Figure 2. PsyCoP profile reveals resistance of BHLHE40^−/−/41^−/− mice to lithium’s beneficial effect on memory and cognition.

(A) Schematic of the experiment design. Four groups, two from each genotype and sex, were tested after three weeks of pre-treatment via with either Vehicle (Ctrl) or lithium chloride solution (LiCl). Treatment was continued throughout the experiments. (B) Circadian 24h activity plotted as group means of 1-hour bins and ribbons show the standard error of the mean. The light and dark bars visualize the light and dark phase, respectively. Black line indicates time points used to assess peak activity differences revealing significant genotype (G* = p < 0.05) and lithium treatment (T *** p < 0.001) dependent effects, as indicated. (C-E) Boxplots showing lithium-affected phenotypes in DKO animals. Data are shown as box plots with whiskers extending to no more than 1.5-fold IQR. (C) Nocturnality (relative activity differences between L and D phases) revealed a non-significant tendency of Lithium non-response in DKOs. Lithium treatment resistance was found to be significant in DKOs in (D) recent contextual fear memory and (D) Serial Reversal Learning performance, as indicated. (F) Dimension reduction showing the canonical scores of the first two canonical components Can1 and Can2 (explaining 63.5% and 21.5% of the overall canonical correlation, respectively) depicts the aggregated Li-treatment dependent difference in WT but not DKO animals. Datapoints are overlayed with a 75% data ellipse. (G) A heatmap of the weights of single variables in the structure of the CDA for each term of the profile’s linear model. The variables are grouped in RDoC Top Level Domains as assigned a priori. Multivariate ANOVA results are shown on top. Univariate contrasts reaching significance are indicated with asterisks in the respective panel.* p < 0.05; ** p < 0.01; *** p < 0.001; n.s. not significant; p-values are FDR-adjusted and refer to Wilk’s lambda testing two-way ANOVA; simple effects were tested in a similar but univariate and unifactorial ANOVA procedure; WT: wildtype mice; DKO: BHLHE40^−/−/41^−/− mice; Ctrl: vehicle control; LiCl: lithium-treated; OF: Open Field Test; YM: Y-Maze Test; IC: IntelliCage; Act: circadian activity; PcL: Place Learning; SRL: Serial Reversal Learning; ScP: Sucrose Preference Test; PPI: Prepulse Inhibition Test; TST: Tail Suspension Test; FC: Fear Conditioning Test; G: genotype main effect; T: treatment main effect; GxT: interaction effect; simple T: simple effects; DKO-T: DKO simple treatment effect; WT-T: WT simple treatment effect; C: Cognitive Systems Domain; S: Sensorimotor Systems Domain; “+”: Positive Valence Systems Domain; “−“: Negative Valence Systems; A: Arousal and Regulatory Systems Domain