. 2019 Jan 16;101(2):246-259.e6.

doi: 10.1016/j.neuron.2018.11.018. Epub 2018 Dec 3.

Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder

Martina Sgritta¹, Sean W Dooling², Shelly A Buffington¹, Eric N Momin³, Michael B Francis¹, Robert A Britton⁴, Mauro Costa-Mattioli⁵

Affiliations

¹ Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: costamat@bcm.edu.

PMID: 30522820
PMCID: PMC6645363
DOI: 10.1016/j.neuron.2018.11.018

Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder

Martina Sgritta et al. Neuron. 2019.

. 2019 Jan 16;101(2):246-259.e6.

doi: 10.1016/j.neuron.2018.11.018. Epub 2018 Dec 3.

Authors

Martina Sgritta¹, Sean W Dooling², Shelly A Buffington¹, Eric N Momin³, Michael B Francis¹, Robert A Britton⁴, Mauro Costa-Mattioli⁵

Affiliations

¹ Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: costamat@bcm.edu.

PMID: 30522820
PMCID: PMC6645363
DOI: 10.1016/j.neuron.2018.11.018

Abstract

Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host's gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.

Keywords: autism; dopamine; gut-microbiota-brain axis; microbiome; oxytocin; probiotic; social behavior; vagus nerve.

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Figures

**Figure 1.. *Shank3B^−/−* mice exhibit changes in their microbial composition, reduced *L. reuteri* levels, and social deficits that were rescued by treatment with *L. reuteri*.**
(A) Principal coordinates analysis (PCoA) of unweighted UniFrac distances from the 16S rRNA gene sequencing data set shows that *Shank3B^−/−* samples clustered separately from those of WT littermates (n = 6-7 per group; p < 0.01, R² = 0.225; 8024 reads/sample). (B) qPCR analysis shows lower levels of *L. reuteri* in *Shank3B^−/−* mice (as % of total bacteria, n = 9-16 per group; WT vs. *Shank3B^−/−:* Mann-Whitney Test p < 0.0001). (c)Schematic of experimental design. (D)Schematic of the three-chamber task. (E-F) In *Shank3B^−/−* mice, *L reuteri* rescued social behavior deficits in the three chamber test (E, Sociability, n = 7-13 per group; WT: t = 5.68, p < 0.0001; *Shank3B^−/−* + vehicle: t = 0.14, p = 0.99; *Shank3B^−/−* + *L. reuteri: t* = 8.066, p < 0.0001; two-way ANOVA F_2,52 = 17.9, p < 0.0001; F, Social Novelty, n = 7-13 per group; WT: t = 5.01, p < 0.0001; *Shank3B^−/−* + vehicle: t = 3.75, p < 0.01; *Shank3B^−/−* + *L. reuteri: t* = 4.63, p < 0.0001; two-way ANOVA F_2,52 = 0.52, p = 0.59). (G)Schematic of the reciprocal social interaction task. (H)*L. reuteri* rescued reciprocal social interaction deficits in *Shank3B^−/−* mice (n = 9-12 pairs per group; WT vs. *Shank3B^−/−* + vehicle: t = 3.03, p < 0.05; *Shank3B^−/−* + vehicle vs. *Shank3B^−/−* + *L. reuteri*: t = 3.20, p < 0.01; WT vs. *Shank3B^−/−* + *L. reuteri*: t = 0.32, p > 0.99; one-way ANOVA F_2,28 = 6.3, p = 0.0055). ns, not significant. Plots show mean ± SEM. See also Figure S1-S5, S15.

