Serotonergic regulation of corticoamygdalar neurons in the mouse prelimbic cortex

Neuromodulatory transmitters, such as serotonin (5-HT), selectively regulate the excitability of subpopulations of cortical projection neurons to gate cortical output to specific target regions. For instance, in the mouse prelimbic cortex, 5-HT selectively excites commissurally projecting intratelencephalic (COM) neurons via activation of 5-HT2A (2A) receptors, while simultaneously inhibiting corticofugally projecting pyramidal neurons targeting the pons via 5-HT1A (1A) receptors. Here we characterize the physiology, morphology, and serotonergic regulation of corticoamygdalar (CAm) projection neurons in the mouse prelimbic cortex. Layer 5 CAm neurons shared a number of physiological and morphological characteristics with COM neurons, including higher input resistances, smaller HCN-channel mediated responses, and sparser dendritic arbors than corticopontine neurons. Across cortical lamina, CAm neurons also resembled COM neurons in their serotonergic modulation; focally applied 5-HT (100 {micro}M; 1 s) generated 2A-receptor-mediated excitation, or 1A- and 2A- dependent biphasic responses, in ipsilaterally and contralaterally projecting CAm neurons. Serotonergic excitation depended on extrinsic excitatory drive, as 5-HT failed to depolarize CAm neurons from rest, but could enhance the number of action potentials generated by simulated barrages of synaptic input. Finally, using dual tracer injections, we identified double-labeled CAm/COM neurons that displayed primarily excitatory or biphasic responses to 5-HT. Overall, our findings reveal that prelimbic CAm neurons overlap with COM neurons, and that both neuron subtypes exhibit 2A-dependent serotonergic excitation. Our findings suggest that 5-HT, acting at 2A receptors, will promote cortical output to the amygdala.\n\nSignificance StatementCortical projections to the amygdala allow for executive \"top-down\" control of emotional responses. Corticoamygdalar (CAm) neurons in the prelimbic cortex contribute to the learning and expression of conditioned fear responses, processes that may also be regulated by serotonin (5-HT). Our study provides a physiological and morphological characterization of prelimbic CAm neurons, and demonstrates that the excitability of CAm neurons is regulated by 5-HT acting at 5-HT2A receptors alone, or in combination with 5-HT1A receptors. Our results suggest that 5-HT may regulate corticoamygdalar circuits during the learning and expression of conditioned fear.