The Neural Circuit Study Of Contextual Fear Extinction

Learning and memory are the fundamental issues in neuroscience,they are the biological basis for human beings to create civilization and history.Learning and memory are the processes by which the brain acquires,stores,and extracts information,and links the individual's feelings,psychology,and behavioral activities.Fear conditioning is a form of associative learning with a long history as a model of emotional learning and memory processes in both animals and human.It is a form of learning which an aversive stimulus(e.g.an electrical shock,the unconditioned stimulus,US)is associated with a particular neutral context(e.g.,a room,the conditioned stimulus,CS),resulting in the expression of fear responses to the originally neutral stimulus or context.As a consequence of this pairing,exposure to the previously neutral context CS elicits a conditioned response(CR).When a CS is presented alone repeatedly without US,it no longer predicts the coming unconditioned stimulus and the CR gradually reduces,which is called fear extinction.The mechanism of fear extinction has drawn more attention in the field of neuroscience research,as some mental disorders such as post-traumatic stress disorder(PTSD)and drug addiction have increasingly become a challenge for human society.If we can understand the mechanisms of negative memory extinction,it will have a profound impact on the treatment of such diseases and can better serve human mental health.Brain regions involved in fear memory acquisition and extinction include amygdala,medial prefrontal cortex(m PFC)and hippocampus.Previous researches have found that interneurons in the basolateral amygdala(BLA)play a key role in the extinction of fear memory.So far there is no direct evidence showing a behavioral effect from specifically regulating the GABAergic interneurons activated during fear extinction.Nor is there any direct evidence showing that direct manipulation of interneuron activity during fear extinction interferes fear expression.Immediate Early Genes(IEGs)can be transiently and rapidly activated in response to a variety of cellular stimuli.Commonly used IEGs are Arc(Activity regulated cytoskeletal)and c Fos(a complex of the cellular Fos).To better study the neural network mechanism in fear extinction,we take advance of specific promoters described above to construct Arc-ER^T2Cre ER^T2,c Fos-ER^T2Cre ER^T2,GAD67-ER^T2Cre ER^T2transgenic mice,which can be crossbreed with R26RSTOP-floxed-td Tomato(Ai9)mice to label various types of neural circuits stimulated by fear acquisition and extinction.Our study reveals that activation of inhibitory GABAergic(?-aminobutyric acid,GABA)interneurons located in the basolateral amygdala occurs during fear extinction in both Arc-ER^T2Cre ER^T2 x Ai9 and c Fos-ER^T2Cre ER^T2 x Ai9 transgenic mice.Furthermore,specifically inhibition of interneurons activated during memory extinction by interneuron-specific adenovirus associated virus(AAV)could block the fear extinction.With the help of these transgenic mice and chemogenetics,our data provide direct evidence of interneurons involvement in fear extinction.Fear acquisition and fear extinction are two different forms of learning.A variety of inhibitory CS-'no US'associations are established during fear extinction to interfere with existing fear memory(CS-US association)and suppress conditional fear responses.Chemogenetics stimulation of BLA neurons activated during fear acquisition(fear neurons)could block the fear extinction in Arc-ER^T2Cre ER^T2 and c Fos-ER^T2Cre ER^T2transgenic mice,which proves that interneurons form new inhibitory connections with CS-US-CR neural network during fear extinction to suppress original fear memory.In summary,our results directly show the key regulatory role of GABAergic interneurons in fear memory extinction,and provide a new way to promote the understanding of the acquisition and extinction of conditional fear memory.