The Functional Role Of MPFC GABA（B） Receptors And The Cecal Microbiota In Stress Resilience And Susceptibility

Stress events in living environment are one of the main causes of mental diseases such as anxiety and depression.However,there are individual differences in human and animal responses to stress,namely resilience and susceptibility.To explore the neural mechanism of “resilience/susceptibility” is an important part of the research on the pathogenesis of psychiatric illnesses such as depression.GABA（B）receptor is a kind of G protein coupled receptor,which including GABA（B1）and GABA（B2）subunits.Preclinical studies suggest that GABA（B）receptors are potential targets for the treatment of major depression,but the regulatory mechanisms of this receptor in stress resilience/susceptibility is unclear.In the first part of this thesis,we assessed the functional role of GABA（B）receptors in stress resilience and vulnerability by using chronic unpredictable stress（CUS）model in male mice.As the medial prefrontal cortex（m PFC,which including the anterior cingulate cortex（ACC）,prelimbic cortex（Pr L）and infralimbic cortex（IL）subregions in rodents）plays a key role in the top-down modulation of stress responses,we focused our study on this brain structure.Our results showed that:（1）approximately 41.9% of subjects exhibited anxiety-or despair-like behaviors after exposure to CUS;（2）the vulnerable mice showed higher c-Fos expression in the IL subregion of the m PFC when exposed to a social stressor;（3）Western-blot results showed that the expression of GABA（B1）but not GABA（B2）receptors was significantly downregulated in IL subregion of susceptible mice;（4）intra-IL administration of baclofen,a GABA（B）receptor agonist,rapidly relieved the social avoidance symptoms of the “stress-susceptible” mice.The above results show that the GABA（B1）receptor within the IL may play an important role in stress resilience and vulnerability in male mice.Growing evidence suggests that perturbations within the composition of the gastrointestinal microbiota plays a crucial role in the pathogenesis of depression,and regulating gastrointestinal microbiota is expected to become a novel way in depression treatment.However,the relationship between gastrointestinal microbiota and stress resilience and susceptible and the underlying neural mechanisms remains largely unknown.Therefore,in the second part of this thesis,we addressed these questions and focus on particularly on catecholamine neurotransmitters,which including dopamine（DA）,5-hydroxytryptamine（5-HT）,and noradrenaline（NA）.Our results show that:（1）the stress susceptibility rate is about 50% after exposure to chronic social defeat stress（CSDS）;（2）compared with resilient groups,the composition of cecal microbiota were significantly changed in stress-susceptible subjects,mainly manifested in the decreased abundance of Lactobacillus;（3）the depression-like symptoms of stress-susceptible mice were significantly improved by 14-day oral administration of Lactobacillus murinus（L.murinus）;（4）compared with the vehicle control group,administration of L.murinus significantly increased tryptophan hydroxylase 2（TPH2）expression within the dorsal raphe nucleus（DR）in susceptible groups,but the expression of tyrosine hydroxylase（TH）in the ventral tegmental are（VTA）and dopamine-β-hydroxylase（DBH）in the locus coeruleus（LC）showed no obvious difference.The above results indicated that L.murinus may play an important regulatory role in stress reactions through 5-HTergic pathway.Overall,the above results contribute to a deeper understanding of the neural mechanisms underlying stress susceptible /resilient,and thus provide new ideas and methods to develop novel,personalized approaches in treating stress-related psychiatric disorders.