Wiley: Genes, Brain and Behavior: Table of Contents

Genetic Architecture of Addiction‐Relevant Behaviors in Outbred Sprague–Dawley Rats Reveals Loci for Anxiety‐Like and Nociceptive Traits

Mon, 18 May 2026 02:30:47 -0700

Genome-wide association analyses in outbred Sprague–Dawleys identified loci for anxiety-like and nociceptive behavior on chromosomes 1, 14, and 17, which are distinct from facets of exploratory locomotion significant in our GWAS of a F₂ intercross of selectively bred high- and low-responder (to a novel environment) Sprague–Dawleys.

ABSTRACT

Studies have shown that substance use liability is associated with novelty seeking, anxiety-like behavior, and pain sensitivity. We examined whether common genetic variation in outbred Sprague–Dawley rats explained variation in behavioral measures from three assays with established links to substance use: locomotor response to a novel environment, elevated plus maze, and tail flick. We estimated single-nucleotide polymorphism heritability and performed genome-wide association analyses using permutation-derived significance thresholds (N = 534–654 rats across traits). Heritability estimates ranged from 0.14 to 0.38 across 11 traits. Three independent loci were identified: chromosome 1 for elevated plus maze open-arm behavior (α = 0.05), chromosome 14 for elevated plus maze immobility (α = 0.10), and chromosome 17 for tail flick latency (α = 0.05). Candidate genes included Slc18a2, Gfra1, and Pdzd8 (chromosome 1); Rel and Bcl11a (chromosome 14); and Eci2 and Eci3 (chromosome 17). We compared these loci with our genome-wide association study of a F₂ intercross of selectively bred high- and low-responder rats, originally derived from Sprague–Dawleys, that model individual differences in externalizing and internalizing behavior. The current loci are distinct from the ones identified in the bred lines. This difference likely reflects selection history in the high- and low-responder F₂s, which focused on facets of exploratory locomotion, while loci for anxiety and pain sensitivity traits were identified in the outbreds. This highlights the benefit of using both outbred and selectively bred rats to probe causal variants contributing to individual differences in substance use liability. The current outbred findings implicate monoaminergic signaling, transcriptional control, and lipid metabolism as testable mechanisms for addiction-relevant behaviors.

Issue Information

Mon, 04 May 2026 09:11:51 -0700

Genes, Brain and Behavior, Volume 25, Issue 3, June 2026.

∆FOSB in the Nucleus Accumbens Core Is Required for Increased Anxiety, but Not Decreased Social Motivation, Following Estrogen Withdrawal in Female Mice

Mon, 04 May 2026 09:09:45 -0700

In female mice, estrogen withdrawal following a hormone-simulated pseudopregnancy is associated with increased levels of ∆FOSB in the Nucleus Accumbens Core and increased anxiety behaviors. However, using viral-mediated expression of ∆JUND to decrease ∆FOSB-mediated transcription in the Nucleus Accumbens Core prevents the increase in anxiety following estrogen withdrawal.

ABSTRACT

During pregnancy, estrogen levels rise dramatically, but quickly drop to prepartum levels following birth and remain suppressed until ovulation resumes. This “postpartum estrogen withdrawal” state has been linked to changes in the brain and behavior in humans and rodents. Previous research has demonstrated that following a hormone-simulated pseudopregnancy (HSP), an experimental model of postpartum estrogen withdrawal, female mice show increased anxiety-like behaviors and decreased social motivation. Further, these behavioral changes occur concurrently with an increase in ∆FOSB, a transcription factor associated with stable long-term plasticity, in the nucleus accumbens core. To test whether this increase in ∆FOSB is required for these behavioral changes, we used a viral-mediated gene transfer approach to prevent ∆FOSB-mediated transcription in the NAcC during HSP and found that it reduced the high-anxiety behavioral phenotype in estrogen-withdrawn females. However, preventing ∆FOSB-mediated transcription had little effect on social motivation. Together, these results suggest that postpartum estrogen withdrawal increases ∆FOSB in the NAc core to impact anxiety-like behaviors but not social motivation following estrogen withdrawal.