Serotonergic modulation of the basal amygdala and fear learning

Authors

• A Sengupta
• D Bannerman
• M Capogna
• T Sharp
• A Holmes

Abstract

The neurotransmitter serotonin (5-HT) is targeted by drugs (e.g. SSRIs) widely used to treat mood disorders such as anxiety and depression, but mechanisms of 5-HT involvement still remain unclear. Fear learning, which is important for avoiding environmental threats and crucial for survival, can become maladaptive in mood disorders. Dysfunctional neural fear circuits may contribute to emotional dysregulation in the etiology of such disorders. Lesion studies demonstrate intact 5-HT fibers in the amygdala are necessary for normal fear behavior. Basal amygdala (BA) circuits are a locus of fear learning and receive dense 5-HT input from the dorsal raphe (DR). To understand the involvement of 5-HT signaling and to optimize the efficacy of 5-HT-targeting drugs, characterizing the mechanisms of 5-HT modulation during fear behavior is essential. Here, we investigate the regulation of BA circuits by 5-HT projections during fear learning. We virally delivered light-gated opsins, or a control inert protein, in mice to selectively control 5-HT inputs to the BA. First, we manipulated 5-HT fiber activity during a fear learning task to establish the role of 5-HT projections to the BA. We provide bidirectional evidence for the involvement of 5-HT by showing 5-HT fiber excitation or inhibition enhances or reduces fearful behavior, respectively. We then conducted in vivo electrophysiology recordings that suggest 5-HT fiber excitation alters the responsiveness of BA neurons to sensory stimuli during fear learning. To study the mechanisms of this modulation, we excited 5-HT fibers in ex vivo brain slices and recorded light-evoked postsynaptic potentials in BA neurons that were abolished by 5-HT or glutamate receptor antagonists. Thus, we demonstrate the co-release of 5-HT and glutamate from 5-HT fibers in the amygdala. 5-HT and glutamate signals were targeted to distinct BA cell types. Combining retrograde tracing with immunohistochemistry, we found a majority of DR neurons projecting to the BA co-express 5-HT and glutamate markers. C-fos staining indicated the co-expressing neurons are preferentially recruited in fear-learned mice compared to context-control mice. Collectively, our study provides new insight into serotonergic mechanisms in amygdala function and in emotional behaviors that are aberrant in psychiatric illnesses. Specifically, we find 5-HT inputs to the BA modulate particular cell types through 5-HT and glutamate co-release, thereby regulating fear learning.

Scientific Focus Area: Neuroscience

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