3 - Modeling disorders of fear and anxiety in animals

Abstract

Anxiety disorders, like depressive disorders, are quite common, with a lifetime prevalence of approximately 29% in the United States. Anxiety and depressive disorders are often comorbid, with generalized anxiety disorder (GAD) having a particularly close relationship to depression. These internalizing disorders are suggested to represent an anxiety–depression spectrum, ranging from depression and GAD on one end (so-called distress disorders), to panic disorder and specific phobia on the other (“fear” disorders). Categorically defined anxiety disorders align themselves on the spectrum according to measures of distress (low positive affect and high negative affect) and fear (autonomic arousal, or fear-potentiated startle reactions). These two symptom dimensions are inversely related; thus, GAD is associated with high distress and low autonomic arousal, whereas specific phobia is characterized by lower distress and high autonomic arousal. The processing of fear-related stimuli, the emotional, behavioral, and physiologic responses to these stimuli, as well as fear conditioning, are key processes involved in pathologic anxiety. At the most general level, these processes involve the amygdala and bed nucleus of the stria terminalis and their hypothalamic and brainstem targets: the former receive and integrate sensory and memory information related to danger as well as trigger behavioral and physiologic responses via their output to the latter. Prefrontal regions, including the ventromedial prefrontal cortex, appear to mediate negative top-down control over amygdala responses. Pathologic anxiety is related to the malfunction of normal, highly adaptive fear response systems that include panic (an intense, fight or flight emergency response), anxiety (cautious assessment of possible threats), and other more circumscribed fear responses such as those associated with social threat, snakes, spiders, and other small animals. Endophenotypes identified for anxiety disorders include enhanced startle reactivity, behavioral inhibition, carbon dioxide sensitivity, anxiety sensitivity, and fear generalization. With the exception of anxiety sensitivity, all of these endophenotypes can be assessed in rodent models. A number of candidate genes have been implicated in anxiety disorders, including many associated with monoaminergic neurotransmitter systems and stress and fear responses, as well as some whose biologic function is not completely clear. Early life stress and adversity appear to program fear and stress response systems for later life responses, generally sensitizing these systems and amplifying their responses. Rodent models for anxiety disorders include those that involve fear-conditioning paradigms, experimentally applied early life stress, lines selectively bred to display increased anxiety-like behavior, and genetic manipulations of candidate gene expression. Nonhuman primates are also very informative subjects for anxiety research, since they are more similar to humans than are rodents, on a number of levels. Zebrafish, chicks, Drosophila, and Caenorhabditis elegans are also very useful model animals, each model offering its own distinct advantages.