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

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: 7.05). 02/2008; 33(11):2595-604. DOI: 10.1038/sj.npp.1301665
Source: PubMed


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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Available from: Robert W Williams, Jul 02, 2014
    • "Relevant brain regions include the amygdala, where information about the conditioned stimulus (CS) and unconditioned stimulus (US) converges to facilitate fear acquisition; the hippocampus and ventromedial prefrontal cortex (vmPFC), which support extinction learning and retrieval; and the dorsal anterior cingulate cortex (dACC), which is involved in fear expression. Morphology of these regions relates to individual differences in fear acquisition and extinction; amygdala volume is negatively associated with fear acquisition in rodents and human adults (Hartley et al, 2011; Yang et al, 2008). dACC thickness is associated with enhanced fear acquisition (Milad et al, 2007), whereas vmPFC thickness is associated with retention of extinction learning in humans (Hartley et al, 2011; Milad et al, 2005). "
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    ABSTRACT: Alterations in learning processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n=94) aged 6-18 years, 40.4% (n=38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells as conditioned stimuli (CS+/CS-) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. Children without maltreatment exposure exhibited strong differential conditioning to the CS+ versus CS-, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ versus CS- during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although these associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat-safety discrimination might reflect either enhanced fear generalization or a deficit in associative learning, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children.Neuropsychopharmacology accepted article preview online, 18 December 2015. doi:10.1038/npp.2015.365.
    No preview · Article · Dec 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "We also examined amygdala and cortex, other brain regions that were suggested to play important roles in the regulation of memory and fear associative responses (LeDoux, 2003;van Strien et al., 2009). It has been shown previously that amygdala volume associates with differences in fear associative responses (Yang et al., 2008). However, we found that VPA-treated mice have a similar amygdala size to that of MC-treated mice, both at P7 and P84 (Figures S3A–S3D). "
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    ABSTRACT: Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running.
    Full-text · Article · Nov 2015 · Stem Cell Reports
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    • "The amygdala plays an important role in fear learning and fear expression [21]. MRI studies reveal different results on the volume of the amygdala in patients with PTSD: smaller and unchanged amygdala volumes in patients with PTSD [22,23]. In vivo proton magnetic resonance spectroscopy (1H-MRS) revealed the high NAA/Cr and Cho/Cr ratios, which reflect a hyperresponsive amygdala [10,11]. "
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    ABSTRACT: Background Post-traumatic stress disorder (PTSD) is an anxious disorder associated with low levels of corticosterone and enhanced negative feedback of the hypothalamic–pituitary–adrenal (HPA) axis. Previous studies showed that the amygdala not only has an excitatory effect on the HPA axis but also plays a key role in fear-related behaviors. Coticosterone exert actions through binding to the mineralocorticoid (MR) and glucocorticoid receptor (GR), which are abundant in the amygdala. In our previous study, down-regulation of MR and GR in the hippocampus of PTSD rats was found. But the roles of MR and GR in the amygdala of PTSD rats is incompletely understood. Results wistar rats were divided into 1 d, 7 d, 14 d groups after single prolonged stress (SPS) and control group. SPS is a reliable animal model of PTSD. Open field test (OF) and elevated plus maze tests (EPM) were performed to examine fear-related behaviors. Morphological changes of the ultrastructure of the amygdala neurons were assessed by transmission electron microscopy (TEM). Dual-immunofluorescence histochemistry was used to determined subcellular distribution and colocalization of MR- and GR-ir. Protein and mRNA of MR and GR was examined by western blotting and RT-PCR. OF and EPM showed enhanced fear in SPS rats. Abnormal neuronal morphology was discovered in the amygdala of SPS rats. The expression of MR- and GR-ir intensity, mRNA and protein within the amygdala decreased after SPS at 1 day, and then gradually recovered by 14 days, although the degree of decrease and recovery were different amongst techniques. We found no change in the MR/GR ratio at 3 levels of the amygdala. But more cytoplasmic distribution and decreased colocalization of MR- and GR-ir were observed in the amygdala after 7 days of SPS. Conclusion These data suggest that change of MR and GR in the amygdala are involved in the mechanisms of fear in PTSD.
    Full-text · Article · Jun 2014 · BMC Neuroscience
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