**Figure 2.. BTBR mice exhibit changes in microbial composition, reduced *L. reuteri* levels, and social deficits that were rescued by treatment with *L. reuteri*.**
(A) PCoA of unweighted UniFrac distances from the 16S rRNA gene sequencing data set shows that BTBR samples clustered separately from C57BL/6J samples (n = 10-11 per group; p < 0.01, R² = 0.164; 8024 reads/sample). (B) qPCR analysis shows lower levels of *L. reuteri* (as % of total bacteria, n = 9-10 per group; C57BL/6J vs. BTBR: Mann-Whitney Test p < 0.0001) in BTBR mice. (C-E) In *BTBR* mice, *L. reuteri* rescued social behavior deficits in the three chamber test (C, Sociability, n = 16-17 per group; C57BL/6J: t = 7.033, p < 0.0001; BTBR + vehicle: t = 0.93, p > 0.99; BTBR + *L. reuteri*: t = 2.75, p < 0.05; two-way ANOVA F_2,94 = 9.54, p < 0.001; D, Social Novelty, n = 16-17 per group; C57BL/6J: t = 6.35, p < 0.0001; BTBR + vehicle: t = 0.67, p > 0.99; BTBR + *L. reuteri*: t = 2.87, p < 0.05; two-way ANOVA F_2,94 = 7.935, p < 0.001) and the reciprocal social interaction test (E, n = 8-11 pairs per group; C57BL/6J vs. BTBR + vehicle: t = 3.03, p < 0.05; BTBR + vehicle vs. BTBR + *L. reuteri*: t = 4.57, p < 0.001; C57BL/6J vs. BTBR + *L. reuteri*: t = 1.25, p =0.67; one-way ANOVA F_2,27 = 10.79, p < 0.001). ns, not significant. Plots show mean ± SEM. See also Figure S6, S7, S15.

**Figure 3.. *L. reuteri* does not change the microbial composition of *Shank3B^−/−* mice and is sufficient to rescue social deficits in germ-free (GF) mice.**
(A)PCoA of unweighted UniFrac distances from the 16S rRNA gene sequencing data set shows treatment with *L. reuteri* did not significantly alter the clustering of *Shank3B^−/−* samples (n = 6-10 per group; p < 0.001; R² = 0.215, 8024 reads/sample). (B-D) In GF mice, *L. reuteri* reversed social behavior deficits in the three-chamber test (B, Sociability, n = 8-16 per group; Controls: t = 5.44, p < 0.0001; GF + vehicle: t = 1.87, p = 0.20; GF + *L. reuteri*: t = 3.85, p < 0.001; two-way ANOVA F_2,68 = 16.64, p < 0.0001; C, Social Novelty, n = 8-16 per group; Controls: t = 3.00, p < 0.05; GF + vehicle: t = 1.28, p = 0.61; GF + *L. reuteri*: t = 4.10, p < 0.001; two-way ANOVA F_2,68 = 7.63, p = 0.0010) and the reciprocal social interaction test (D, n = 8-13 pairs per group; Controls vs. GF + vehicle: t = 5.89, p < 0.0001; Controls vs. GF + *L. reuteri*: t = 0.77, p > 0.99; GF + vehicle vs. GF + *L. reuteri*: t = 6.03, p < 0.0001; one-way ANOVA F_2,30 = 24.87, p < 0.0001). ns, not significant. Plots show mean ± SEM. See also Figure S8.

**Figure 4.. *Shank3B^−/−* mice show no alterations in intestinal permeability and *L. reuteri* fails to improve social behavior in vagotomized *Shank3B^−/−* mice.**
(A) Intestinal permeability assay by FITC intensity shows no difference between *Shank3B^−/−* mice and WT littermates (n = 6-7 per group; WT + DSS vs. WT: t = 3.17, p < 0.05; WT+ DSS vs. *Shank3B^−/−*: t = 3.95, p < 0.01; WT vs. *Shank3B^−/−*: t = 0.81, p > 0.99; one-way ANOVA F_2.17 = 8.6, p = 0.0026). (B) Expression of gut tight junction components was unaltered in *Shank3B^−/−* mice, as determined by RT-qPCR (n = 5-6 per group; WT vs. *Shank3B^−/−*: *Cdh1 t* = 0.17, p > 0.99; *Ocln t* = 0.13, p > 0.99, *Cldn5 t* = 1.03, p > 0.99; *Jam1 t* = 0.87, p > 0.99; one-way ANOVA F_3,39 = 0.62, p = 0.60). (C) Schematic of the vagotomy experimental design. (D-F) In vagotomized *Shank3B^−/−* mice, *L. reuteri* failed to reverse social behavior deficits in the three-chamber test (D, Sociability, n = 7 per group; *Shank3B^−/−* Sham + *L. reuteri*: t = 3.22, p < 0.05; *Shank3B^−/−* Vagotomized + *L. reuteri*: t = 1.33, p = 0.35; two-way ANOVA F_1,24 = 10,4, p = 0.003; E, Social Novelty, n = 7 per group; *Shank3B^−/−* Sham + *L. reuteri*: t = 2.56, p < 0.05; *Shank3B^−/−* Vagotomized + *L. reuteri*: t = 2.60, p < 0.05; two-way ANOVA F_1,22 = 0.028, p = 0.86) and reciprocal social interaction test (F, n = 6-7 pairs per group; *Shank3B^−/−* Sham + *L. reuteri* vs. *Shank3B^−/−* Vagotomized + *L. reuteri*: Mann-Whitney Test p < 0.01). DSS, dextran sodium sulfate; ns, not significant. Plots show mean ± SEM. See also Figure S9.

