Sex differences in contextual fear learning and generalization: a behavioral and computational analysis of hippocampal functioning.

ABSTRACT

There are sex differences in anxiety disorders with regard to occurrence and severity of episodes such that females tend to experience more frequent and more severe episodes. Contextual fear learning and generalization are especially relevant to anxiety disorders, which are often defined by expressing fear and/or anxiety in safe contexts. In contextual fear conditioning, a representation of the context must first be created, and then that representation must be paired with an aversive consequence. With some variation, the experiments presented here use a 3-d procedure in which day 1 consists of pre-exposure to the to-be-shocked context, day 2 consists of a single context-shock pairing after some placement-to-shock interval (PSI), and day 3 consists of testing in either the same or a novel context. With shorter pre-exposure periods, male rats showed more contextual fear, consistent with previous literature; however, after longer pre-exposure periods, female rats showed greater contextual fear. Additionally, while pre-exposure and PSI are both periods of time prior to the shock, it was found that they were not equivalent to each other. Animals with 120 sec of pre-exposure and a 30-sec PSI show a differential level and time course of fear expression than animals who received no pre-exposure and a 150-sec PSI, and this further depended on sex of the rat. Additionally, an experiment comparing recently versus remotely acquired contextual fear was run. Males were again shown to have greater contextual fear at both time points, and this contextual fear incubated/increased over time in males but not females. To facilitate identification of what processes caused sex differences, we used BaconX, a conceptual and computational model of hippocampal contextual learning. Computational simulations using this model predicted many of our key findings. Furthermore, these simulations suggest potential mechanisms with regard to hippocampal computation; namely, an increased feature sampling rate in males, which may account for the sex differences presented here and in prior literature.