SEX DIFFERENCES IN NEURAL PROJECTIONS OF FEAR MEMORY PROCESSING IN MICE AND HUMANS

Abstract Background The Tac2 pathway is a pharmacological opportunity for brain disorders since Tac2 antagonists are safe and well tolerated in humans and modulate memory in rodents. Aims & Objectives It remains unexplored whether the connectivity between two brain areas is necessary for one sex, but not in the other one, for the formation of the same memory. Method In mice we used fear procedures, chemogenetics, clozapine N-oxide delivered intracerebrally and systemically, immunohistochemistry, electrophysiology and in vivo calcium imaging in freely moving mice. In humans we used fear procedures, neuroimaging and genetic analyses of post-mortem brain tissue. Results Here, the chemogenetic silencing of CeM-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreases fear memory consolidation in male mice, but not females. Optogenetic excitation of CeM-Tac2 shows increased inhibitory post-synaptic currents in the BNSTpl of males compared to females. In vivo calcium imaging analysis reveals a sex-dimorphic fear memory engram in the BNSTpl. In humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreases the CeM-BNST connectivity in a fear task, impairs fear memory consolidation and increases the expression of the TAC3R mRNA in AA-carrier men but not in women. Discussion & Conclusion These sex differences in necessary neuronal projections of fear memory formation may be relevant for mental disorders with memory alterations. Also, these data highlight the role of Tac2 antagonists in treating and preventing fear-based disorders.