Neural Circuit Mechanism For Midbrain Dopaminergic Modulation In Repetitive Stereotyped Behavior

Repetitive stereotyped behavior is a common symptom in several neuropsychiatric diseases,including obsessive compulsive disorder(OCD).In rodent models of OCD,self-grooming behavior is often used as an evaluation for repetitive stereotyped behaviors.The current neurobiological understanding of repetitive stereotyped behavior focuses on dysregulated neural activities within the fronto-striatal circuits and altered monoamine transmission.Dopamine(DA)level regulative drugs have been applied to OCD patients with observable benefits in reducing compulsive behaviors,however,the exact circuitry mechanism underlying such effects remains elusive.The goal of our study is thus to explore the precise brain circuits underlying DA’s control over this behavioral phenotype in OCD-like mice.We employed optogenetics,neural tracer technology and behavioral assay to uncover an SNc DAN mediating dual gating mechanism,which regulates self-grooming through either suppressing striatal(direct projection to VMS)or activating cortical(to l OFC then VMS)projections.However,another midbrain dopamine neuron containing region,VTA,does not facilitate OCDlike repetitive behavior.What is more,we combined in vivo single-unit electrophysiological recording and optogenetics in different Cre-line mice to establish the "opto-tag" method,which enabled us to classify different cell types in the striatum,and to explore how the two long-range neural circuits described above achieve differential regulation of repetitive stereotyped behaviors by regulating different microcircuits in VMS.In addition,we demonstrated that dopaminergic activity coordinates VMS microcircuitry and l OFC activity to regulate repetitive stereotyped behaviors through postsynaptic dopamine D1 receptors in PV neuron in VMS and presynaptic dopamine D2 receptors in l OFC,respectively.These results suggest that SNc dopaminergic neurons regulate repetitive stereotyped behaviors through striatal and cortical projection as a dual gating mechanism.Our findings thus provide experimental basis and promising target for clinical treatment of repetitive stereotyped behaviors in multiple neuropsychiatric diseases.