Gene networks associated with conditional fear in mice identified using a systems genetics approach

Christopher C Park,Anatole Ghazalpour,Peter Langfelder,Roel A Ophoff,Greg D Gale,Eleazar Eskin,Charles R Farber,Brian J Bennett,Desmond J Smith,Simone De Jong,Steve Horvath,Andy Lin,Aldons J Lusis,Arshad H Khan

doi:10.1186/1752-0509-5-43

Abstract

BackgroundOur understanding of the genetic basis of learning and memory remains shrouded in mystery. To explore the genetic networks governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP) with high mapping resolution.ResultsA total of 27 behavioral quantitative trait loci were mapped with a false discovery rate of 5%. By integrating fear phenotypes, transcript profiling data from hippocampus and striatum and also genotype information, two gene co-expression networks correlated with context-dependent immobility were identified. We prioritized the key markers and genes in these pathways using intramodular connectivity measures and structural equation modeling. Highly connected genes in the context fear modules included Psmd6, Ube2a and Usp33, suggesting an important role for ubiquitination in learning and memory. In addition, we surveyed the architecture of brain transcript regulation and demonstrated preservation of gene co-expression modules in hippocampus and striatum, while also highlighting important differences. Rps15a, Kif3a, Stard7, 6330503K22RIK, and Plvap were among the individual genes whose transcript abundance were strongly associated with fear phenotypes.ConclusionApplication of our multi-faceted mapping strategy permits an increasingly detailed characterization of the genetic networks underlying behavior.

Highlights

Our understanding of the genetic basis of learning and memory remains shrouded in mystery
To identify regions of the genome associated with fearrelated behavior, mice from the hybrid mouse diversity panel (HMDP) were subjected to a fear conditioning procedure and characterized on 48 unique behavioral phenotypes drawn from different test phases
This species-specific defense response can be reliably acquired in a single conditioning trial, making it a widely used model for fear expression and learning and memory

Summary

Introduction

Our understanding of the genetic basis of learning and memory remains shrouded in mystery. To explore the genetic networks governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP) with high mapping resolution. Advances in both genetic and behavioral techniques are providing unprecedented opportunities for dissecting the gene networks governing behavior. Through a variety of approaches, promising candidate genes have been identified for a wide collection of clinically relevant traits such as anxiety, conditional fear and spatial memory [1,2,3]. Intercrosses and backcrosses have been widely used to identify behavior quantitative trait loci (QTLs) in mice, but suffer from poor mapping resolution. The largely undefined and likely complex contribution of environmental factors to both the etiology and maintenance of behavior represents another formidable obstacle to reliable QTL mapping

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Discussion

Conclusion