Resting-state dopaminergic cell firing in the ventral tegmental area negatively regulates affiliative social interactions in a developmental animal model of schizophrenia

Hidekazu Sotoyama,Dai Watanabe,Kenji Sakimura,Taku Hasegawa,Hiroyuki Nawa,Tomoyuki Furuyashiki,Ena Nakatsukasa,Yutaro Kobayashi,Hisaaki Namba

doi:10.1038/s41398-021-01346-2

Abstract

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.

Highlights

The impairment of human social behavior is one of the major pathological traits of psychiatric disorders such as schizophrenia and depression[1,2,3]
The main findings of the present study are as follows: (1) Among dopaminergic, noradrenergic, and serotonergic cell firing as monitored under the anesthetic condition, only putative dopaminergic cells of the epidermal growth factor (EGF) model exhibited an abnormal increase in their firing frequency but not in their spikes within bursts (SWB). (2) In the free-moving condition, the baseline firing frequency and SWB of putative dopaminergic cells were elevated in EGF model rats, whereas the social stimuli-triggered firing and bursting were blunted in these rats
Haloperidol treatment of this model fails to alter the dopaminergic cell firing (HS unpublished data). These findings appear to be concordant with the reports that the chronic medication of atypical antipsychotics involving serotonin antagonism is beneficial for treating negative symptoms of schizophrenia patients, this argument is still controversial[54,55]

Summary

Introduction

The impairment of human social behavior is one of the major pathological traits of psychiatric disorders such as schizophrenia and depression[1,2,3]. The neuropharmacology of antipsychotics or antidepressants medicating these social deficits indicates that monoamines like dopamine and serotonin are involved in the neuropathology of social behaviors in these disorders[4,5,6,7] These monoamines are known to independently and/or interactively regulate animal social behaviors through cognitive and/or. Sotoyama et al Translational Psychiatry (2021)11:236 negative symptoms of schizophrenia[19,20,21,22], many controversies remain[23,24] It is sometimes unclear whether the reported dopaminergic states of patients reflect a baseline resting condition, an acute event-related response, or a mixture of both[25,26,27]. Which has a crucial role in the regulation of social behaviors, baselineor event-triggered dopamine release26,30,31?

Methods

Results

Conclusion