Genetic background influences the behavioural and molecular consequences of neurokinin-1 receptor knockout.
Genetic background affects animal phenotype and therefore is of particular relevance to studies using genetically manipulated mice. Strain differences in hypothalamic-pituitary-adrenocortical (HPA) axis activity may contribute to background-specificity of some mutations. Here, we analysed components of the HPA axis in mice lacking a functional neurokinin-1 receptor (NK1-/-) on two backgrounds: backcrossed C57BL/6 (B6) and mixed C57BL/6 x 129/sv (129B6). We hypothesized that HPA axis activity would vary between these strains, leading to differences in the NK1-/- phenotype. We compared levels of plasma corticosterone between the groups, and found 129B6 mice exhibited elevated levels of stress-induced corticosterone compared with B6 mice, regardless of genotype. Although the level of basal corticotrophin-releasing factor and stress-induced c-fos mRNAs did not differ between the genotypes of either strain, examination of glucocorticoid receptor immunoreactivity within the hippocampus revealed that NK1-/- mice on the 129B6 background had elevated expression compared with wild-type, whilst there was no difference between genotypes in the B6 strain. Similarly, hippocampal neurogenesis in NK1-/- mice was greater than in wild-type on the 129B6 strain, and did not differ between genotypes on the B6 background. Finally, novelty- and morphine-induced locomotion were assessed. NK1-/- mice on the 129B6 background exhibited hyperlocomotion in response to novelty and greater sensitivity to the locomotor-stimulating properties of morphine than wild-type. In contrast, in B6 mice, no differences were observed between genotypes for either locomotor behaviour. In summary, we find that HPA axis activity differs between the strains and that there are profoundly background-specific effects of the NK1 receptor mutation.
McCutcheon
J E
JE
Department of Anatomy & Developmental Biology, UCL, Gower St, London, UK. james.mccutcheon@rosalindfranklin.edu
Fisher
A S
AS
Guzdar
E
E
Wood
S A
SA
Lightman
S L
SL
Hunt
S P
SP
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics*; D013045:Species Specificity; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015320:Tachykinins / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D011965:Receptors, Glucocorticoid; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D009020:Morphine; D003345:Corticosterone