The Function Role Of Metabotropic Glutamate Receptors And Related Neural Circuits Within The Lateral Septum In Stress Vulnerability

Major depression and related mood disorders are among the greatest public health problems in current society.The etiology of depression are multifactorial which including but not limited to genetic susceptibility,stress emotional trauma,viral infections and abnormal brain development processes.Among them,exposure to a variety of stresses is an important predisposing environmental factor.However,individuals perceive stressful events differently.Only a few of them develop a variety of mental diseases after exposure to a series of setbacks.In psychological terms,this trait is called“resilience”.It is therefore interesting and meaningful to investigate the neural mechanisms underlying stress resilience and susceptibility which may represent an innovative approach to drug development for depression prevention and treatment.The lateral septum（LS）is a limbic structure located in the subcortical forebrain,slightly dorsocaudal to the nucleus accumbens,and plays an important role in emotion,cognition,motor,reward and a few of social behaviors.According to previous studies,metabolic glutamate receptors（mGluRs）play an important role in stress susceptibility and are abundantly expressed within the LS.Therefore,in the first part of this thesis,we assessed the functional roles of the mGlu2/3Rs and mGlu5Rs within different subregions of the LS in modulating stress resilience and susceptibility by using chronic social defeat stress（CSDS）paradigms in C57BL/6J male mice.Our results showed that:（1）approximately 47.9%of individuals showed anxiety and depression-like behavior after exposure to CSDS,which could be called stress susceptibility;（2）compared with the control group and the resilient group,c-Fos expression（a marker of neural activation）in the LS significantly increased in susceptible subjects;（3）Western-Blot results showed the expression of mGlu2/3Rs but not mGlu5Rs were significantly down-regulated in the ventral part of LS（LSv）in“stress-susceptible”mice;（4）LSv microinjection of LY379268,an agonist for mGlu2/3Rs,could rapidly relieve the typical social avoidance symptoms of stress susceptible mice.The paraventricular nucleus of the hypothalamus（PVN）is an important component of the hypothalamic-pituitary-adrenal cortex axis（HPA）,which plays an essential role in stress reactions.There are bidirectional interconnections between hypothalamus and LS.As the neurons in the LS are GABAergic,we investigated the function role of LSv^GABA→PVN in stress reactions in the second part of this thesis.Our results showed that:（1）LSv GABA neurons are activated by CSDS;（2）chemogenetic activation or inhibition of LSv GABAergic neurons had no significant effect on anxiety and depression-like behavior;（3）chemogenetic activation of LSv GABAergic neurons during CSDS aggravated social anxiety;（4）there are plenty of LS GABAergic projections in the PVN;（5）chemogenetic activation of LSv^GABA→PVN induced anxiety-and depression-like behavior while inhibition of this circuit had an opposite function;（6）chemogenetic activation of LSv^GABA→PVN during CSDS alleviated anxiety,while inhibition aggravated it.In summary,our study suggests that LSv mGlu2/3Rs and LSv^GABA→PVN play important roles in stress reactions.These results provide new understandings into the mechanisms underlying stress resilience and vulnerability and provide opportunities to develop novel,personalized approaches to treat stress-related psychiatric disorders,such as anxiety and depression and promote stress resilience.