Abstract
Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.
Highlights
Impaired motivation is a cardinal symptom of depression [1, 2]
Using fiber photometric recordings of bulk neural activity, we show that stress effects on goal-directed motivation are associated with perturbations in ventral hippocampal activity, and stress-induced motivational impairments can be alleviated with appropriately timed manipulation of ventral hippocampus (vHP) activity
We previously demonstrated that performance is sensitive to outcome devaluation [20], indicating that behavior is goal-directed in this task
Summary
Impaired motivation is a cardinal symptom of depression [1, 2]. Among depression symptoms, diminished motivational drive is one of the strongest predictors of a depression diagnosis [3]. Motivational impairments potentially involve perturbations to at least two distinct motivational processes: changes in the hedonic impact (liking or pleasure) derived from rewards (RWs), and changes in cost-benefit calculations that control the willingness to engage in and sustain effortful behaviors required to earn a RW [4, 5]. There is indirect evidence suggesting that hedonic responses to RW are blunted in depressed patients, studies directly assessing pleasure responses have not yielded evidence of impaired hedonic impact in depressed patients [7]. Depressed patients do exhibit deficits in effortful RWbased tasks [8], leading some researchers to conclude that motivational deficits in depressed patients reflect a decreased willingness to expend effort to obtain RWs [9]
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