**Figure 5.. *L. reuteri* treatment corrects oxytocin levels in the PVN of the hypothalamus of *Shank3B^−/−* mice.**
(A) Representative images of oxytocin positive neurons at different antero-posterior levels of the PVN of control mice. (B) Oxytocin immunoreactivity in the PVN of WT and *Shank3B^−/−* mice treated with either vehicle or *L. reuteri*. (C-F) Oxytocin positive cell number (C, n = 5 mice per group; WT vs. *Shank3B^−/−* + vehicle: t = 2.96, p < 0.05; Shank3B^−/− + vehicle vs. *Shank3B^−/−* + *L. reuteri*: t = 3.64, p < 0,05; WT vs. *Shank3B^−/−* + *L. reuteri*: t = 0.59, p > 0.99; one-way ANOVA F_2,12 = 7.28, p = 0.0085) and oxytocin immunofluorescence intensity (E, n = 5 mice per group; WT vs. *Shank3B^−/−* + vehicle: t = 5.38, p < 0.001; *Shank3B^−/−* + vehicle vs. *Shank3B^−/−* + *L. reuteri*: t = 4.41, p < 0.01; WT vs. *Shank3B^−/−* + *L. reuteri*: t = 0.96, p = 0.0025; one-way ANOVA F_2,12 = 16.49, p = 0.0004) are restored after *L. reuteri* treatment. The number (D, n = 5 mice per group, WT vs. *Shank3B^−/−* + vehicle: t = 0.62, p > 0.99; *Shank3B^−/−* + vehicle vs. *Shank3B^−/−* + *L. reuteri*: t = 1.01, p = 0.99, WT vs. *Shank3B^−/−* + *L. reuteri*: t = 0.38, p > 0.99; one-way ANOVA F_2.12 = 0.52, p = 0.60) and the fluorescence intensity (F, n = 5 mice per group, WT vs. *Shank3B^−/−* + vehicle: t = 1.34, p = 0.61; *Shank3B^−/−* + vehicle vs. *Shank3B^−/−* + *L. reuteri*: t = 1.42, p = 0.54; WT vs. *Shank3B^−/−* + *L. reuteri*: t = 0.07, p > 0.99; one-way ANOVA F_2,12 = 1.27, p = 0.31) of NeuN positive cells did not change between the groups. ns, not significant. Plots show mean ± SEM.

**Figure 6.. Oxytocin administration rescues social deficits in both *Shank3B^−/−* and *Shank3B^−/−* vagotomized mice.**
(A) Schematic of experimental design. (B-C) In *Shank3B^−/−* mice, oxytocin improved social behavior deficits in the three-chamber test (B, Sociability, n = 8-10 per group; WT: t = 3.84, p < 0.01; *Shank3B^−/−* + vehicle: t = 0.28, p > 0.99; *Shank3B^−/−* + oxytocin: t = 2.88, p < 0.05; two-way ANOVA F_2,48 = 2.94, p = 0.06) and reciprocal social interaction test (C, n = 7-9 pairs per group; WT vs. *Shank3B^−/−* + vehicle: t = 2.70, p < 0.05; *Shank3B^−/−* + vehicle vs. *Shank3B^−/−* + oxytocin: t = 4.02, p < 0.01; WT vs. *Shank3B^−/−* + oxytocin: t = 1.45, p = 0.49; one-way ANOVA F_2,19 = 0.0025). (D-E) In *Shank3B^−/−* vagotomized mice, oxytocin also improved social behavior deficits in the three-chamber test (D, Sociability, n = 7 per group; *Shank3B^−/−* Vagotomized + *L. reuteri*: t = 1.35, p = 0.33; *Shank3B^−/−* Vagotomized + oxytocin: t = 2.76, p < 0.05, two-way ANOVA F_1,24 = 8.46, p = 0.0077) and reciprocal social interaction test (E, n = 5-6 pairs per group; *Shank3B^−/−* Vagotomized + *L. reuteri* vs. *Shank3B^−/−* Vagotomized + oxytocin: Mann-Whitney Test p < 0.05). ns, not significant. Plots show mean ± SEM. See also Figure S10-S11.

