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
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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.
    BMC Neuroscience 06/2014; 15(1):77. DOI:10.1186/1471-2202-15-77 · 2.67 Impact Factor
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    • "From earlier studies in mice (Loos et al., 2009) and rats (Molander et al., 2011) it is established that high levels of impulsive responding in a 5CSRT task are not related to levels of locomotor activity. Furthermore, both our own data and that of other labs1 indicated similar, if anything reduced activity in BXD16 compared with C57BL/6J mice (e.g., ID 10910; Yang et al., 2008; ID 10037; Bolivar and Flaherty, 2003). Observations of reduced activity in BXD16 compared with C57BL/6J may be the result of elevated levels of anxiety in novel test apparatuses, as shown by the decreased time on the open arm of the EPM and time in the brightly lit compartment of the DLB. "
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    ABSTRACT: Deficits in executive control have frequently been associated with alcohol use disorder. Here we investigated to what extent pre-existing genetically encoded levels of impulsive/inattentive behavior associate with motivation to take alcohol and vulnerability to cue-induced reinstatement of alcohol seeking in an operant self-administration paradigm. We took advantage of BXD16, a recombinant inbred strain previously shown to have enhanced impulsivity and poor attentional control. We compared BXD16 with C57BL/6J mice in a simple choice reaction time task (SCRTT) and confirmed its impulsive/inattentive phenotype. BXD16 mice were less active in a novel open field (OF), and were equally active in an automated home cage environment, showing that increased impulsive responding of BXD16 mice could not be explained by enhanced general activity compared to C57BL/6J mice. After training in a sucrose/alcohol fading self-administration procedure, BXD16 showed increased motivation to earn 10% alcohol solution, both under fixed ratio (FR1) and progressive ratio (PR2) schedules of reinforcement. Responding on the active lever readily decreased during extinction training with no apparent differences between strains. However, upon re-exposure to alcohol-associated cues, alcohol seeking was reinstated to a larger extent in BXD16 than in C57BL/6J mice. Although further studies are needed to determine whether impulsivity/inattention and alcohol seeking depend on common or separate genetic loci, these data show that in mice enhanced impulsivity coincides with increased motivation to take alcohol, as well as relapse vulnerability.
    Frontiers in Behavioral Neuroscience 10/2013; 7:151. DOI:10.3389/fnbeh.2013.00151 · 3.27 Impact Factor
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    • "These strains have been genotyped at over 3000 markers enabling quantitative trait loci (QTL) mapping with high precision using established tools [15]. The BXD family has now been systematically analyzed using advanced stereological methods for close to 15 years, and is part of a comprehensive genetic dissection of the CNS including deep data on the hippocampus [16]–[18], several thalamic nuclei [19], basolateral amygdala [20]–[22], striatum [23], [24], neocortex [25]–[27], olfactory bulb [28], and cerebellum [29]. Even more remarkably, there are deep gene expression data sets for many brain regions and thousands of behavioral phenotypes, which allows for detailed construction of networks of covariation [30]. "
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    ABSTRACT: The lateral septum has strong efferent projections to hypothalamic and midbrain regions, and has been associated with modulation of social behavior, anxiety, fear conditioning, memory-related behaviors, and the mesolimbic reward pathways. Understanding natural variation of lateral septal anatomy and function, as well as its genetic modulation, may provide important insights into individual differences in these evolutionarily important functions. Here we address these issues by using efficient and unbiased stereological probes to estimate the volume of the lateral septum in the BXD line of recombinant inbred mice. Lateral septum volume is a highly variable trait, with a 2.5-fold difference among animals. We find that this trait covaries with a number of behavioral and physiological phenotypes, many of which have already been associated with behaviors modulated by the lateral septum, such as spatial learning, anxiety, and reward-seeking. Heritability of lateral septal volume is moderate (h(2) = 0.52), and much of the heritable variation is caused by a locus on the distal portion of chromosome (Chr) 1. Composite interval analysis identified a secondary interval on Chr 2 that works additively with the Chr 1 locus to increase lateral septum volume. Using bioinformatic resources, we identified plausible candidate genes in both intervals that may influence the volume of this key nucleus, as well as associated behaviors.
    PLoS ONE 08/2012; 7(8):e44236. DOI:10.1371/journal.pone.0044236 · 3.23 Impact Factor
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