Abstract

A Stress-Sensitive Frontostriatal Circuit Supporting Effortful Reward-Seeking Behavior

Fetcho R, Parekh P, Kenwood M, Chalencon L, Estrin D, Chou J, Johnson M, Liston C
61st Annual Meeting of the American College of Neuropsychopharmacology. 2022.

Abstract

Background: Effort valuation—a process for selecting actions based on the anticipated value of rewarding outcomes and expectations about the amount of work required to obtain them—plays a fundamental role in decision-making. Effort valuation is disrupted in chronic stress states and is supported in part by the anterior cingulate cortex (ACC), but the circuit-level mechanisms by which the ACC represents effort-related signals and regulates effort-based decision-making and reward-seeking are not well defined.

Methods: We developed an automated, physiology-compatible platform for high-throughput assessments of effort valuation in freely moving mice. In an elevated T-maze apparatus, animals (male C57Bl/6 mice, age 8-12 weeks) were presented with the choice between water rewards of varying magnitudes that are associated with varying effort expenditure requirements. We utilized fiber photometry and optogenetics to record from and manipulate nucleus accumbens projecting ACC neurons (ACC-NAc) as mice performed this effort-based decision-making task. Following training, a subset of mice underwent chronic corticosterone exposure - a model of the neuroendocrine response to stress - and following exposure were retested on the behavioral paradigm alongside ACC-NAc recordings.

Results: We found that ACC-NAc activity anticipates and responds to reward acquisition; however, the circuit does not appear to encode reward magnitude. Instead, the magnitude of ACC-NAc reward-related activity scaled with the level of effort expenditure required to obtain the reward (N = 16 mice, 4384 behavioral trials, 3 experiments; linear mixed effects model: significant interaction between reward type and effort level – F(2,4378) = 135.38 p < 0.0001). We next found that optogenetic silencing of this effort-sensitive reward signal led to significant reductions in future effortful decisions within a behavioral session (Two-way repeated measures ANOVA: N = 18 mice (11 control, 7 experimental), 2 experiments. Significant interaction F(1,16) = 13.06, p = 0.0023. Post-hoc bonferonni testing control: baseline vs. stim p = 0.7, experimental: baseline vs. stim p = 0.0001). Finally, chronic corticosterone treatment led to significant impairments in effortful reward-seeking behavior that strongly correlated with impaired ACC-NAc circuit function (N = 5 mice, 10 sessions from 2 experiments. Linear mixed effects model T(10) = 4.56, p = 0.002, R2 = 0.72).

Conclusions: Our results show that ACC neurons support effort valuation behavior through projections to the NAc. Specifically, ACC-NAc circuit activity integrates both reward- and effort-related information and this activity is critical for reinforcing future effortful decisions. Chronic corticosterone leads to disruptions in this effort-sensitive reinforcement signal that correlate with impaired effortful reward-seeking behavior, suggesting one potential mechanism underlying stress-induced motivational deficits.