**Figure 7.. *L. reuteri* rescues the impaired social interaction-induced synaptic plasticity in VTA DA neurons of *Shank3B^−/−* mice, but not in mice lacking oxytocin receptors.**
(A) Schematic of electrophysiology experiments. (B) AMPAR/NMDAR ratio in lateral VTA DA neurons recorded at baseline and 24 hours after reciprocal social interaction (n = 6-8; WT baseline vs. *Shank3B^−/−* + vehicle baseline: t = 1.81, p > 0.99; WT baseline vs. WT social interaction: t = 5.70, p < 0.0001; WT baseline vs. *Shank3B^−/−* + vehicle social interaction: t = 0.29, p > 0.99; WT baseline vs. *Shank3B^−/−* + *L. reuteri*: t = 1.07, p > 0.99; WT baseline vs. *Shank3B^−/−* + *L. reuteri* social interaction: t = 4.04, p < 0.01; WT baseline vs. *Shank3B^−/−* + cocaine: t = 3.64, p < 0.05; WT baseline vs. *Shank3B^−/−* + oxytocin social interaction: t = 4.29, p < 0.01; *Shank3B^−/−* baseline + vehicle vs. WT social interaction: t = 7.51, p < 0.0001; *Shank3B^−/−* + vehicle baseline vs. *Shank3B^−/−* + vehicle social interaction: t = 1.58, p > 0.99; *Shank3B^−/−* + vehicle baseline vs. *Shank3B^−/−* + *L. reuteri*: t = 0.66, p > 0.99, *Shank3B^−/−* + vehicle baseline vs. *Shank3B^−/−* + *L. reuteri* social interaction: t = 5.78, p < 0.0001; *Shank3B^−/−* + vehicle baseline vs. *Shank3B^−/−* + cocaine: t = 5.38, p < 0.0001; *Shank3B^−/−* + vehicle baseline vs. *Shank3B^−/−* + oxytocin social interaction t = 6.1, p < 0.0001; WT social interaction vs. *Shank3B^−/−* + vehicle social interaction: t = 6.18, p < 0.0001; WT social interaction vs. *Shank3B^−/−* + *L. reuteri*: t = 6.55, p < 0.0001; WT social interaction vs. *Shank3B^−/−* + *L. reuteri* social interaction: t = 1.43, p > 0.99; WT social interaction vs. *Shank3B^−/−* + cocaine: t = 1.83, p > 0.99; WT social interaction vs. *Shank3B^−/−* + oxytocin social interaction: t = 1.41, p > 0.99; *Shank3B^−/−* + vehicle social interaction vs. *Shank3B^−/−* + *L. reuteri*: t = 0.82, p > 0.99; *Shank3B^−/−* + vehicle social interaction vs. *Shank3B^−/−* + *L. reuteri* social interaction: t = 4.44, p < 0.01; *Shank3B^−/−* + vehicle social interaction vs. *Shank3B^−/−* + cocaine: t = 4.03, p < 0.01; *Shank3B^−/−* + vehicle social interaction vs. *Shank3B^−/−* + oxytocin social interaction: t = 4.72, p < 0.001; *Shank3B^−/−* + *L. reuteri* vs. *Shank3B^−/−* + *L. reuteri* social interaction: t = 4.93, p < 0.001; *Shank3B^−/−* + *L. reuteri* vs. *Shank3B^−/−* + cocaine: t = 4.55, p < 0.01; *Shank3B^−/−* + *L. reuteri* vs. *Shank3B^−/−* + oxytocin social interaction: t = 5.19, p < 0.001; *Shank3B^−/−* + *L. reuteri* social interaction vs. *Shank3B^−/−* + cocaine: t = 0.38, p > 0.99; *Shank3B^−/−* + *L. reuteri* social interaction vs. *Shank3B^−/−* + oxytocin social interaction t = 0.07, p > 0.99; *Shank3B^−/−* + cocaine vs. *Shank3B^−/−* + oxytocin social interaction t = 0.47, p > 0.99; one-way ANOVA F_7,46 = 16.68, p < 0.0001). Representative AMPA and NMDA traces are shown above each group. (C) Reciprocal social interaction was impaired in DA-*Oxtr^−/−* mice and neither *L. reuteri* or oxytocin reversed the social