Proteomic Analysis Of Olfactory Bulb In Mic Robiota-induced Depression

Background:Major depressive disorders impact approximately 17% of the population worldwide,whose high morbidity and considerable adversity have resulted in enormous social and economic burden.As the first relay station of olfactory conduction,olfactory bulb of adult mammals can perform neurogenesis for life to maintain olfactory function,while the depressed patients sometimes display reduced volume of olfactory bulb(OB)and decreased olfactory sensitivity.Although mounting evidence conveyed that the gut microbiota may implicate the pathophysiology of major depressive disorder(MDD)via the microbe–gut–brain axis,knowledge about its distinctive molecular mechanism is rudimentary.Whether the disorders of olfactory bulb cells and molecules exist in the occurrence and development of microbiota-induced depression is still unknown.Methods:Herein,iTRAQ coupled with LC–MS/MS was employed to compare the OB proteome between “pathological microbiota” and “healthymicrobiota” germ-free mice.Overall,5192 proteins and 25173 unique peptides were identified,all of which had been merged and filtered using the criterion of 1% peptide FDR.A set of 367 proteins were differentially identified in the OB,involving 119 up-regulated and 248 down-regulated proteins compared with the levels in controls.To explore neurological disorders and investigate biological functions,the IPA database was chosen to integrate and comprehensively analyze the information from iTRAQ.Results:The biological analysis system ingeniously summarizes these differentiated data into three major types: “disease and disorder”,“molecular and cell functions”,and “physiological system development and functions”.To be exact,Neurological Disease was signally observed in“disease and disorder”.In addition,“molecular and cell functions”indicated some concepts that are highly compatible with depression research,such as Cellular Growth and Proliferation.It even comes first for Nervous System Development and Function in “physiological system development and functions” rank.A combined analysis with significantly changed OB proteins from the depression model of CUMS highlighted the depression-related CREB signaling,whose dysregulation is likely to disrupt the neuroplasticity,cell survival,cognitive and behavioral abilities of individuals and the axonogenesis of OB under microbiota condition.With that,the down-regulated CACNA1 E and its downstream proteins(CALM/ CaMKII/ CREB/ BDNF)in CREB signaling were validated by Western blot.The expression of CACNA1E(p < 0.01),CALM(p < 0.01),and BDNF(p < 0.001)was found significantly decreased comparing to the controls.There was a decreasing trend(P = 0.07)in the expression of p-CREB.No changes were found in P-CaMKII(p > 0.05).Meanwhile,the canonical pathways involved Nuclear Receptor Signaling highlighted the fecal microbiota transplantation(FMT)model,which would be a new breakthrough for depressive research.Conclusions:These results supplement the previous research achievements about the gut microbiota in psychiatric disorders,providing a creative insight into the intricate mechanisms of OB dysfunction in depression.