| Anxiety disorders are the most common type of mental disorders,characterized by anxiety and fear,including generalized anxiety disorder,panic disorder,phobia,social anxiety disorder,obsessive-compulsive disorder and post-traumatic stress disorder.Anxiety disorders are the highest prevalence mental illnesses worldwide and have become a major burden of social and economic development in countries around the world.The pathogenesis of anxiety disorders is largely unknown.Cognitive behavior therapy(CBT)is a psychosocial intervention,and is an effective treatment for anxiety disorders.However,its therapeutic mechanism is still unclear.The prelimbic cortex(PL)is a subregion of the medial prefrontal cortex(mPFC),projecting to multiple subcutaneous brain regions and participating in regulating multiple functional activities.Although PL is involved in the regulation of anxiety and fear,it is not clear which neurons and circuits mediate this function and how.Here we identified two anatomically distinct subpopulations of PL projection neurons that targeted the mediodorsal thalamic nucleus(MD)and the ventral tegmental area(VTA),respectively,and found that they had task-related firing patterns in the elevated plus maze(EPM)test.Moreover,we found that the firing rates of the MD-projecting PL neurons exerted an immediately increasing when the mice preformed headdips in the EPM,but not the VTA-projecting PL neurons.Activation of the MD-projecting PL neurons or VTA-projecting PL neurons elicited anxiogenic and anxiolytic behavior,respectively.Inhibition of the MD-projecting PL neurons with Chemogenetic tools led to anti-anxiety like behaviors,while inhibiting PL projection to VTA had no effect.Using antegrade trans-synaptic virus tracking technology,we found both PL-MD and PL-VTA projections targeted the basolateral amygadala(BLA).Activation of PL-MD-BLA and PL-VTA-BLA projections also induced anxiogenic and anxiolytic behavior,respectively.Moreover,MD-and VTA-projecting PL neurons were required for retrieval of remote and recent fear,respectively.Lastly,we show that the inhibitory inputs were decreased in MD-projecting PL neurons and increased in VTA-projecting PL neurons in a mouse anxiety model induced by acute restrain stress,and inhibition of PL-MD projection could rescue the stress-induced anxiety behavior.Our study demonstrates that the PL outputs two parallel projections that produce opposite effects on anxiety and fear. |
