Sex and age differences in mice models of effort-based decision-making and anergia in depression: the role of dopamine, and cerebral-dopamine-neurotrophic-factor

Abstract

Mesolimbic dopamine (DA) regulates vigor in motivated behavior. While previous results have mainly been performed in male rodents, the present studies compared CD1 male and female mice in effort-based decision-making tests of motivation. These tests offered choices between several reinforcers that require different levels of effort (progressive ratio/choice task and 3-choice-T-maze task). Sweet reinforcers were used in both tasks. In the operant tasks, females worked harder as the task required more effort to access a 10% sucrose solution. Although males and females did not differ in preference for 10% vs 3% solutions under free concurrent presentation, females consumed more of the 10% solution when tested alone. The operant task requires a long period of training and changes in the DA system due to age can be mediating long-term changes in effort. Thus, age and sex factors were evaluated in the T-maze task, which requires only a short training period. Both sexes and ages were equally active when habituated to the running wheel (RW), but females consumed more sweet pellets than males, especially at an older age. Both sexes had a strong preference for the RW compared to more sedentary reinforcers in the 3-choice-T-maze test, but older animals spent less time running and ate more than the young ones. The DA-depleting agent tetrabenazine reduced time running in older mice but not in adolescents. Cerebral-dopamine-neurotrophic-factor was reduced in older mice of both sexes compared to adolescent mice. These results emphasize the importance of taking into account differences in sex and age when evaluating willingness to exert effort for specific reinforcers.

Keywords: Age; Dopamine; Effort; Mice; Neurotrophic factors; Operant; Running wheel; Sex; Vigor.

Fig. 1

Schematics with the timeline and age of the animals in the different experiments

Fig. 2

Impact of sex on operant performance across different ratio schedules performed in consecutive weeks. Lever presses (A) and 10.0% sucrose intake (B). Sessions lasted 15 min. Bars represent the mean ± SEM number of lever presses or ml sucrose consumed. *p<0.05, **p<0.01, significant differences between sexes. ^#p<0.05, ^##p<0.01 significantly different from FR1 in each sex

Fig. 3

Upper: Effect of concurrent free access presentation of two concentrations of sucrose (10.0 and 3.0%) on volume consumed in a 30-min session in both sexes (A). Bars represent mean ± SEM of ml sucrose consumed. *p<0.05 significant differences between sexes. ^#p<0.05, ^##p<0.01 significant differences between concentrations. Lower: Effect of introducing a free option (3.0% sucrose) on PROG lever presses (B), operant-dependent 10.0% sucrose intake (C), and free 3.0% sucrose intake (D). Bars represent the mean ± SEM number of lever presses or ml consumed in an operant session of 15 min. **p<0.01, significant differences between sexes

Fig. 4

Body weight of both sexes across time. Data represent mean + SEM of body weight in grams during the week that corresponded with the operant data represented. **p<0.01 significant differences between sexes. ^##p<0.01 significant differences with the FR1 week

Fig. 5

Left: Spontaneous running wheel activity or sweet food intake in naïve adolescent (A, D) and naïve middle-aged (B, E) male and female mice on 5 consecutive days. Right: Comparison of both ages and both sexes when animals have already reached a stable baseline of voluntary RW (C), and sweet food consumed (F) on day 5, when animals were already habituated. Data are expressed as mean ± S.E.M of number of turns or pellets consumed during a session of 15 minutes. ^##p<0.01 statistically significant main effect of session, or significant differences from day 1 in the same sex. *p<0.05 significant difference between sexes, **p<0.01 statistically significant main effect of sex

Fig. 6

Preference for stimuli with different levels of vigor requirements in the 3-choice T-maze task. Time eating palatable food (A), time running (B), time sniffing the non-social odor (C), pellets consumed (D), and motor exploration of the 3-compartments T-maze (E). Data are expressed as mean ± S.E.M of time (seconds), number of pellets consumed or number of entries in the 3 compartments during a 15-min session. *p<0.05, **p<0.01 significant main effect of sex. ^#p<0.05, ^##p<0.01 statistically significant main effect of age

Fig. 7

Effect of TBZ (vehicle or 8.0 mg/kg) on time eating (A), time running (B), time sniffing (C), pellets consumed (D), and entries into compartments (E) in adolescent mice of both sexes as measured in the T-maze task. Bars represent the mean ± S.E.M. of accumulated seconds, number of pellets, or number of entries in 15 min. *p<0.05, **p<0.01 significant differences between sexes. ^#p<0.05, ^##p<0.01 significant main effect of treatment or significant differences between VEH and TBZ in the same sex

Fig. 8

Effect of TBZ (vehicle or 8.0 mg/kg) on time eating (A), time running (B), time sniffing (C), pellets consumed (D), and entries into compartments (E) in middle-aged adult mice of both sexes as measured in the T-maze task. Bars represent the mean ± S.E.M. of accumulated seconds, number of pellets, or number of entries in 15 min. *p<0.05, **p<0.01 statistically significant main effect of sex or differences between sexes in the same treatment. ^#p<0.05 significant main effect of treatment or significant differences between VEH and TBZ in the same sex

Fig. 9

(A) CDNF immunoreactivity in Nacb Core at different ages in both sexes. Bars represent the mean ± S.E.M. of positive cell counts per mm². *p<0.05 significantly different from 6w old animals. (B) Representative pictures (40×) showing expression of CDNF immunoreactivity in the Nacb Core of males and females at 6 and 29 weeks. Scale bar represents 50 μm. (C) Diagram of coronal sections with bregma coordinates showing location of Nacb Core taken from Paxinos and Franklin (2019)