1. ¹Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD, USA
2. ²Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
3. ³Unit on Neuroplasticity, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, Bethesda, MD, USA

Correspondence: Dr A Holmes, Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane Room 2N09, Rockville, MD 20852-9411, USA. Tel: +1 301 402 3519; Fax: +1 301 480 1952; E-mail: holmesan@mail.nih.gov

Received 15 October 2007; Revised 5 November 2007; Accepted 7 November 2007; Published online 9 January 2008.

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 DBA/2 (B 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.