Fear Engram Encoding Underlying Memory Erasure

The fear response of an organism to threats in the environment is an important adaptation to the condition.This fear response of either animal or human could help them anticipate and respond appropriately to threats.However,this fear response may also lead to the formation of pathological fear memories,causing severe fear and anxiety,and ultimately causing diseases such as panic disorder and posttraumatic stress disorder(PTSD).Therefore,erasing pathological memories such as fear memories has always been a concern in the field of neuroscience,which has significant implications for the treatment of related diseases such as PTSD.It’s known that post-retrieval extinction but not extinction alone could erase fear memory.However,whether the coding pattern of original fear engrams is persistently remodeled or inhibited during memory erasure remains largely unknown.From the introduction of the term "engram" by the German biologist Richard Semon in 1904 to describe the neural basis of memory storage and retrieval,to the present day where multiple laboratories,such as Tonegawa’s,have demonstrated that memories are stored in engram cells,whether the original memory engram cells are suppressed or reconstructed during memory erasure remains unknown.In addition,the relationship between fear and extinction cells and the dynamic modification of fear engram coding pattern underlying memory erasure are still unclear.In particular,specific conditioned stimulus(CS)retrieval before extinction(CS+Ext)could selectively erase the reactivated CS rather than other cues associated fear memory while unconditioned stimulus(US)retrieval before extinction(US+Ext)could prevent multiple CS associated fear memory with that US.What are the neural encoding mechanisms that underlie these two paradigms?To answer these questions,we do the study by activity-dependent neuronal-tagging technology,neuronal tracing technique combined with optogenetic manipulation and in vivo calcium imaging to investigate the mechanism and function of memory cell encoding during fear memory erasure.The following research results were obtained:1.By developing the memory erasure behavioral paradigm and engram cell labeling,we identified that the basolateral amygdala(BLA)and prelimbic cortex(PrL)were activated during CS-initiated memory erasure,and the reactivation of engram cells was increased during memory erasure.We further identified the necessity of PrL in CS-initiated memory erasure.2.We found that PrL cells receiving infralimbic cortex(IL)projections displayed increased activation during extinction while PrL cells projecting to BLA was activated during retrieval by neuronal tracing technique and c-Fos staining.In addition,we found that BLA projecting PrL neurons were mainly responsible for fear encoding while PrL neurons receiving IL inputs were involved in memory extinction.3.We used optogenetic manipulation and in vivo calcium imaging to investigate the the dynamic encoding of memory engram ensembles in the PrL during CS-initiated memory erasure.We found that the overlapped percentage of fear and extinction cells in the PrL was increased and the original fear engrams encoding in the PrL was altered during CS-initiated memory erasure which the activation of PrL engram cells could not induce fear memory recovery.4.We used optogenetic manipulation and in vivo calcium imaging to investigate the the dynamic encoding of memory engram ensembles in the BLA during US-initiated memory erasure.We found that the overlapped percentage of multi-CS related fear cells and extinction cells in the BLA was increased and the original fear engrams encoding in the BLA was altered during US-initiated memory erasure which the activation of BLA engram cells could not induce fear memory recovery.In all,our study identified the crucial role of PrL engram cell in CS-initiated memory erasure,the increased overlapped ensembles between fear and extinction cell and the alteration of original fear engrams encoding in PrL.Correspondingly,we identified the increased overlapped ensembles between multi-CS related fear cells and extinction cells in the BLA and the alteration of original multi-CS related fear engrams encoding in BLA during US-initiated memory erasure.These findings provide new insights into the neural encoding mechanisms underlying memory erasure and memory updating,which have implications for the treatment of related mental disorders such as PTSD.