deficits in these mice (n = 10-12 pairs per group; Controls vs. DA-*Oxtr^−/−* + vehicle: t = 6.095, p < 0.0001; Controls vs. DA-*Oxtr^−/−* + *L. reuteri*: t = 5.517, p < 0.0001; Controls vs. DA-*Oxtr^−/−* + oxytocin: t = 5.148, p < 0.0001; DA-*Oxtr^−/−* + vehicle vs. DA-*Oxtr^−/−* + *L. reuteri*: t = 0.6059, p > 0.99; DA-*Oxtr^−/−* + vehicle vs. DA-*Oxtr^−/−* + oxytocin: t = 0.8639, p > 0.99; DA-*Oxtr^−/−* + *L. reuteri* vs. DA-*Oxtr^−/−* + oxytocin: t = 0.2712, p > 0.99; one-way ANOVA F_3,41 = 15.34, p < 0.0001). (D) AMPA/NMDA ratio of DA neurons in the lateral VTA at baseline and 24 hours after reciprocal social interaction (n = 6-7 per group; DA-*Oxtr^−/−* + vehicle social interaction vs. DA-*Oxtr^−/−* social interaction + *L. reuteri*: t = 0.02, p > 0.99; DA-*Oxtr^−/−* + vehicle social interaction vs. Controls baseline: t = 0.40, p > 0.99; DA-*Oxtr^−/−* + vehicle social interaction vs. DA-*Oxtr^−/−* + cocaine: t = 5.47, p < 0.0001; DA-*Oxtr^−/−* + vehicle social interaction vs. DA- *Oxtr^−/−* + vehicle: t = 0.44, p > 0.99, DA-*Oxtr^−/−* + vehicle social interaction vs. Controls social interaction: t = 4.92, p < 0.001; DA-*Oxtr^−/−* + vehicle social interaction vs. DA-*Oxtr^−/−* + oxytocin social interaction: t = 0.089, p > 0.99; DA-*Oxtr^−/−* + *L. reuteri* social interaction vs. Controls baseline: t = 0.37, p > 0.99; DA-*Oxtr^−/−* + *L. reuteri* social interaction vs. DA- *Oxtr^−/−* + cocaine: t = 5.49, p < 0.0001; DA-*Oxtr^−/−* + *L. reuteri* social interaction vs. DA-*Oxtr^−/−* + vehicle: t = 0.47, p > 0.99; DA-*Oxtr^−/−* + *L. reuteri* social interaction vs. Controls social interaction: t = 4.94, p < 0.001; Controls baseline vs. DA-*Oxtr^−/−* + cocaine: t = 6.08, p < 0.0001; Controls baseline vs. DA-*Oxtr^−/−* + vehicle: t = 0.88, p > 0.99; Controls baseline vs. Controls social interaction: t = 5.50, p < 0.0001; Controls baseline vs. DA-*Oxtr^−/−* + oxytocin social interaction: t = 0.32, p > 0.99; DA-*Oxtr^−/−* + cocaine vs. DA-*Oxtr^−/−* + vehicle: t = 5.23, p < 0.001; DA-*Oxtr^−/−* + cocaine vs. Controls social interaction: t = 0.55, p > 0.99; DA-*Oxtr^−/−* + cocaine vs. DA-*Oxtr^−/−* + oxytocin social interaction: t = 5.76, p < 0.0001; DA- *Oxtr^−/−* + vehicle vs. Controls social interaction: t = 4.66, p < 0.001; DA-*Oxtr^−/−* + vehicle vs. DA-*Oxtr^−/−* + oxytocin social interaction: t = 0.55, p > 0.99; Controls social interaction vs. DA-*Oxtr^−/−* + oxytocin social interaction t = 5.19, p < 0.001; one-way ANOVA F_6,38 = 13.46, p < 0.0001). ns, not significant. Plots show mean ± SEM. See also Figure S12-S14.

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Gut Microbes Join the Social Network.
Vuong HE, Hsiao EY. Vuong HE, et al. Neuron. 2019 Jan 16;101(2):196-198. doi: 10.1016/j.neuron.2018.12.035. Neuron. 2019. PMID: 30653931 Free PMC article.

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Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder

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Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder

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