Neural Computations Underpinning Anxiety in Health and Disease

Abstract

Motivational conflict is thought to take one of three possible forms: approach-approach conflict,avoid-approach conflict, and avoid-avoid conflict. While approach-approach conflict paradigms have primarily been used to study the neural basis of reward-based decision-making, avoid-approach conflict paradigms are typically used to model anxiety because they capture the complex, bivalent nature of most naturalistic environments. Research suggests that approach-approach conflict initiates a distinct neural algorithm: a hippocampally-mediated mental simulation of the future that is paired with evaluations of anticipated outcomes. However, it is unknown whether a similar form of episodic future thinking also occurs during avoid-approach conflict. Here I present research I have conducted to address this gap in the literature. First, I used apharmacological approach in tandem with a semi-naturalistic avoid-approach predator-inhabited foraging arena task to show that anxiety-like hesitation behaviors are attenuated by anxiolytic drugs. I then modeled these hesitation behaviors as a belief-state updating loop using a partially observable Markov decision process that involves fictive representations of potential future outcomes. Next, I explored the neural representations underpinning these anxiety-like behaviors, aiming to determine whether non-local representations occur during periods of anxious conflict. To do this, I recorded from ensembles of neurons in dorsal hippocampal layer CA1 of rats as they freely behaved in the predator-inhabited foraging arena task. I identified distinct hippocampal fictive representations that co-occurred with two anxiety-like behaviors: (1) forward sequences during choice-point hesitation that shifted from representing reward in a safe environment to representing reward and threat in a dangerous environment, and (2) discrete representations of threat during a change-of-mind behavior. Altogether, these results support the view that anxiety resulting from avoid-approach conflictinvolves representations of hypothetical scenarios and that these fictive representations are, at least in part, neurally encoded in the hippocampus. These data highlight hippocampal fictive representations as a potential target for the treatment of anxiety disorders.