Serotonin and prefrontal cortex function: neurons, networks, and circuits

Abstract

Higher-order executive tasks such as learning, working memory, and behavioral flexibility depend on the prefrontal cortex (PFC), the brain region most elaborated in primates. The prominent innervation by serotonin neurons and the dense expression of serotonergic receptors in the PFC suggest that serotonin is a major modulator of its function. The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations (brain waves). Serotonergic signaling is altered in many psychiatric disorders such as schizophrenia and depression, where parallel changes in receptor expression and brain waves have been observed. Furthermore, many psychiatric drug treatments target serotonergic receptors in the PFC. Thus, understanding the role of serotonergic neurotransmission in PFC function is of major clinical importance. Here, we review recent findings concerning the powerful influences of serotonin on single neurons, neural networks, and cortical circuits in the PFC of the rat, where the effects of serotonin have been most thoroughly studied.

Figure 1. Localization of 5-HT receptors within the prefrontal cortex microcircuit

Many pyramidal neurons in deep layers co-express 5-HT1A and 5-HT2A receptors. In addition, distinct populations of local inhibitory interneurons that express 5-HT receptors innervate different compartments of the pyramidal tree: 5-HT1A- and 5-HT2A-expressing fast-spiking interneurons are preferentially located in deep layers where they contact pyramidal neurons at the soma and proximal dendrites; slow-spiking interneurons that express 5-HT3A receptors are located in superficial layers where they innervate pyramidal neurons at the distal dendrites. Modified from references ,.

Figure 2. Three 5-HT response types are observed in layer 5 pyramidal neurons from the mouse prefrontal cortex slice

(A) In most layer 5 pyramidal neurons, focal application of 5-HT (100 μM, green), but not drug-free saline (blue), generates a long-lasting inhibition of action potential firing (top). A plot of instantaneous spike frequency for each action potential is shown below. (B) In a minority of layer 5 pyramidal neurons, focal 5-HT application increases action potential generation. (C) Some layer 5 pyramidal neurons display biphasic responses to 5-HT. In all examples shown, DC somatic current injection was used to depolarize neurons and induce action potential generation. Dashed lines show the level of zero Hz. Scale bars in A apply to data in B and C. Unpublished data courtesy of Daniel Avesar and Allan T. Gulledge.

Figure 3. 5-HT inhibits and activates distinct populations of prefrontal neurons in vivo

Peri-stimulus histograms depicting the firing rate of pyramidal neurons, fast-spiking and slow-spiking interneurons recorded in the prefrontal cortex of anesthetized rats during electrical stimulation of the dorsal raphe nucleus (time 0), which induces release of 5-HT in the prefrontal cortex. Note that 5-HT1A-mediated inhibitions are shorter in fast-spiking interneurons compared to pyramidal neurons and that 5-HT3A-mediated excitations have a shorter delay and duration than 5-HT2A-mediated excitations. Modified from references ,,,.

Figure 4. 5-HT modulates slow waves in prefrontal cortex

(A) Stimulation of the dorsal raphe nucleus (DRN) increases the frequency of cortical slow waves (< 1 Hz). Top, Local field potential (LFP) signal depicting an epoch of desynchronization (absence of slow waves) preceding anesthesia-induced slow-wave sleep (SWS), during which the DRN was stimulated electrically at 1 Hz. Boxes 1 and 2 are expanded in (B). Bottom, Change in power (root mean square of the amplitude) of slow waves over time (red indicates high power, blue low power). White dashed line marks the frequency of stimulation. Note that the predominant band (~ 0.7 Hz) increases in frequency towards the frequency of stimulation during DRN stimulation. (B) Top, expanded 10-second traces from (A). Vertical lines correspond to times of DRN stimulation. Power spectra for 1 min segments that contain the 10 s traces in boxes 1 and 2 are shown on the far right. Bottom, LFPs were processed off-line for an accurate measure of UP-state duration. A threshold was set (red line) to discriminate UP states [21,141]. Note the increase in UP-state potentials during the stimulations (arrow). (C) Effect of WAY (WAY100635, 5-HT1A receptor antagonist), RIT (ritanserin, 5-HT2A/2C receptor antagonist) and SB (SB242084, 5-HT2C receptor antagonist) on the power of slow waves in the rat prefrontal cortex. The power of slow waves decreases after injection of RIT but not SB or WAY, indicating a modulation by 5-HT2A receptors. Modified from reference .