Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Abstract

Little is known about the molecular similarities and differences between neurons in the ventral (vSt) and dorsal striatum (dSt) and their physiological implications. In the vSt, serotonin [5-Hydroxytryptamine (5-HT)] modulates mood control and pleasure response, whereas in the dSt, 5-HT regulates motor behavior. Here we show that, in mice, 5-HT depolarizes cholinergic interneurons (ChIs) of the dSt whereas hyperpolarizing ChIs from the vSt by acting on different 5-HT receptor isoforms. In the vSt, 5-HT1A (a postsynaptic receptor) and 5-HT1B (a presynaptic receptor) are highly expressed, and synergistically inhibit the excitability of ChIs. The inhibitory modulation by 5-HT1B, but not that by 5-HT1A, is mediated by p11, a protein associated with major depressive disorder. Specific deletion of 5-HT1B from cholinergic neurons results in impaired inhibition of ACh release in the vSt and in anhedonic-like behavior.5-HT1A | 5-HT1B | cholinergic interneurons | ventral striatum | TRAP C holinergic interneurons (ChIs) represent only 1-2% of all striatal neurons (1). Despite their low abundance, ChIs play a major role in striatal function, by modulating both inputs to and outputs from spiny projection neurons (SPNs) (2). In the ventral striatum (vSt), ChIs are thought to play a major role in mediating reward, motivation, food intake, and hedonic behavior, whereas ChIs of the dorsal striatum (dSt) are implicated in motor behavior and action selection (3-5). Despite their functional differences, only a few morphological differences between vSt and dSt ChIs have been demonstrated, but no molecular differences between these two populations have been reported (6).Serotonin [5-Hydroxytryptamine (5-HT)] signaling in the striatum has long been implicated in modulating locomotion as well as in mood control (7-9). Striatal 5-HT levels are high, and multiple 5-HT receptors (5-HTRs) are thought to mediate the function of 5-HT in these circuits (7, 10). In dSt ChIs, several 5-HTRs (5-HT7, 5-HT6, and 5-HT2) have been reported to induce membrane depolarization (11,12), but the role of 5-HT signaling in vSt ChIs and its implication for mood regulation are poorly understood. To elucidate the role of 5-HT in vSt ChIs, we used electrophysiological recordings, optogenetics, and cell type-specific gene expression analysis. We demonstrate that 5-HT1A and 5-HT1B synergistically inhibit the function of vSt ChIs. The effect of activation of 5-HT1B, but not that of 5-HT1A, is mediated by p11. Furthermore, deletion of 5-HT1B from cholinergic neurons resulted in a loss of pleasure response (anhedonia), a core symptom of major depressive disorder. ResultsOpposite Effects of 5-HT on Cell Excitability Between vSt ChIs and dSt ChIs. To investigate the effect of 5-HT on ChIs from the vSt and dSt, we carried out electrophysiological recordings from visually identified neurons in acute brain slices. To identify ChIs, we used translating ribosome affinity purification (TRAP) mice expressing a GFP-tagged ribosomal protein, L10a, under the choline acetyltrans...

HCN2 Channels in Cholinergic Interneurons of Nucleus Accumbens Shell Regulate Depressive Behaviors

“…ChIs are spontaneous firing neurons in vitro and in vivo. Tonic firing rates of ChIs have been reported ranging from 0.3 to 10 Hz previously (Witten et al, 2010;Virk et al, 2016). Strikingly, we found that the tonic firing rate of ChIs was selectively diminished in NAc shell in susceptible mice compared to that in control mice ( Figure 1D).…”

“…CD-1 male retired breeders were purchased from Charles River Laboratories. p11 cKO mice were generated as previously described (Warner-Schmidt et al, 2012;Virk et al, 2016). ChAT-Cre mice, ChAT-eGFP mice and ChAT bacTRAP mice were maintained heterozygous as described previously .…”

Nucleus accumbens cholinergic interneurons oppose cue-motivated behavior

“…NAc CRF receptor activation increases cholinergic interneuron activity (90) and acetylcholine release (91), and regulates dopamine release (90). Moreover, serotonin, a neuromodulator long linked to motivation and mood, and recently in the NAc linked to adaptive social behavior (92), attenuates the excitability of NAc cholinergic interneurons via presynaptic 5-HT1A and postsynaptic 5-HT1B receptors (93).…”

Cell‐ and region‐specific expression of depression‐related protein p11 (S100a10) in the brain

“…Dysfunction of the cholinergic connectivity between the basal forebrain and cortex has been extensively studied (for review, see Drevets et al, 2008;Sarter, 2008;Price and Drevets, 2012). While the role of p11 in choline acetyltransferase (ChAT) cells in the nucleus accumbens has been elucidated (Warner- Schmidt et al, 2012;Virk et al, 2016), p11 signaling in the basal forebrain may be different, since these are projection neurons and their circuitry differs from the accumbal ChAT interneurons.…”