH mice. h, i, Assessment of intrinsic excitability of PFC->cPFC neurons in the presence of DNQX, D-AP5, and picrotoxin. h, (Left) Input-output curve showing no differences in spike frequency (two-way RM ANOVA, housing (GH/jSI) × current step interaction F19,798 = 1.861, *P = 0.014, effect of housing F1,42 = 0.648, P = 0.425, effect of current step F4.628, 194.4 = 395.900, P = 0.001×10-12, n = 26 cells from 8 biologically independent GH mice, n = 20 cells from 8 biologically independent jSI mice). (right) No significant differences in spike frequency at 200pA between jSI and GH (two tailed t-test, t44 = 1.650, P = 0.106, n = 26 cells from 8 biologically independent GH mice, n = 20 cells frm 8 biologically independent jSI mice). i, No significant differences in spike threshold (two tailed t-test, t44 = 0.635, P = 0.529, n = 26 cells from 8 biologically independent GH mice, n = 20 cells from 8 biologically independent jSI mice), j, sEPSC frequency (two tailed t-test, t36 = 0.847, P = 0.403, n = 20 cells from 8 biologically independent GH mice, n = 18 cells from 8 biologically independent jSI mice), sEPSC amplitude (two tailed t-test, t36 = 1.370, P = 0.179, n = 20 cells from 8 biologically independent GH mice, n = 18 cells from 8 biologically independent jSI mice), k, sIPSC frequency (two tailed t-test, t36 = 0.758, P = 0.454, n = 20 cells from 8 biologically independent GH mice, n = 18 cells from 8 biologically independent jSI mice,), sIPSC amplitude (two tailed t-test, t36 = 0.493, P = 0.625, n = 20 cells from 8 biologically independent GH mice, n = 18 cells from 8 biologically independent jSI mice), or (l) sEPSC/IPSC frequency (two tailed t-test, t36 = 0.147, P = 0.884, n = 20 cells from 8 biologically independent GH mice, n = 18 cells from 8 biologically independent jSI mice) between jSI and GH. m–r, Whole-cell patch clamp recording from pPVT neurons in adult jSI or GH mice. n, o, Assessment of intrinsic excitability of pPVT neurons in the presence of DNQX (20 µM), D-AP5 (50 µM), and picrotoxin (30 µM). n, (Right) Input-output curve showing no differences in spike frequency (two-way RM ANOVA, housing (GH/jSI) × current step interaction F14,826 = 0.686, P = 0.790, effect of housing F1,59 = 0.017, P = 0.898, effect of current step F1.843, 108.7 = 93.580, P = 0.001×10-12, n = 26 cells from 8 biologically independent GH mice, n = 35 cells from 9 biologically independent jSI mice). (left) No significant differences in spike frequency at 200pA (two tailed t-test, t59 = 0.434, P = 0.666, n = 26 cells from 8 biologically independent GH mice, n = 35 cells from 9 biologically independent jSI mice), o, spike threshold (two tailed t-test, t59 = 0.376, P = 0.708, n = 26 cells from 8 biologically independent GH mice, n = 35 cells from 9 biologically independent jSI mice), p, sEPSC frequency (two tailed t-test, t39 = 0.356, P = 0.724, n = 20 cells from 8 biologically independent GH mice, n = 21 cells from 9 biologically independent jSI mice), or sEPSC amplitude (two tailed t-test, t39 = 0.636, P = 0.529, n = 20 cells from 8 biologically independent GH mice, n = 21 cells from 9 biologically independent jSI mice) between jSI and GH. q, sIPSC frequency was significantly higher in jSI mice compared to GH mice (two tailed t-test, t39 = 2.316, *P = 0.026, n = 20 cells from 8 biologically independent GH mice, n = 21 cells from 9 biologically independent jSI mice), but no diff erences in sIPSC amplitude (two tailed t-test, t39 = 1.804, P = 0.079, n = 20 cells from 8 biologically independent GH mice, n = 21 cells from 9 biologically independent jSI mice) were observed. r, No significant differences in sEPSC/IPSC frequency from pPVT neurons (two tailed t-test, t39 = 0.682, P = 0.499, n = 20 cells from 8 biologically independent GH mice, n = 21 cells from 9 biologically independent jSI mice) between jSI and GH. Data in b-f, h-l, n-r are presented as mean ± s.e.m.

