Alerts induce the activation of several adaptive response alternatives, which compete in the DM mode to win the response decision. There are two different DM modes, urgent (competition) and non-urgent (planning), the former using Rgens that shorten it and push towards a decision (DA and ACh, see below), the latter using an Rgen that prolongs it,
serotonin (SER)50. Response urgency is conveyed by innate+ valence flow and by the
release capacity and receptor expression of the three Rgens. Here we present a detailed novel account of the role of SER and its receptors.
SER is an ancient molecule promoting photosynthesis in plants and having various related peripheral roles [Azmitia, 2010]. The essential amino acid tryptophan is a SER precursor (also of melatonin and the kynurenines). SER acts through at least 14 types of metabotropic G protein-coupled receptors, the main ones being SER1a, SER1b and SER5, which are suppressive via Gi/o, SER4, SER6 and SER7, which are excitatory via Gs, and SER2a, SER2b and SER2c, which are excitatory via Gq. There is one ionotropic SER receptor, SER3, which is excitatory and close to nicotinic ACh and GABAA receptors in structure. All SER receptors promote neurite growth.
SER is released by neurons in the dorsal and median raphe nuclei (DRN, MRN). The DRN is connected with a wide variety of brain areas, including PFC (specifically mPFC [Maier, 2015]), secondary motor areas, the lateral habenula (LHb), the hypothalamus, DA and other Rgen nuclei, and the BG [Dorocic et al., 2014]. The MRN is connected most strongly with the medial habenula, IPN and the hippocampus, all of them areas in which ACh acts strongly (below). Thus, the DRN and MRN are geared towards the DA and ACh systems, respectively. According with the general connectivity pattern, adaptive areas (PFC, LHb) project to the DRN bilaterally, while innate areas (LH, POA, SNc, amygdala) project ipsilaterally [Zhou et al., 2017].
50The formal term is 5-hydroxytryptamine (5-HT). We use SER for readability, including in receptor
Behaviorally, SER is associated with patient waiting for reward [Fonseca et al., 2015], which is a decision making situation. DRN SER levels are higher during waiting for a delayed reward, and SER neurons stop firing only when rats give up [Miyazaki et al., 2011]. Tryptophan depletion promotes waiting impulsivity in humans [Worbe et al., 2014]. Similarly, SER reduces panic and avoid innates in general [Graeff, 2017], and low SER levels are associated with high trait aggression in males [da Cunha-Bang et al., 2016]. SER is not limited to positive situations, as SER and CRH (extended alert) mutually excite each other, according with reduced action during general need-driven DM.
Mechanisms. SER promotes the DM mode in four ways. First, it suppresses fight and flight (panic) innate responses in the amygdala CeA via SER1a [Li et al., 2012]. Second, it suppresses the alert mode by opposing NE and inhibiting CeA-HT projections. Third, it suppresses responses. SER inhibits mPFC pons-projecting response network neurons via postsynaptic SER1a [Avesar and Gulledge, 2012]. SER1aRs are mostly located on the axon initial segment, exerting rapid action [Czyrak et al., 2003]. High doses of SER, as would be released during acute situations, suppress motoneurons via SER1a on the axon initial segment [Perrier and Cotel, 2015]. Thus, SER cooperates with the response suppression network. SER also suppresses contralateral and ventral hippocampal inputs onto the mPFC execution networks via presynaptic SER1bRs, while not harming BU thalamocortical flow [Kjaerby et al., 2016]. Similarly, SER2a excites cell body-targetting IINs, including those in the response suppression network [Jakab and Goldman-Rakic, 2000]. SER suppresses Rgens promoting execution, including ACh [Fink and Göthert, 2007], DA (see below), and MCH [Devera et al., 2015]. SER suppresses quick cerebellum responses by inhibiting parallel fiber-PC synapses [Kawashima, 2017]. SER nuclei are not directly innervated by the BG, showing that SER is not needed for response execution. It exerts an overall inhibitory effect on automated BG execution by suppressing STN inputs and outputs via SER1b [Ding and Zhou, 2014].
Finally, SER directly promotes planning. It excites the DM cortical network via SER2a [Avesar and Gulledge, 2012], mostly on apical dendrites [Jakab and Goldman-Rakic, 2000], excites the competition coordination network (CCN) neurons via SER3, and excites the amygdala BLA, which drives the DM network, via SER2c [Li et al., 2012]. These actions have the combined effect of prolonging the competition process and broadening the range of solutions considered during decision making. In addition, SER and CRH are mutually supportive (SER via SER2c), to promote slow, vigilant responses during decision making. As discussed extensively under imagery below, planning involves response network neu- rons in high level frontal areas. SER2c excites a subset of mPFC L5 pyramidal cells via SER2c [Santana and Artigas, 2017]. Planning also primes motor circuits, and indeed, SER facilitates mossy fiber-deep nuclei synapses [Kawashima, 2017].
The relationship between SER and DA seems paradoxical. On one hand, they should oppose each other, since SER prolonges DM and DA shortens it (see also the habenula below). Indeed, SER reduces DA [Guiard et al., 2008, De Deurwaerdère and Di Gio- vanni, 2017] (specifically SER2c [Bailey et al., 2018]). On the other hand, DA excites SER [Guiard et al., 2008], the SER reuptake inhibitor fluoxetine greatly increases PFC DA [Klomp et al., 2014], and DRN stimulation strongly reinforces behavior and releases SER (and glut) in rewards [Qi et al., 2014]. This can be explained as follows. DA excites SER via D2R using non-selective cation channels [Haj-Dahmane, 2001]. That is, this occurs in the automated mode, in which there are no urgent DM responses. Fluoxetine increases DA by stimulating SER1a/1b autoreceptors, which downregulates SER and reduces its suppres- sion of DA. SER should be rewarding, because it is part of the acute response. In addition, there are glut DRN projections onto the VTA, whose activation reinforces behavior [Liu
et al., 2014, McDevitt et al., 2014].
Like other Rgens (NE, DA, see below), small amounts of SER support automaticity, e.g. by SER1a and SER1b autoreceptors and by facilitating motoneurons via dendritic SER2 and SER7 [Kawashima, 2017, Perrier and Cotel, 2015]. In addition, SER7 cooperates with HCN (Ih current) channels [Santello and Nevian, 2015], which induce a membrane potential that is close to the firing threshold, thereby supporting relaxed oscillations. In cortex, HCN channels are present on response network neurons. SER4 binds to SER with high affinity and couples to Gs, which induces immediate responses. Hence, SER4 seems to support automated responses. Indeed, it is widely expressed at the hippocampus and the BG, and is known to facilitate cognition [Hagena and Manahan-Vaughan, 2017]. SER2c excites dSTR cholinergic IINs (CINs, see below), which support motor areas, via SER6 and SER7 [Virk et al., 2016].
In summary, SER promotes decision making, flexibility and creativity, favoring pro- longed planning and thinking (patience) over acting. It reduces alerts, response urgency and innate-driven (emotional) responses without impairing long term motivation.