The Central Nervous System Control Of The Brain-gut Axis Implicated In Stress Responses

Resilience and psychological adaptation to stress varies considerably among people based on adaptive coping behaviors,it has been strongly associated with mental and physical functioning.However little is known about the underlying mechanisms on systemic physiological regulation of stress response.Further research is needed to gain knowledge about the psychobiological mechanisms,especially neural regulation for strategies employed to confront stress.These may facilitate our understanding on early identification as well as prevention of stress-related disorders.Here we have administered passive stress coping trainings and behavioral assessments to characterize the individual differences in stress resilience in mice.Particularly,we performed predictable chronic mild stress(PCMS)or unpredictable chronic moderate stress(UCMS)for a month and evaluate the stress adaptation by classical behavioral tests including open field,elevated plus maze,dark/light box,and sucrose preference test et al.,as well as 3D tracking and AI based video analysis on behaviors related to anxiety states in mouse model and we have classified “stressresistant/stress-sensitive mice” by their stress coping associated behavioral characteristics.Further,we aim to identify the physiological signature for a "biological intrinsic" resilience,especially the intestinal characteristics of “stress-resilient mice”.We have recognized the significant changes in the composition of the gut microbiota by 16 S r RNA gene sequencing and fecal microbiota profiling,and significant reductions in the relative levels of abundance of microbiota such as Staphylococcus,Roseburia and significant increase in the relative levels of abundance of microbiota such as Rikenellaceae?RC9 in stress-resilient mice.In addition,metabolomic profiling and pathway analyses of feces samples revealed that purine and pyrimidine metabolic pathways were significantly up-regulated in stress-resilient mice.Finally we investigated the neurocircuit mechanism in defining the “stress resilient colon”.By retrograde and trans-synaptic virus tracing and whole brain imaging,we identified multiple brain regions that send neuronal projections to colon,including locus coeruleus(LC),which has been widely described in manipulating responses to anxiety.The co-localization of TH positive neurons with PRV152-labeled cells in LC by performing immune-stain suggested that TH neurons in LC may have central control on colon.Disrupted sympathetic control from brain by the celiac ganglia lesion led to decreased anxiety levels in mice.Meanwhile,chronic antibiotic treatments that reduced the diversity of gut microbiota resulted in the increased level of stress resilience in mice.Our data indicated the bidirectional regulation of gut-brain axis in stress resilience.Our current study provides physiological basis for the individual differences on adaptive coping behaviors to stress.The characterization of gut-brain axis mechanisms on stress adaptation may provide novel therapeutic targets for anxiety and stress disorders.