TY - JOUR
T1 - Resting-state dopaminergic cell firing in the ventral tegmental area negatively regulates affiliative social interactions in a developmental animal model of schizophrenia
AU - Sotoyama, Hidekazu
AU - Namba, Hisaaki
AU - Kobayashi, Yutaro
AU - Hasegawa, Taku
AU - Watanabe, Dai
AU - Nakatsukasa, Ena
AU - Sakimura, Kenji
AU - Furuyashiki, Tomoyuki
AU - Nawa, Hiroyuki
PY - 2021/4/22
Y1 - 2021/4/22
N2 - Hyperdopaminergic activities are often linked to positive symptoms of schizophrenia, but their neuropathological implications on negative symptoms are rather controversial among reports. Here, we explored the regulatory role of the resting state-neural activity of dopaminergic neurons in the ventral tegmental area (VTA) on social interaction using a developmental rat model for schizophrenia. We prepared the model by administering an ammonitic cytokine, epidermal growth factor (EGF), to rat pups, which later exhibit the deficits of social interaction as monitored with same-gender affiliative sniffing. In vivo single-unit recording and microdialysis revealed that the baseline firing frequency of and dopamine release from VTA dopaminergic neurons were chronically increased in EGF model rats, and their social interaction was concomitantly reduced. Subchronic treatment with risperidone ameliorated both the social interaction deficits and higher frequency of dopaminergic cell firing in this model. Sustained suppression of hyperdopaminergic cell firing in EGF model rats by DREADD chemogenetic intervention restored the event-triggered dopamine release and their social behaviors. These observations suggest that the higher resting-state activity of VTA dopaminergic neurons is responsible for the reduced social interaction of this schizophrenia model.
AB - Hyperdopaminergic activities are often linked to positive symptoms of schizophrenia, but their neuropathological implications on negative symptoms are rather controversial among reports. Here, we explored the regulatory role of the resting state-neural activity of dopaminergic neurons in the ventral tegmental area (VTA) on social interaction using a developmental rat model for schizophrenia. We prepared the model by administering an ammonitic cytokine, epidermal growth factor (EGF), to rat pups, which later exhibit the deficits of social interaction as monitored with same-gender affiliative sniffing. In vivo single-unit recording and microdialysis revealed that the baseline firing frequency of and dopamine release from VTA dopaminergic neurons were chronically increased in EGF model rats, and their social interaction was concomitantly reduced. Subchronic treatment with risperidone ameliorated both the social interaction deficits and higher frequency of dopaminergic cell firing in this model. Sustained suppression of hyperdopaminergic cell firing in EGF model rats by DREADD chemogenetic intervention restored the event-triggered dopamine release and their social behaviors. These observations suggest that the higher resting-state activity of VTA dopaminergic neurons is responsible for the reduced social interaction of this schizophrenia model.
U2 - 10.1038/s41398-021-01346-2
DO - 10.1038/s41398-021-01346-2
M3 - Article
C2 - 33888687
VL - 11
SP - 236
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
IS - 1
ER -