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Adolescent social isolation induces distinct changes in the medial and lateral OFC-BLA synapse and social and emotional alterations in adult mice

Abstract

Early-life social isolation is associated with social and emotional problems in adulthood. However, neural mechanisms underlying how social deprivation impairs social and emotional development are poorly understood. Recently, the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) have been highlighted as key nodes for social and emotional functions. Hence, we hypothesize that early social deprivation disrupts the information processing in the OFC-BLA pathway and leads to social and emotional dysfunction. Here, we examined the effects of adolescent social isolation on the OFC-BLA synaptic transmission by optogenetic and whole-cell patch-clamp methods in adult mice. Adolescent social isolation decreased social preference and increased passive stress-coping behaviour in adulthood. Then, we examined excitatory synaptic transmissions to BLA from medial or lateral subregions of the OFC (mOFC or lOFC). Notably, adolescent social isolation decreased the AMPA/NMDA ratio in the mOFC-BLA synapse in adulthood, while the ratio was increased in the lOFC-BLA synapse. Furthermore, we optogenetically manipulated the mOFC-BLA or lOFC-BLA transmission in behaving mice and examined the effects on social and stress-coping behaviours. Optogenetic manipulation of the mOFC-BLA transmission altered social behaviour without affecting passive stress-coping behaviour, while optogenetic manipulation of the lOFC-BLA transmission altered passive stress-coping behaviour without affecting social behaviour. Our results suggest that adolescent social isolation induces distinct postsynaptic changes in the mOFC-BLA and lOFC-BLA synapses, and these changes may separately contribute to abnormalities in social and emotional development.

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Fig. 1: Adolescent social isolation decreased social behaviour and increased passive stress-coping behaviour in mice.
Fig. 2: Adolescent social isolation induced distinct effects on postsynaptic properties in the medial and lateral OFC-BLA pathways.
Fig. 3: Adolescent social isolation did not induce significant effects on the paired-pulse ratio in both mOFC-BLA and lOFC-BLA synapses.
Fig. 4: mOFC-BLA pathway modulates social but not passive stress-coping behaviour.
Fig. 5: lOFC-BLA pathway modulates passive stress-coping but not social behaviour.

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Acknowledgements

We would like to thank Ms. Yasuko Nakamura, Ms. Hiromi Fujita, Ms. Masako Shikama, Ms. Yoshiko Hara, Mr. Shuhei Kayashima, and Dr. Misa Yamada for their assistance with the experiments and animal care. We would like to thank Editage (www.editage.com) for English language editing.

Funding

The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. This research was supported by KAKENHI (grant number: 18K15533, 21J01636), an Intramural Research Grant (grant number: 30-1 and 3-1) for Neurological and Psychiatric Disorders funded by the National Centre of Neurology and Psychiatry (NCNP) and research grant from Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics, Japan.

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HK, MY, and MS conceived and designed the experiments. HK and YN performed the experiments and analysed the data. HK, MY, and MS contributed to writing the manuscript. All authors discussed the results and implications and critiqued the manuscript.

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Correspondence to Hiroshi Kuniishi.

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Kuniishi, H., Nakatake, Y., Sekiguchi, M. et al. Adolescent social isolation induces distinct changes in the medial and lateral OFC-BLA synapse and social and emotional alterations in adult mice. Neuropsychopharmacol. 47, 1597–1607 (2022). https://doi.org/10.1038/s41386-022-01358-6

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