Neural Circuit Mechanisms Of Behavioral And Cognitive Flexibility Deficits In Primates

Objective: Flexibility is the ability to make appropriate adjustment of thoughts and behaviors in response to changing environment and demands.It comprises both cognitive and behavioural components.Flexibility is essential for everyday decision-making.Deficits in flexibility are associated with many human diseases,such as abnormal behavioral flexibility of food intake in obesity and cognitive flexibility impairment in autism spectrum disorder.Resting-state f MRI(rs-f MRI)is a convenient and effective noninvasive research technique,which has a wide range of applications in the pathological mechanisms of various diseases,intervention studies and animal models.As a prioritized surgical intervention for patients with obesity,vertical sleeve gastrectomy(VSG)is able to efficaciously change eating behaviors and control food intake in obesity;however,the brain circuits that mediate its effects and predict surgical outcome remain largely unclear.The clinical heterogeneity of patients with autism is large,and the results of previous studies are poorly consistent.Using non-human primate models that are closer to humans with known genetic background allows us to study the neural mechanisms of flexibility from many aspects.In transgenic animal model that exhibiting autistic phenotypes,the impairment of cognitive flexibility and its related mechanism is lacking as well.Design: 1)Gut-brain mechanisms underlying VSG.Among 80 obese patients screened,36 patients together with 26 normal-weight healthy controls were enrolled and evaluated using the 21-item Three-Factor Eating Questionnaire(TFEQ),rs-f MRI scanning,plasma intestinal hormone analysis and fecal sample sequencing.32 cases underwent VSG treatment and 19 subjects completed a follow-up evaluation 4 months later.Data-driven regional homogeneity(Re Ho)coupled with seed-based connectivity analysis was used to quantify VSG-related brain activity.Longitudinal alterations of body weight,eating behavior,brain activity,gut hormones and microbiota were detected and subjected to repeated measures correlation analysis.2)Cognitive flexibility deficits and its related brain circuits in transgenic macaques overexpressing MECP2.To examine the cognitive flexibility in transgenic monkeys,five transgenic monkeys and four age-matched wild-type monkeys finally accomplished the touchscreen-based reversal learning task.Errors during the task were more precisely differentiated as perseverative errors and regressive errors to further quantify the cognitive flexibility in switching session.By combining with the rs-f MRI collected under anesthesia,we defined a brain circuit correlated with the behavioral deficits and built the relationships among gene,circuits and behaviors.Results: 1)VSG induced significant functional changes in right putamen and left supplementary motor area,both of which correlated with weight loss and TFEQ scores.Moreover,Re Ho of right putamen was associated with postprandial levels of active glucagon-like peptide-1(a GLP-1)and ghrelin.Meanwhile,relative abundance of Clostridia increased by VSG was associated with improvements in a GLP-1 secretion,putamen activity and weight loss.Furthermore,VSG normalized excessive functional connectivities with right putamen,among which baseline connectivity between right putamen and right orbitofrontal cortex was related to postoperative weight loss.2)Adult transgenic monkeys exhibited significant higher regressive error rate than wild-type monkeys in swith sessions of reversal learning task.Increased regressive error rate was further correlated with disturbed functional brain circuits mainly localized in frontal areas,also including parietal and subcortical regions.These cognitive deficits and abnormal brain circuits were also correlated with copy number of MECP2.Conclusions: VSG causes correlated alterations of gut-brain axis,including Clostridia,postprandial a GLP-1,putamen activity and eating habits.Preoperative connectivity of right putamen may represent a potential predictive marker of surgical outcome in obese patients.Transgenic monkeys exhibit correlated alteration of copy number,brain circuits and cognitive flexibility.Combing the rs-f MRI with behavioral and other omics data,we could dig more about the mechanisms and treatment effects of flexibility deficits in different diseases among different species.