Serotonergic versus Nonserotonergic Dorsal Raphe Projection Neurons: Differential Participation in Reward Circuitry

Abstract

Summary The dorsal raphe nucleus (DRN) contains the largest group of serotonin-producing neurons in the brain and projects to regions controlling reward. Although pharmacological studies suggest that serotonin inhibits reward-seeking, electrical stimulation of the DRN strongly reinforces instrumental behavior. Here, we provide a targeted assessment of the behavioral, anatomical, and electrophysiological contributions of serotonergic and non-serotonergic DRN neurons to reward processes. To explore DRN heterogeneity, we used a simultaneous two-vector knockout/optogenetic stimulation strategy, as well as cre-induced and cre-silenced vectors in several cre-expressing transgenic mouse lines. We found that the DRN is capable of reinforcing behavior primarily via non-serotonergic neurons, whose main projection target is the ventral tegmental area (VTA). Furthermore, these non-serotonergic projections provide glutamatergic excitation of VTA dopamine neurons and account for a large majority of the DRN-VTA pathway. These findings help to resolve apparent discrepancies between the roles of serotonin versus the DRN in behavioral reinforcement.

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

“…Given the anatomic interaction of the DA and 5-HT systems, it is important to mention that the response to cocaine observed in the VMAT2 SERTcre mice could also be due to increased DA release. Although a recent study demonstrated that the majority of dorsal raphe neurons that project to the VTA are nonserotoninergic, 46 neuroanatomical studies have revealed 5-HT immunoreactive fibres in the VTA, 47 and there is evidence that the mesolimbic dopaminergic system is under the control of the 5-HT system. 48,49 Alteration of the 5-HT system alters cocaine sensitization As a psychostimulant, cocaine elicits a dose-dependent increase in motor activity in rodents.…”

Gata2 and Gata3 regulate the differentiation of serotonergic and glutamatergic neuron subtypes of the dorsal raphe

“…+ dorsal raphe glutamatergic neuron subgroup projecting to the VTA (Hioki et al, 2010;Liu et al, 2014;McDevitt et al, 2014;Qi et al, 2014). The spared Vglut3 + cells first appeared in the ventral r1 of the Gata2…”

“…The subtypes of serotonergic neurons are interesting from the perspective of behaviour and psychiatric disease. Vglut3-expressing serotonergic and glutamatergic neurons innervate dopaminergic neurons in the VTA and are important for reward signalling (Liu et al, 2014;McDevitt et al, 2014;Qi et al, 2014). Sert is the target of selective serotonin reuptake inhibitors (SSRIs), the commonly used antidepressants.…”

“…In addition to the Vglut3 + serotonergic neurons, a specific subgroup of non-serotonergic Vglut3 + cells is located in the central dorsal raphe. Furthermore, recent studies demonstrated the importance of glutamatergic neurotransmission from the dorsal raphe to ventral tegmental area (VTA) in the regulation of motivation and reward processing (Hioki et al, 2010;Liu et al, 2014;McDevitt et al, 2014;Qi et al, 2014;Sego et al, 2014). Developmental mechanisms underlying the neuronal heterogeneity in the dorsal raphe are still poorly understood.…”

Reward processing by the dorsal raphe nucleus: 5-HT and beyond

“…Two other studies report that optogenetic stimulation of DRN neurons drives reward behavior and emphasizes the contribution of glutamate (McDevitt et al 2014;Qi et al 2014 Stimulating axonal fibers from VGluT3+ neurons results in glutamate release and activates VTA mesoaccumbens dopamine neurons in brain slices. In addition, optogenetic stimulation of DRN VGluT3 neurons reinforces instrumental behavior and establishes conditioned place preference, suggesting the strong potential of glutamate neurons in reward signaling (Qi et al 2014).…”