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Extended Data Fig. 6 mEPSC and mIPSC of mPFC→pPVT neurons, mPFC→NAc neurons, and mPFC→cPFC neurons.

a–c, Whole-cell slice patch clamp recording from mPFC→pPVT neurons in adult jSI mice (20 cells from 6 biologically independent mice) or GH mice (19 cells from 5 biologically independent mice). b, mEPSC frequency was significantly lower in jSI mice compared to GH mice (two tailed t-test, t37 = 2.730, **P = 0.964×10-2) but there were no significant differences in mEPSC amplitude (two tailed t-test, t37 = 1.150, P = 0.258). c, There were no significant differences in mIPSC frequency (two tailed t-test, t37 = 0.101, P = 0.920) or mIPSC amplitude (two tailed t-test, t37 = 0.303, P = 0.764) between jSI and GH. d-f, Whole-cell patch clamp recording from mPFC→NAc neurons in adult jSI mice (n = 20 cells from 6 biologically independent mice) or GH mice (n = 20 cells from 6 biologically independent mice). e, There were no significant differences in mEPSC frequency (two tailed t-test, t38 = 0.002, P = 0.998) or mEPSC amplitude (two tailed t-test, t38 = 0.495, P = 0.624) between jSI and GH. f, There were no significant differences in mIPSC frequency (two tailed t-test, t38 = 0.066, P = 0.948) or mIPSC amplitude (two tailed t-test, t38 = 0.455, P = 0.652) between jSI and GH. g-i, Whole-cell patch clamp recording from mPFC→cPFC neurons in adult jSI mice (n = 19 cells from 5 biologically independent mice) or GH mice (n = 18 cells from 5 biologically independent mice). h, There were no significant differences in mEPSC frequency (two tailed t-test, t35 = 1.559, P = 0.128), or mEPSC amplitude (two tailed t-test, t35 = 1.275, P = 0.211) between jSI and GH. i, There were no significant differences in mIPSC frequency (two tailed t-test, t35 = 0.247, P = 0.807) or mIPSC amplitude (two tailed t-test, t35 = 1.579, P = 0.123) between jSI and GH. Data in b, c, e, f, h, i are presented as mean ± s.e.m.

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Extended Data Fig. 7 Optogenetic interrogation of mPFC→pPVT projection inputs onto pPVT neurons.

a, ChR2-encoding AAV1 was injected into the mPFC to express ChR2 in mPFC neurons. Whole cell patch-clamp recordings were performed while optogenetically activating mPFC→pPVT projection terminals in pPVT slices. b, Excitatory connectivity was assessed by normalized postsynaptic currents (PSCs) recorded at -70 mV from pPVT neurons before and after application of tetrodotoxin (TTX; 1 µM) with 4-aminopyridine (4-AP; 100 µM). A majority of pPVT neurons received a monosynaptic input from mPFC. There was no difference in mono/polysynaptic ratio (two tailed t-test, t13 = 0.349, P = 0.733, n = 8 cells from 5 biologically independent GH mice, n = 7 cells from 5 biologically independent jSI mice). c, (upper) Representative traces showing that optogenetic activation of mPFC->pPVT axons was blocked by DNQX (20 µM). pPVT neurons were clamped at –70 mV while optogenetically stimulating mPFC→pPVT axons before and after bath application of DNQX. Traces are recorded from 3 cells from 2 biologically independent mice, with similar results obtained. (bottom) Averaged amplitude decreases after application of DNQX (two tailed t-test, t2 = 17.790, **P = 0.003, n = 3 cells from 2 biologically independent mice). d, (left) Representative eEPSC of pPVT neurons upon optogenetic activation of mPFC→pPVT axons in GH and jSI mice through gradually changing the intensity. Traces were recorded from 17 cells from 7 biologically independent mice per group, with similar results obtained. (right) Intensity–amplitude curves showing the relationship between stimulus intensity and normalized eEPSC amplitude. Normalized eEPSC amplitude was lower in jSI mice than GH mice (two-way RM ANOVA, housing (GH/jSI) × current step interaction F5,185 = 3.740, **P = 0.003, effect of housing F1,37 = 4.173, P = 0.048, effect of current step F1.224, 45.29 = 25.830, P = 0.174×10-5, n = 17 cells from 7 biologically independent GH mice, n = 17 cells from 7 biologically independent jSI mice). e, There were no significant differences in PPR at a 500-ms interval (two tailed t-test, t25 = 1.551, P = 0.134, n = 17 cells from 7 biologically independent GH mice, n = 21 cells from 8 biologically independent jSI mice). Data in c, d, e are presented as mean ± s.e.m.

