The Neurobiology of Fear Generalization

Abstract

The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. When confronted with a potential threat, an animal must select an appropriate defensive response based on previous experiences that are not identical, weighing cues and contextual information that may predict safety or danger. Like other aspects of fear memory, generalization is mediated by the coordinated actions of prefrontal, hippocampal, amygdalar, and thalamic brain areas. In this review article, we describe the current understanding of the behavioral, neural, genetic, and biochemical mechanisms involved in the generalization of fear. Fear generalization is a hallmark of many anxiety and stress-related disorders, and its emergence, severity, and manifestation are sex-dependent. Therefore, to improve the dialog between human and animal studies as well as to accelerate the development of effective therapeutics, we emphasize the need to examine both sex differences and remote timescales in rodent models.

Keywords: animal models; fear generalization; fear memory; neural circuits; sex differences.

Figure 1

Fear generalization occurs along a continuum. High discrimination is a product of a heightened defensive response to the conditioned stimulus (CS) and a low defensive response to non-target CSs, reflecting a narrow generalization gradient (left panel). Low discrimination is a product of a heightened defensive response to the CS as well as an elevated defensive response to stimuli that approximate the CS, reflecting a broad generalization gradient (middle panel). No discrimination is a product of a heightened defensive response to the CS as well as stimuli that markedly differ from the CS, reflecting an elevated flat generalization gradient (right panel).