Genetic and Structural Analysis of the Basolateral Amygdala Complex in BXD Recombinant Inbred Mice

Abstract

The amygdala integrates and coordinates emotional and autonomic responses. The genetics that underlie variation in amygdala structure may be coupled to variation in levels of aggression, fear, anxiety, and affiliated behaviors. We systematically quantified the volume and cell populations of the basolateral amygdala complex (BLAc) across 35 BXD recombinant inbred (RI) lines, the parental strains--C57BL/6J (B6) and DBA/2J (D2)--and F1 hybrids (n cases=199, bilateral analysis). Neuron number and volume vary 1.7- to 2-fold among strains (e.g., neuron number ranged from 88,000 to 170,000). Glial and endothelial populations ranged more widely (5- to 8-fold), in part because of higher technical error. A quantitative trait locus (QTL) for the BLAc size is located on chromosome (Chr) 8 near the Large gene. This locus may also influence volume of other regions including hippocampus and cerebellum. Cell populations in the BLAc appear to be modulated more weakly by loci on Chrs 11 and 13. Candidate genes were selected on the basis of correlation with BLAc traits, chromosomal location, single nucleotide polymorphism (SNP) density, and expression patterns in the Allen Brain Atlas. Neurod2, a gene shown to be significant for the formation of the BLAc by knockout studies, is among the candidates genes. Other candidates include Large, and Thra. Responses to drugs of abuse and locomotor activity were the most notable behavioral correlates of the BLAc traits.

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

“…However, this approach cannot exclude the potential contribution of other phenotypic traits that covary with BLA volume. We have recently shown that a common genetic locus may underlie the structures of multiple forebrain regions including amygdala, cerebellum, dorsal striatum, and portions of the hippocampus (Mozhui et al, 2007). Analysis of the volume of these three structures in our three BLA volume groups indicated volume differences in dorsal striatal but not hippocampal or cerebellar volume, raising the possibility that striatal volume variation contributed to behavioral differences between BLA groups, (for example via affects on motor function.…”

“…In an earlier study, we conducted a comprehensive analysis of 35 BXD RI lines (plus the C57BL/6J and DBA/2J parental lines) for BLA volume (Mozhui et al, 2007). This revealed up to twofold variation in BLA volume across this panel of RI lines.…”

“…We selected lines on the basis of a desire to obtain a range of relatively small, medium, and large BLA volumes; but this was limited by the availability of lines from a single commercial vendor (The Jackson Laboratory, Bar Harbor, ME), which was necessary to avoid a potentially confounding source of variability (ie supplier). Of the 15 BXD RI lines (plus the C57BL/6J and DBA/2J parental lines) obtained, we cross-referenced with the dataset (Mozhui et al, 2007) to assign an approximately equal number of lines to 'small,' 'medium,' and 'large' groups. This resulted in five lines in the small group (BXD13, BXD21, BXD28, BXD38, and BXD39), seven lines in the medium group (BXD8, BXD11, BXD12, BXD23, BXD31, BXD34, and DBA/ 2J), and five lines in the large group (BXD16, BXD19, BXD22, BXD32, and C57BL/6J).…”

“…This resulted in five lines in the small group (BXD13, BXD21, BXD28, BXD38, and BXD39), seven lines in the medium group (BXD8, BXD11, BXD12, BXD23, BXD31, BXD34, and DBA/ 2J), and five lines in the large group (BXD16, BXD19, BXD22, BXD32, and C57BL/6J). Next, we took the BLA volume data for each line (an average of n ¼ 4-8 mice per line) from the dataset (Mozhui et al, 2007) and calculated the mean average and within-group variance of BLA volume within each of our three volume groupings. Volume differences between the subgroups were then analyzed using one-way analysis of variance (ANOVA) followed by Newman-Keuls post hoc analysis.…”

“…In the present study, we sought to address this issue by utilizing a genetically defined panel of C57BL/6 Â DBA/2 (BXD) recombinant inbred strains that we have recently shown to exhibit up to twofold variation in BLA volume in large sample of 37 RI lines (Mozhui et al, 2007). BXD RI mice are inbred strains derived from C57BL/6 and DBA/2 (Taylor, 1978;Chesler et al, 2003) that have been used to identify chromosomal loci underlying fear-and anxiety-related phenotypes (Caldarone et al, 1997;Owen et al, 1997;Wehner et al, 1997;Valentinuzzi et al, 1998), as well as volume and cell number variation in various brain regions (Neumann et al, 1993;Airey et al, 2001Airey et al, , 2002Lu et al, 2001;Rosen and Williams, 2001;Williams et al, 2001;Seecharan et al, 2003).…”