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Extended Data Fig. 8 Juvenile social isolation increases excitability of mPFC low-threshold spiking (LTS)-SST interneurons in adulthood.

a, Whole-cell patch clamp recording from mPFC SST interneurons in adult jSI or GH SST-GFP mice (SST-Cre mice crossed with Cre-dependent eGFP-L10a mice). b, Classification of SST cells based on firing patterns. SST cells were classified into 3 sub-types (low-threshold spike: LTS, quasi-fast spiking: QFS, adapting: AD) in L5/6 and mainly AD type in L2/3. c, % of sub-type of SST interneurons in L5/6 and L2/3 in GH and jSI mice. d, Assessment of intrinsic excitability of SST-LTS interneurons in L5/6 in the presence of DNQX, D-AP5, and picrotoxin. Traces were recorded from 14-15 cells from 4 biologically independent mice per group, with similar results obtained. (left) Representative traces at 100 pA injection recorded from SST-LTS cells. jSI group shows reduced spike frequency at 200pA and -100pA (two tailed t-test, t27 = 3.097, **P = 0.005, n = 14 cells from 4 biologically independent GH mice, n = 15 cells from 4 biologically independent jSI mice). e, SST-QFS type show comparable excitability between GH and jSI at 100pA (two tailed t-test, t47 = 1.614, P = 0.113, n = 23 cells from 6 biologically independent GH mice, n = 26 cells from 6 biologically independent jSI mice). f, g, The jSI group shows decreased excitability in (f) L5/6 SST-AD type at 100pA (two tailed t-test, t35 = 2.905, **P = 0.006, n = 17 cells from 6 biologically independent GH mice, n = 20 cells from 6 biologically independent jSI mice), and (g) L2/3 SST-AD type at 100pA (two tailed t-test, t30 = 2.186, *P = 0.037, n = 24 cells from 6 biologically independent GH mice, n = 18 cells from 6 biologically independent jSI mice). Data in d-g are presented as mean ± s.e.m.

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Extended Data Fig. 9 Optogenetic stimulation of mPFC→pPVT projection terminals does not change motor activity or anxiety-related behaviors in adult jSI mice.

a, CaMKII-ChR2 AAV1 was injected into the mPFC and a wireless blue LED was inserted above the pPVT in jSI mice. b, jSI mice underwent testing in the open field and elevated plus maze (EPM) with (ON) or without (OFF) light stimulation (20 Hz) (c) (left) Viral spread validation from behavior-tested mice. Gray areas represent the minimum (lighter colour) and the maximum (darker colour) spread of ChR2 expression into the mPFC. (right) Optic fiber tip location (blue line circles) was validated in all mice. Experimental images were obtained from 13 mice, three images per mouse for both mPFC and pPVT, with similar results obtained. d, ChR2+jSI mice showed no differences in motor activity or anxiety-related behaviors between ON and OFF sessions (Left; two tailed paired t-test, t12 = 0.346, P = 0.735, n = 13 biologically independent jSI mice, Middle; two tailed paired t-test, t12 = 0.431, P = 0.674, n = 13 biologically independent mice, Right; two tailed paired t-test, t12 = 1.364, P = 0.198, n = 13 biologically independent jSI mice). e, Control mCherry+ jSI mice showed no difference in motor activity or anxiety-related behaviors between ON and OFF sessions (Left; two tailed paired t-test, Left; t7 = 0.970, P = 0.365, n = 8 biologically independent jSI mice, Middle; t7 = 0.183, P = 0.860, n = 8 biologically independent jSI mice Right; t7 = 0.083, P = 0.936, n = 8 biologically independent jSI mice). f, g, Investigation time of each stimulus during the first 20 mins of 3 chamber testing from Day 1 to Day 4 of ON group (f) and OFF group (g) during the repeated optogenetic stimulation study in Fig. 8e, f. Data in d-g are presented as mean ± s.e.m.

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Yamamuro, K., Bicks, L.K., Leventhal, M.B. et al. A prefrontal–paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice. Nat Neurosci 23, 1240–1252 (2020). https://doi.org/10.1038/s41593-020-0695-6

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