Basolateral Amygdala Input To The Medial Prefrontal Cortex Controls Obsessive-compulsive Disorder-like Checking Behavior

Obsessive-compulsive disorder(OCD)is a common and debilitating neuropsychiatric disorder,characterized by persistent intrusive thoughts(obsessions)and repetitive actions(compulsions),and affects approximately 1-3%of the world population.Our country's clinical data show that the incidence rate is about 5-10%.Most patients with obsessive-compulsive disorder have an earlier onset time,usually in childhood,and most of them are male patients,seriously affecting their normal daily life.The etiology and pathology of OCD remain unclear,leading severe challenging of efficacious therapies to clinicians.Dysfunction of the cortico-striato-thalamo-cortical(CSTC)circuits,including serotonin,dopamine and glutamate systems,is thought to underlie certain types of OCD symptoms.However,a single model is insufficient to clarify OCD pathophysiology,because different OCD symptom dimensions(e.g.,symmetry/ordering vs.washing/cleaning)may have different underlying neural substrates.For example,the CSTC circuit is proposed to mediate fear of contamination in OCD,while discrete circuits in the insular cortex are elucidated as a primary loci of the symptom generation.Notably,selective serotonin reuptake inhibitors(SSRIs)are the first-line drug for the treatment of OCD,but 40-60%of patients respond poorly to this treatment.This evidence strongly suggests that integration of other brain structures beyond the CSTC circuit may be necessary to establish the causal link in OCD pathophysiology.Preliminary findings with glutamatergic neurotransmission-modulating agents have been promising for treatment of OCD.However,to date,it is not clear whether defects in the glutamatergic system are the primary cause and how the precise glutamate circuits beyond segregated CSTC pathways encode OCD symptoms,such as compulsive checking.Therefore,we target glutamate projecting system to identify the precise circuit and to examine its function in compulsive checking behavior.Using viral neuronal tracing in mice,we found that glutamatergic neurons from the basolateral amygdala(BLAGlu)project onto both medial prefrontal cortex glutamate(mPFCGlu)and GABA(mPFCGABA)neurons that locally innervate mPFCGlu neurons.Next,we developed a new OCD checking mouse model with quinpirole-induced repetitive checking behaviors.This model demonstrated decreased glutamatergic mPFC microcircuit activity regulated by enhanced BLAGlu inputs.Optical or chemogenetic manipulations of this maladaptive circuitry restored the behavioral response.These findings were verified in a mouse functional magnetic resonance imaging(fMRI)study,where the BLA-mPFC functional connectivity was increased in OCD mice.Together,these findings define a unique BLAGlu-mPFCGABA-Glu circuit that controls the checking symptoms of OCD.