Htr1a is expressed in CeA (left panel) and DG (right panel) in Htr1a^CeA and Htr1a^DG mice, respectively. Image reprinted from Nature Neuroscience.

For some people, a weekly spelling quiz can be as nerve-wracking as a college entrance exam. People with anxiety disorders often experience exaggerated responses to relatively innocuous stimuli. How do animals normally weigh the threats posed by different situations? Tsetsenis et al. report that serotonin receptor 1A (Htr1a) and the hippocampal mossy-fiber circuit are important in allowing mice to evaluate threatening stimuli in a recent article in Nature Neuroscience.

Htr1a is coupled to G-protein inward-rectifying K⁺ channels (GIRKs), and Htr1a activation induces membrane hyperpolarization. Htr1a knockout (Htr1a^KO) mice are more anxious than wild-type mice and show hippocampal deficits in dendritic arborization and synaptic transmission. Hippocampal circuits are important in processing complex associative stimuli, so the authors tested Htr1a^KO mice for deficits in associative learning.

In fear conditioning, mice learn to associate cues with shocks. The authors presented a light before every shock. Occasionally, a tone preceded the light; however, the tone also occasionally occurred on its own, in the absence of shocks. Therefore, the light and tone, respectively, were perfect and partial predictors of the shock. Relative to baseline, light induced increased fearful freezing in both Htr1a^KO and wild-type mice. In wild-type mice, the tone induced levels of freezing that were intermediate to baseline and light. However, Htr1a^KO mice showed similar levels of freezing in response to the light and the tone, suggesting that Htr1a^KO mice respond fully to ambiguous stimuli.

Htr1a is important in generating forebrain circuits involved in anxiety-related behaviors. The authors previously showed that conditional expression of Htr1a during development but not in adulthood rescued normal anxiety behavior in Htr1a^KO mice. In the current study, they treated wild-type mice with Htr1a antagonists or vehicle during the third and fourth weeks of life, when dendritic development is maximal. As adults, Htr1a antagonist-treated mice showed increased levels of freezing to a partial stimulus relative to vehicle-treated mice, suggesting that this overreaction to ambiguous stimuli is programmed during development.

What are the brain circuits responsible for this response? The authors generated mice expressing Htr1a only in the central nucleus of the amygdala (CeA), which is important in the physiological and behavioral responses to conditioned stimuli, or the dentate gyrus (DG), which receives input from the entorhinal cortex and sends output to CA3 pyramidal cells in mossy fiber connections. Serotonin treatment silenced CeA and DG neurons in mice expressing Htr1a only in CeA and DG (designated Htr1a^CeA and Htr1a^DG), respectively. In the adult brain, baseline serotonin levels do not activate Htr1a. Vehicle-treated Htr1a^CeA, Htr1a^DG and Htr1a^KO mice responded similarly to fear conditioning cues. An Htr1a agonist reduced freezing in Htr1a^CeA mice in response to both perfect and partial cues. In contrast, Htr1a agonist treatment reduced only partial cue-induced freezing in Htr1a^DG mice, suggesting that hippocampal mossy fibers are important in predicting the value of threatening stimuli.

Together, these data suggest that anxiety disorders may be caused by abnormal hippocampal development. Although treatments that reduce mossy fiber signaling may prevent excessive anxiety, caution should be exercised because dampening hippocampal circuits may affect memory.

1. Tsetsenis, T., Ma, X. H., Iacono, L. L., Beck, S. G. & Gross, C. Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nature Neuroscience 10, 896–902 (2007). | Article | PubMed |