Modulation of anxiety and fear via distinct intrahippocampal circuits

Recent findings indicate a high level of specialization at the level of microcircuits and cell populations within brain structures with regards to the control of fear and anxiety. The hippocampus, however, has been treated as a unitary structure in anxiety and fear research despite mounting evidence that different hippocampal subregions have specialized roles in other cognitive domains. Using novel cell-type- and region-specific conditional knockouts of the GABAA receptor α2 subunit, we demonstrate that inhibition of the principal neurons of the dentate gyrus and CA3 via α2-containing GABAA receptors (α2GABAARs) is required to suppress anxiety, while the inhibition of CA1 pyramidal neurons is required to suppress fear responses. We further show that the diazepam-modulation of hippocampal theta activity shows certain parallels with our behavioral findings, suggesting a possible mechanism for the observed behavioral effects. Thus, our findings demonstrate a double dissociation in the regulation of anxiety versus fear by hippocampal microcircuitry. DOI: http://dx.doi.org/10.7554/eLife.14120.001
eLife digest Fear and anxiety can be thought of as different but related emotional states. Fear is triggered by specific harmful situations, such as the immediate presence of a predator. Anxiety instead results from the possibility of an obscure threat, such as being in an exposed environment, which increases the chance of being detected by a predator. Evidence suggests that slightly different areas of the brain control fear and anxiety, but much remains unknown about the specific brain regions that help to regulate these two emotional states. One brain region that has been implicated in both anxiety and fear – as well as in learning and memory – is the hippocampus. Named after the Greek word for seahorse because of its shape, the hippocampus is made up of three subregions: CA1, CA3 and the dentate gyrus. Each of these subregions has a distinct role in learning and memory. However, their individual contributions to the control of fear and anxiety were not known. An inhibitory receptor protein found in the surface of some hippocampal neurons had previously been shown to be involved in controlling fear and anxiety. Now, Engin et al. have studied three different groups of genetically modified mice, each of which lacks the receptor protein in a different subregion of the hippocampus. The mice completed tests that stimulated anxiety or fear, some while under the influence of the anxiety and fear-reducing drug diazepam. Notably, diazepam failed to reduce fear in animals that lacked the inhibitory receptor protein in the CA1 subregion of the hippocampus, suggesting that this subregion participates in the fear response. However, mice that lacked the receptor in the dentate gyrus or CA3 responded normally to the drug (they showed reduced fear when given diazepam). In tests of anxiety, the picture was exactly the opposite. Diazepam failed to reduce anxiety in animals lacking the inhibitory receptor in the dentate gyrus or CA3, indicating that these subregions are involved in the regulation of anxiety. However, the drug still reduced anxiety in mice that lacked the receptor protein in the CA1 subregion. Further studies are now needed to clarify how manipulating specific subregions of the hippocampus alters how it communicates with other brain structures to generate changes in anxiety or fear-related behaviors. DOI: http://dx.doi.org/10.7554/eLife.14120.002