Ambiguity and anxiety: overreaction and a serotonin receptor

Nader and Alleine describe work of Tsetsenis et al.

When the threat of terrorist attack is elevated, the United States Department of Homeland Security changes its prediction of danger from yellow to orange to red. Most of us can manage our levels of vigilance and of anxiety appropriately in response to these cues. However, imagine how debilitating it would be if you were unable to manage your anxiety and reduce your fear of attack when the threat level was reduced. In fact, many people with anxiety disorders suffer from precisely this kind of condition. The paper by Tsetsenis et al. finds that mice lacking the serotonin 1a receptor overreact to ambiguous predictors of aversive events in this same way, providing insight into factors that could predispose individuals to such disorders and into the neural locus of the effect.

Understanding the neural bases of contingency is not simply an academic question, but very much a mental health one. Unpredictable aversive events can be much more stressful than the same events when they are anticipated. In addition, psychopathologies can influence the perception of contingency. For example, depressed people have a different sense than nondepressed people of how their responses affect the environment, and exposure to unpredictable or uncontrollable aversive events is suggested to directly influence the development of depression.

The new study by Tsetsenis et al. makes a significant contribution to our understanding of the neural mechanisms mediating contingency learning. The authors studied mice in which the serotonin 1a receptor (Ht1a) gene was knocked out or inactivated during development. This receptor causes membrane hyperpolarization of nonserotonergic neurons and acts as an autoreceptor on serotonergic neurons in the raphe. Ht1a dysfunction is linked to anxiety disorders and depression, and mice lacking Ht1a receptors show increased avoidance behavior. This phenotype is attributable to the absence of the Ht1a in the forebrain during development; eliminating these receptors during adulthood does not cause the mice to show the anxious phenotype. Although fear of an aversive context is comparable in knockout and wild-type mice, the knockout mice over-generalize their fear of the 'aversive' context to a similar context containing novel elements, a situation in which wild-type mice are able to decrease their fear levels11. This finding suggested that these mutant mice focus unduly on cues that have been paired with shock rather than on cues that have not.

Figure: Humans and other animals can accurately estimate the probability of danger from their experience of specific environments or cues and use this information to respond appropriately. A normal mouse (top) accurately estimates the threat from an ambiguous cue, a sleeping cat, and a less ambiguous cue, an alert cat, and is appropriately cautious or alarmed, respectively. In contrast, anxious people and animals, such as the Htr1a knockout mouse assessed by Tsetsenis et al. (bottom), often overestimate the danger represented by ambiguous cues and over-respond, given the level of threat. This is likely to interfere with the need to respond to other important events in the environment (such as cheese).

Here is the abstract from Tsetsenis et al.

Serotonin receptor 1A knockout (Htr1aKO) mice show increased anxiety-related behavior in tests measuring innate avoidance. Here we demonstrate that Htr1aKO mice show enhanced fear conditioning to ambiguous conditioned stimuli, a hallmark of human anxiety. To examine the involvement of specific forebrain circuits in this phenotype, we developed a pharmacogenetic technique for the rapid tissue- and cell type–specific silencing of neural activity in vivo. Inhibition of neurons in the central nucleus of the amygdala suppressed conditioned responses to both ambiguous and nonambiguous cues. In contrast, inhibition of hippocampal dentate gyrus granule cells selectively suppressed conditioned responses to ambiguous cues and reversed the knockout phenotype. These data demonstrate that Htr1aKO mice have a bias in the processing of threatening cues that is moderated by hippocampal mossy-fiber circuits, and suggest that the hippocampus is important in the response to ambiguous aversive stimuli.