Sex differences in neural projections of fear memory processing in mice & humans

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DOI: 10.1126/sciadv.adk3365

10 Jul 2024

Abstract:

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)–Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females.

Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl.

Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women.

These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

INTRODUCTION Excerpt:

Neuronal circuits play an essential role in encoding, storing, and retrieving environmental threat-predicting cues, forming the basis of what is known as fear memory.

These memories are not only crucial for decision-making but also trigger automatic responses to threats.This neurobiological understanding, enriched by comparative studies in humans and mice, who share key neural aspects of fear response, is crucial for advancing the treatment of fear-based disorders.

Our study builds upon seminal work that uncovered the role of the tachykinin 2 (Tac2) pathway in the central amygdala (CeA) in modulating fear memory consolidation. .

This prior research revealed a sex-specific effect in which CeA-Tac2 antagonism and its pharmacogenetic temporal inhibition impaired fear memory in male mice but, unexpectedly, enhanced it in female mice.

These findings, alongside the identification of CeA-testosterone and CeA-estradiol, in addition to Akt/GSK3β/β-catenin signaling, as mediators of this sex-differential regulation, set a precedent for further exploration into the molecular mechanisms of fear memory.