Sex-Specific Neural Networks of Cued Threat Conditioning: A Pilot Study

Kamryn C. du Plessis, Sreetama Basu, Timothy H. Rumbell, Elizabeth K. Lucas

Research output: Contribution to journalArticlepeer-review

Abstract

Cued threat conditioning is the most common preclinical model for emotional memory, which is dysregulated in anxiety disorders and post-traumatic stress disorder. Though women are twice as likely as men to develop these disorders, current knowledge of threat conditioning networks was established by studies that excluded female subjects. For unbiased investigation of sex differences in these networks, we quantified the neural activity marker c-fos across 112 brain regions in adult male and female mice after cued threat conditioning compared to naïve controls. We found that trained females engaged prelimbic cortex, lateral amygdala, cortical amygdala, dorsal peduncular cortex, and subparafasicular nucleus more than, and subparaventricular zone less than, trained males. To explore how these sex differences in regional activity impact the global network, we generated interregional cross-correlations of c-fos expression to identify regions that were co-active during conditioning and performed hub analyses to identify regional control centers within each neural network. These exploratory graph theory-derived analyses revealed sex differences in the functional coordination of the threat conditioning network as well as distinct hub regions between trained males and females. Hub identification across multiple networks constructed by sequentially pruning the least reliable connections revealed globus pallidus and ventral lateral septum as the most robust hubs for trained males and females, respectively. While low sample size and lack of non-associative controls are major limitations, these findings provide preliminary evidence of sex differences in the individual circuit components and broader global networks of threat conditioning that may confer female vulnerability to fear-based psychiatric disease.

Original languageEnglish
Article number832484
JournalFrontiers in Systems Neuroscience
Volume16
DOIs
StatePublished - 17 May 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2022 du Plessis, Basu, Rumbell and Lucas.

Keywords

  • associative memory
  • classical conditioning
  • fear conditioning
  • functional connectivity
  • graph theory
  • immediate early gene
  • memory encoding
  • negative valence systems

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Developmental Neuroscience
  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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