Arc regulates a second-guessing cognitive bias during naturalistic foraging through effects on discrete behavior modules.

Foraging in animals relies on innate decision-making heuristics that can result in suboptimal cognitive biases in some contexts. The mechanisms underlying these biases are not well understood, but likely involve strong genetic effects. To explore this, we studied fasted mice using a naturalistic foraging paradigm and discovered an innate cognitive bias called "second-guessing." This involves repeatedly investigating an empty former food patch instead of consuming available food, which hinders the mice from maximizing feeding benefits. The synaptic plasticity gene Arc is revealed to play a role in this bias, as Arc-deficient mice did not exhibit second-guessing and consumed more food. In addition, unsupervised machine learning decompositions of foraging identified specific behavior sequences, or "modules", that are affected by Arc. These findings highlight the genetic basis of cognitive biases in decision making, show links between behavior modules and cognitive bias, and provide insight into the ethological roles of Arc in naturalistic foraging.