Abstract
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 (COM) intratelencephalic neurons via activation of 5-HT2A (2A) receptors, while simultaneously inhibiting, via 5-HT1A (1A) receptors, corticofugally projecting pyramidal neurons targeting the pons. 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 μM; 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 in layer 5 overlap, at least partially, with COM neurons, and that neurons projecting to either, or both targets, exhibit 2A-dependent serotonergic excitation. These results suggest that 5-HT, acting at 2A receptors, may promote cortical output to the amygdala.
Highlights
Output from the neocortex is organized into multiple information channels formed by subclasses of glutamatergic pyramidal neurons defined by their long-distance axonal projections to distinct cortical and subcortical targets
Retrograde-labeled pyramidal neurons projecting to either the ipsilateral or contralateral amygdala were targeted for whole-cell recordings in layer 5 of the mouse prelimbic cortex
Measurements were made of resting membrane potentials (RMPs), input resistance (RN), and Hyperpolarization-activated cyclic-nucleotide gated (HCN)-channel-mediated rebound “sag” potentials (% sag; see section “Materials and Methods”; Table 1 and Figure 1)
Summary
Output from the neocortex is organized into multiple information channels formed by subclasses of glutamatergic pyramidal neurons defined by their long-distance axonal projections to distinct cortical and subcortical targets. Systemic injection of a 2A agonist (Zhang et al, 2013) enhances freezing in tests of cued and contextual fear memory in mice, while systemic activation of 1A receptors reduces freezing behavior in similar tests in rats (Inoue et al, 1996; Ohyama et al, 2016) or mice (Youn et al, 2009) Consistent with these findings, local activation of 1A receptors in the prelimbic cortex reduces conditioned fear responses and fear-potentiated startle (Ferreira and Nobre, 2014; Almada et al, 2015), whereas blockade of prelimbic 2A receptors impairs the expression of conditioned fear in a rat strain selectively bred to exhibit heightened anxiety (León et al, 2017). Our results demonstrate that prelimbic CAm neurons are in many ways similar to, and overlap with, COM neurons, and suggest that 5-HT, acting on 2A receptors, may promote CAm output to the amygdala
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