Effects of sex and COMT genotype on environmentally modulated cognitive control in mice

Abstract

Cognitive functioning differs between males and females, likely in part related to genetic dimorphisms. An example of a common genetic variation reported to have sexually dimorphic effects on cognition and temperament in humans is the Val/Met polymorphism in catechol-O-methyltransferase (COMT). We tested male and female wild-type mice ((+/+)) and their COMT knockout littermates ((+/-) and (-/-)) in the five-choice serial reaction time task (5CSRTT) to investigate the effects of sex, COMT genotype, and their interactions with environmental manipulations of cognitive functions such as attention, impulsivity, compulsivity, motivation, and rule-reversal learning. No sex- or COMT-dependent differences were present in the basic acquisition of the five-choice serial reaction time task. In contrast, specific environmental manipulations revealed a variety of sex- and COMT-dependent effects. Following an experimental change to trigger impulsive responding, the sexes showed similar increases in impulsiveness, but males eventually habituated whereas females did not. Moreover, COMT knockout mice were more impulsive compared with wild-type littermates. Manipulations involving mild stress adversely affected cognitive performance in males, and particularly COMT knockout males, but not in females. In contrast, following amphetamine treatment, subtle sex by genotype and sex by treatment interactions emerged primarily limited to compulsive behavior. After repeated testing, female mice showed improved performance, working harder and eventually outperforming males. Finally, removing the food-restriction condition enhanced sex and COMT differences, revealing that overall, females outperform males and COMT knockout males outperform their wild-type littermates. These findings illuminate complex sex- and COMT-related effects and their interactions with environmental factors to influence specific executive cognitive domains.

Fig. 1.

Performance displayed by COMT^+/+, ^+/−, and ^−/− mice during 4-wk impulsivity screening at different ITI delays (5-s ITIs: Mondays, Tuesdays, Thursdays, and Fridays; 7-s ITIs: Wednesdays). For clarity, data from consecutive days with the normal 5-s ITIs were averaged. Choice accuracy in males (A) and females (B). Correct responses in males (C) and females (D). Trial omissions in males (E) and females (F). Premature responses in males (G) and females (H). Perseverative responses in males (I) and females (J). n = 7/11 per group throughout the figures. *P < 0.05, **P < 0.005, and ***P < 0.0005 vs. 5-s ITI performance; ^#P < 0.05, ^##P < 0.005, and ^###P < 0.0005 vs. same time point in males. ^ØP < 0.05 and ^ØØØP < 0.0005 vs. ^+/+ same-sex littermates. Values represent mean ± SEM in all figures.

Fig. 2.

Performance displayed by COMT^+/+, ^+/−, and ^−/− mice during 2 wk of pretest exposure to a mild stressor every other day (nonstress days: Mondays, Wednesdays, and Fridays; stress days: Tuesdays and Thursdays). For clarity purposes, data from a consecutive Friday and Monday were averaged. Choice accuracy displayed by males (A) and females (B). Correct responses in males (C) and females (D). Trial omissions in males (E) and females (F). Premature responses in males (G) and females (H). Perseverative responses in males (I) and females (J). *P < 0.05 and ***P < 0.0005 vs. performance on days with no stress; ^#P < 0.05, ^##P < 0.005, and ^###P < 0.0005 vs. same time point in males. ^ØØØP < 0.0005 vs. ^+/+ same-sex littermates.

Fig. 3.

Performance displayed by COMT^+/+, ^+/−, and ^−/− mice during amphetamine manipulation (no injection: Mondays, Wednesdays, and Fridays; 0.75 or 0.375 mg⋅kg⁻¹⋅10 mL⁻¹ i.p. amphetamine injection immediately before the test: Tuesdays and Thursdays). Data are reported as the average from the same injection conditions. Choice accuracy in males (A) and females (B). Correct responses in males (C) and females (D). Trial omissions in males (E) and females (F). Premature responses in males (G) and females (H). Perseverative responses in males (I) and females (J). ***P < 0.0005 vs. no injection; ^##P < 0.005 vs. same injection condition in males. ^ØØP < 0.005 vs. ^+/+ same-sex littermates.

Fig. 4.

Performance displayed by COMT^+/+, ^+/−, and ^−/− mice with food ad libitum. As no time-dependent effect was present, data are reported as the average of the 10 d of testing under this condition. (A) Choice accuracy in males and females. (B) Correct responses in males and females. (C) Trial omissions in males and females. (D) Premature responses in males and females. (E) Perseverative responses in males and females. ^#P < 0.05 and ^###P < 0.0005 vs. males. ^ØP < 0.05 vs. ^+/+ same-sex littermates.