The Function Role Of GABS（B） Receptors Within The Habenula In Stress Response And Dopamine Receptors Within The MPFC In Social Hierarchy In Mice

Depression and anxiety disorders are the most prevalent psychiatric disorders affecting a large number of people in current society.The etiology of depression and anxiety are complex.Among which,exposure to a variety of stressor is an important predisposing environmental factor.However,both human and animal individuals perceive stressful events differently,i.e.,resilience or susceptibility.Understanding the neural substrates underlying this kind of difference represents an innovative approach to drug development for more effective treatments of stress-related psychiatric disease such as depression.The habenula is an important part of limbic brain structure,which plany important roles in emotion regulation.In mammals,the habenula splits into two main subregions:the medial and lateral habenula（MHb and LHb,respectively）.GABA（B）receptors play an important regulatory role in habenular activity.Our results showed that:（1）about 47.1%of C57 mice showed anxiety-or depression-like behaviors when exposed to CSDS;（2）the vulnerable subjects also showed elevated serum CORT levels,which indicated a dysregulated hypothalamic–pituitary–adrenal（HPA）axis;（3）when confronted with a social stressor,the vulnerable subjects presented elevated c-Fos expression in the LHb,which indicated an inceased neural activity;（4）Western-Blot results showed that the expression of GABA（B）receptors,which including both GABA（B1）and GABA（B2）subunits,were significantly down-regulated in the LHb of the susceptible mice;（5）the stress-induced social withdrawal symptoms could be rapidly relieved by intra-LHb injection of both baclofen and CGP36216（a GABA（B）receptor agonist and antagonist respectively）.The above results indicated that GABA（B）receptors in the LHb may play an important role in stress resilience and vulnerability,and thus,may be an important therapeutic target for treatments of stress-induced psychiatric disorders.Formation of dominance hierarchies is recognized as a universal and fundamental organizing mechanism for social animals.Stable social hierarchy could reduce unnecessary conflicts among individuals,and contribute to the wellbeing and survival of animal populations.On the other hand,lower social hierarchy is particularly relevant for some psychiatric disorders such as anxiety and depression.Previous studies had indicated that social hierarchy largely relies on the neuronal activity in the medial prefrontal cortex（m PFC）.The m PFC of rodents can be roughly divided into dorsal and ventral regions,i.e.,dm PFC and vm PFC,respectively.Dopamine D1 receptors（D1Rs）and D2 receptors（D2Rs）are abundantly expressed in the m PFC and modulate its functions.Therefore,in the second part of this thesis,we investigated the function role of D1Rs and D2Rs within the m PFC in establishing social hierarchy in C57BL/6 male mice.Our results showed that:（1）the social rank of the four mice housed within the same cage were relative stable from day three;（2）compared with the 1^st-rank mice,the 4^th-rank mice showed more anxiety and depression-like behavior;（3）after a confrontation tube test,the c-Fos expression of m PFC were significantly increased in the 4^th-rank mice;（4）Western-blot results showed that the expression of D2Rs in the 4^th-rank mice were significantly down-regulated in the dorsal m PFC（dm PFC）,but remain unchanged in the ventral m PFC（vm PFC）;（5）q RT-PCR results showed that the expression of D2Rs in the4^th-rank mice were significantly down-regulated in the whole m PFC;（6）knock-down of D2Rs within the dm PFC by using r AAV-sh RN（Drd2）-CMV-p A significantly reduced their social ranks.The vulnerable subjects also showed higher anxiety both in the elevated plus maze test and three-chamber test.The above results indicated that D2Rs within the dm PFC may play an important role in social hierarchy in male mice.Our findings provide novel insight into the divergent functions of prefrontal D1Rs and D2Rs neurons in social hierarchy,which may contribute to ameliorating social dysfunctions and associated impairments in mental health.