Regulation of Fear and Anxiety in the Hippocampus

Cross section showing three domains of mouse hippocampus. Image credit: Panel from Figure 1B, 2016, Engin et al. Licensed CC BY 4.0.

Our responses to fear and anxiety are regulated by several regions in the brain, including the hippocampus. The hippocampus has neurons which express a receptor for the inhibitory neurotransmitter GABA, a molecule known to be important for modulating fear and anxiety. Anatomically, the hippocampus is divided into three subregions, but studies have yet to show conclusively that these subregions are also functionally unique. There is evidence to suggest there is some overlap in the types of neurons in the hippocampus which mediate anxiety and fear, though it’s not clear if there is an “anxiety” neural circuit and a “fear” circuit, or if they share a common circuit. To try and distinguish between these possibilities, Engin and colleagues selectively “silenced” neurons in each of the three hippocampal subregions (CA1, CA3, and DG) of the mouse brain and asked which, if any, of the mice could respond to fear or anxiety stimuli. To do this, they generated three different transgenic mouse lines, each of which was mutant for a receptor of GABA in one of the three hippocampal subregions. Without this receptor, the neurons in these regions can’t communicate with other neurons in their respective or shared circuits. The three sets of transgenic mice completed behavioral tests which simulate anxiety or fear; during some of the tests they were given the anxiety/fear-reducing drug diazepam. When given diazepam, mice which were mutant for the GABA receptor in the CA1 subregion still showed a response to fear and not anxiety (diazepam couldn’t reduce reaction to fear stimulus); conversely, mice which were mutant for the GABA receptor in the CA3 subregion still responded to anxiety, but not fear (response to anxiety stimulus not reduced by diazepam). This suggests that anxiety and fear are mediated by distinct neural circuits located in different subregions of the mouse hippocampus (CA1 = fear; CA3 = anxiety). These findings provide a neurobiological basis for the idea that anxiety and fear are separate emotional states, each mediated by its own set of neurons within the brain.

Jennifer Lovick (@drjkyl)
Senior Editor, Science in Entertainment, Signal to Noise
PhD, Molecular, Cell, and Developmental Biology

Engin E, Smith KS, Gao Y, Nagy D, Foster RA, Tsvetkov E, Keist R, Crestani F, Fritschy JM, Bolshakov VY, Hajos M, Heldt SA, Rudolph U. Modulation of anxiety and fear via distinct intrahippocampal circuits. eLife. 5,e14120 (2016). DOI: 10.7554/eLife.14120