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. 2017 Mar 29;140(5):1447–1465. doi: 10.1093/brain/awx060

Figure 6.

Figure 6

Neuronal progranulin depletion with CaMKII-Cre impairs social dominance, nesting, and the amygdala response to a novel, social environment, but does not produce gliosis or lipofuscinosis.CaMKII-Cre N-KO mice developed many of the same behavioural abnormalities that have been observed in global Grn+/– mice, including a losing phenotype in the tube test versus Cre− littermates (A, P = 0.0325). CaMKII-Cre N-KO mice also exhibited a deficit in nesting behaviour (B, P = 0.0129). After exposure to a novel, social environment, CaMKII-Cre N-KO mice had fewer c-Fos-positive cells across the three major amygdala nuclei (C, ANOVA effect of genotype, P = 0.0142). Representative images of c-Fos immunostaining are shown with lines drawn to illustrate boundaries between amygdala nuclei (D). The boxed areas in the central amygdala are enlarged in the panels below the top images. The scale bars in the larger image in D represent 100 µm, and the scale bar in the smaller central amygdala image represents 50 µm. For assessment of pathology, brains from 20-month-old CaMKII-Cre N-KO mice and Cre− littermates were immunostained for markers of microgliosis (E, CD68) and astrogliosis (F, GFAP). The presence of autofluorescent lipofuscin granules was measured by imaging brain sections with an epifluorescence microscope (G). No differences were detected between CaMKII-Cre N-KO mice and controls (repeated measures ANOVA effect of genotype and genotype × region interaction were not statistically significant for all measures), showing that neuronal progranulin deficiency is not sufficient to produce pathology. A limited sample of brains from Grn–/– mice were processed in parallel with the sections to serve as a positive control, but were not included in the statistical analysis given the small sample size. Representative ×20 images of CD68, GFAP, and lipofuscin are shown for each group. Scale bars = 50 µm. Nesting behaviour and tube test winning percentage were analysed by Mann-Whitney test, and c-Fos and pathology data were analysed by repeated measures ANOVA with Sidak’s post hoc test. n = 35–38 mice per group for the tube test, 26–29 per group for nesting, eight per group for c-Fos, and five to eight per group for pathology measures. BLA = basolateral amygdala; CeA = central amygdala; Ctx = cortex; HPC = hippocampus; MeA = medial amygdala; Thal = thalamus. *P < 0.05, **P < 0.01.