Anxiety—a sustained state of heightened apprehension in the absence of immediate threat—becomes severely debilitating in disease states1. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence)2 and contribute to the aetiology of major depression and substance abuse3, 4. Although it has been proposed that the amygdala, a brain region important for emotional processing5, 6, 7, 8, has a role in anxiety9, 10, 11, 12, 13, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics14, 15, 16 to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)—achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA—exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin15 (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA–CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.
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- Supplementary Information (11M)
This file contains Supplementary Figures 1-15 with legends, Supplementary Materials and Methods and additional references.
- Supplementary Movie 1 (6.4M)
This movie shows a representative mouse from the ChR2:BLA-CeA group on elevated plus maze. The 15-minute elevated plus maze session is shown at 5x speed; each 5-min epoch is shown in 1 min and the duration of the light epoch is indicated by the appearance of blue text detailing light stimulation parameters. During the light-on epoch, the mouse increased open arm entry and open arm time.