Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine

The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non-target stimuli (discrimination sensitivity, or d’). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0–1.0 mg/kg, i.p.) dose-dependently improved d’ in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d’ impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure.

mice where comprehensive and clear null effects were observed in many alternative paradigms, and (ii) assess the cross-cohort reproducibility using animals differing in cognitive testing experience and age. We tested this older cohort of Df(h22q11)/+ and wild-type littermate controls on the rCPT task using probe tests of varying difficulty that are briefly described below. The probe tests consisted of manipulations to the stimulus durations (SD), target probability, inter-stimulus interval (ISI) length, and stimulus contrast: Varying SDs. Animals were assessed in 6 separate tests of different  implemented between sessions. The limited hold (LH) was set to 2.5s at the 2.5-1.5s SDs, and 1.5s at the 1.0-0.25s SDs. The target probability was set to 50% at the 2.5-1.5s SDs, and 30% at the 1.0-0.25s SDs. The tests were presented in order of decreasing SDs. The ISI was 5s throughout.
Varying stimulus durations when controlling for event-rate. We performed two probe tests where the LH was held constant (2.5s) and the SD was manipulated (2s vs. 0.5s) across sessions. Other task parameters remained constant (ISI: 5s; CS+ probability: 30%).
Varying target probability. Animals were tested in four probe tests of decreasing target probabilities (CS+ trial probability: 50%-10%). The probe tests were implemented between sessions and presented in order of decreasing target probability with other task parameters remaining constant (SD: 2s, LH: 2.5s, ISI: 5s).
Varying ISIs. Animals were tested in three probe tests of different ISIs (5s, 10s, and 15s) implemented across sessions. The probe tests were presented in order of increasing ISI. Other task parameters remained constant (SD: 2s, LH: 2.5s, CS+ probability: 30%).
Stimuli contrast. Animals were tested in four between-session probe tests of different stimuli contrasts (100-25%). The probe tests were presented in order of decreasing stimuli contrasts. Other task parameters remained constant (SD: 1s; ISI: 5s; CS+ probability: 30%).

THE RODENT CONTINUOUS PERFORMANCE TEST
The performances the older cohort of Df(h22q11)/+ mice and wild-type littermates is presented in Figure S1 and Table S2. Similar to the younger cohort, this older cohort of Df(h22q11)/+ animals showed impaired rCPT performance. Impairments were observed as decreased hit rates and increased response criterion c at when animals were challenged with decreased SDs and increased ISI time.
Varying SDs. The Df(h22q11)/+ mice had decreased hit rates at tests of shorter SDs (Fig. S1b; genotype: F 1,26 =0.996, p=0.335, genotype × SD: F 5,130 =4.795, p<0.0001). There was no effect of genotype on hit rate at the baseline rCPT test parameter (p=0.498) but the Df(h22q11)/+ had a decrease in hit rate when the SD was set to 1s (p=0.042) and non-significant decreases in hit rates at the 0.75s-0.25s SDs (p≥0.106). There was a trend for Df(h22q11)/+ mice to have increased c ( Fig Varying stimulus duration when controlling for event-rate. One Df(h22q11)/+ mutant was excluded from further testing due to bad health. Decreasing the SD (from 2s to 0.5s) while holding the LH constant (2s) produced a significant genotype × SD interactions on c (genotype: F 1,25 =1.397, p=0.248, genotype × SD: F 1,25 =4.324, p=0.048). Reducing the SD from 2s to 0.5s increased response criterion in wild-types (p=0.015) but more so in Df(h22q11)/+ mice (p<0.0001). Accordingly, the Df(h22q11)/+ tended to show lower hit rates at the 0.5s SD, however, there effect of genotype was not significant      Figure S1. Performance of Df(h22q11)/+ and wild-type littermates (older, extensively trained, cohort) when challenged with shorter SDs (a-b) and longer ISIs (c-d). Discrimination sensitivity (d') is an index of the subject's ability to distinguish target from non-target stimuli, while response criterion (c) describes the subject's propensity to respond to any stimulus (a) Varying SDs: d' and c. No significant effect of genotype or genotype × SD interaction on either d' or c. (b) Varying SDs: hit rate and false alarm rate. Df(h22q11)/+ mice had reduced hit rate at shorter stimulus durations.
There was no effect of genotype on false alarm rate. (c)Varying ISIs: d' and c. Df(h22q11)/+ mice had elevated response criterion c at longer ISIs relative to littermate controls. There was no effect of genotype on d'. (d) Varying ISIs: hit rate and false alarm rate. Df(h22q11)/+ mice tended to show reduced hit rate at the longer ISI. There was no significant effect of genotype on hit rate or false alarm rate.