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Variation in mouse basolateral amygdala volume is associated with differences in stress reactivity and fear learning. Neuropsychopharmacology

Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD 20852-9411, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.83). 02/2008; 33(11):2595-604. DOI: 10.1038/sj.npp.1301665
Source: PubMed

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 x DBA/2 (B x 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.

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    • "While numerous studies have reported a significant difference in amygdala volumes in individuals with various psychiatric conditions versus normal controls (Szeszko et al. 1999; Zetzsche et al. 2006; Rosso et al. 2007), few have explored the relationship between amygdala volume and differences in affective responding in healthy individuals. A recent study found that strains of mice with smaller basolateral amygdala nucleus (BLA) volume exhibited stronger fear responses to conditioned stimuli when compared with larger BLA groups (Yang et al. 2008). Furthermore, this variation in BLA volume was unrelated to the display of anxiety or depression-like behavior in individual animals. "
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    • "Although increased activation of fear expression networks could result in subtle structural and chemical changes, which might increase the propensity to experience anxiety in the absence of identifiable triggers, it is also possible that developmental structural variations predispose individuals to experience exaggerated fear. In recombinant inbred strains of rats, strains with relatively small basolateral amygdala (BL) volumes exhibited stronger conditioned fear responses to both auditory tone and contextual stimuli, as compared to groups with larger BL (Yang et al., 2008), suggesting the possibility of a genetic contribution to the relationship between smaller amygdala volumes and increased fear proclivity. In other words, it remains unclear whether structural variations in the amygdala and orbitofrontal cortex are the result of experience dependent neuronal reorganization or whether genetically driven variations may predispose an individual to a heightened anxiety response. "
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