Mild maternal separation in mice of both sexes: impact in adultthood on vigor to approach or to escape motivational stimuli and interaction with dopamine depletion

Abstract

Early-life stress affects brain development and can lead to psychiatric disorders such as depression later in life. Little is known about the effect of early-life stress on motivational processes such as effort-based decision-making, which could be impaired in people with depression. Mesolimbic dopamine (DA) regulates behavioral activation and effort in motivated behaviors, and stress produces opposite effects on DA release depending if it is acute or chronic. Maternal Separation (MS) could act as an early-life stressor depending on its duration and intensity. Using CD1 male and female mice, we evaluate the impact of early but mild MS (PND3-5, 90 min), on selection of effortful responses in adulthood under positive or aversive conditions. In a three-choice-T-maze, mice preference for active reinforcers such as a running wheel (RW) versus sedentary ones was evaluated, and in a forced swim task (FST), time dedicated to escape or passively floating was measured. In addition, we studied if MS interacts with DA depletion in adulthood, administering tetrabenazine (TBZ), a VMAT-2 inhibitor that induces fatigue and anergia. Males and females do not differ; they spend more time in the RW and less eating or sniffing a neutral odor in the T-maze, independently of separation. However, separated mice of both sexes spent more time in the RW, and climbing in the FST compared to non-separated mice. Only among males, TBZ reduced time in RW, increased time eating, reduced climbing and increased immobility. Females were not affected by DA depletion. Anxiety was evaluated in a dark-light box, and separated males where less anxious than non-separated, but TBZ did not affect either sex.