Variation in Mouse Basolateral Amygdala Volume is Associated With Differences in Stress Reactivity and Fear Learning

Abstract

A wealth of research identifies the amygdala as a key brain region mediating negative affect, and implicates amygdala dysfunction in the pathophysiology of anxiety disorders. Although there is a strong genetic component to anxiety disorders such as posttraumatic stress disorder (PTSD) there remains debate about whether abnormalities in amygdala function predispose to these disorders. In the present study, groups of C57BL/6 Â DBA/2 (B Â D) recombinant inbred strains of mice were selected for differences in volume of the basolateral amygdala complex (BLA). Strains with relatively small, medium, or large BLA volumes were compared for Pavlovian fear learning and memory, anxiety-related behaviors, depression-related behavior, and glucocorticoid responses to stress. Strains with relatively small BLA exhibited stronger conditioned fear responses to both auditory tone and contextual stimuli, as compared to groups with larger BLA. The small BLA group also showed significantly greater corticosterone responses to stress than the larger BLA groups. BLA volume did not predict clear differences in measures of anxiety-like behavior or depression-related behavior, other than greater locomotor inhibition to novelty in strains with smaller BLA. Neither striatal, hippocampal nor cerebellar volumes correlated significantly with any behavioral measure. The present data demonstrate a phenotype of enhanced fear conditioning and exaggerated glucocorticoid responses to stress associated with small BLA volume. This profile is reminiscent of the increased fear processing and stress reactivity that is associated with amygdala excitability and reduced amygdala volume in humans carrying loss of function polymorphisms in the serotonin transporter and monoamine oxidase A genes. Our study provides a unique example of how natural variation in amygdala volume associates with specific fear-and stress-related phenotypes in rodents, and further supports the role of amygdala dysfunction in anxiety disorders such as PTSD.

Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity

“…Interestingly, in the basolateral amygdala, the ERK1/2 signaling pathway has been shown to be critical for mediating stress effects on hippocampal synaptic plasticity (Yang et al, 2008). This similarity in the pattern of ERK1/2 activation in these two structures might appear surprising given the contrasting patterns of structural remodeling frequently reported for chronic stress effects in the hippocampus (dendritic atrophy in the CA3 area) and the amygdala (dendritic hypertrophy in the BLA) (Vyas et al, 2002).…”

Reduced Stress-Sensitivity or Increased Reward Experience: The Psychological Mechanism of Response to Antidepressant Medication

“…There is much evidence for a role of the amygdala in stress-induced negative emotions as fear and anxiety (Vyas et al, 2006;Sajdyk et al, 2008;Yang et al, 2008). In addition, serotonin function has been hypothesized to regulate emotional processes related to Stress-Sensitivity (Hariri and Holmes, 2006).…”

Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance

“…The C57BL/6 (B6) and DBA/2 (D2) strains, which show significant differences in multiple learning paradigms (Paylor et al 1996;Dellu et al 2000;Schimanski and Nguyen 2004;Restivo et al 2006;Graybeal et al 2014), have been used by several groups to identify genetic and molecular contributions to fear conditioned learning, including long-standing hypotheses regarding the role of the hippocampus and amygdala (Schimanski and Nguyen 2004;Yang et al 2008;Andre et al 2012). However, the behavioral findings for fear conditioning in these strains are highly variable across labs, particularly with regard to differences in CS responses (e.g., AmmassariTeule et al 2001;Balogh et al 2002;Gale et al 2009).…”