Abstract: The neuromodulator serotonin (5-HT) gates affective states and regulates fear memory and psychiatric disorders. For this reason, it is important to ascertain the physiological effects of serotonin in emotional brain structures such as the amygdala. To address this question, Sengupta et al. expressed channelrhodopsin in serotonergic neurons of the dorsal raphe nucleus and optically stimulated terminals in the basal amygdala of mouse brain slices. Surprisingly, the optogenetic activation of serotonergic fibers in the amygdala evoked the release of glutamate that excited subsets of interneurons under baseline conditions. However, when the frequency of stimulation of serotonergic fibers increased, as it occurs during reward anticipation and receipt, release of serotonin occurred, which exerted multiple effects and decreased the firing of principal neurons. Thus, 5-HT neurons exert a frequency-dependent, cell type-specific control over amygdala circuitry via 5-HT and glutamate co-release to inhibit the amygdala output

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