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Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition.

ABSTRACT: The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant responding for saccharin, a measure of motivated behavior. However, combining optogenetic stimulation of DRN 5-HT neurons with a low dose of the selective serotonin reuptake inhibitor (SSRI) citalopram synergistically reduced operant responding. We then examined whether these effects could be recapitulated if optogenetic stimulation specifically targeted 5-HT terminals in the ventral tegmental area (VTA) or nucleus accumbens (NAc) of the mesolimbic DA system. Optogenetic stimulation of 5-HT input to the VTA combined with citalopram treatment produced a synergistic decrease in responding for saccharin, resembling the changes produced by targeting 5-HT neurons in the DRN. However, this effect was not observed when optogenetic stimulation targeted 5-HT terminals in the NAc. Taken together, these results suggest that DRN 5-HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA. These studies support an oppositional interaction between 5-HT and DA systems in controlling motivation and goal-directed behavior, and have important implications for the development and refinement of treatment strategies for psychiatric disorders such as depression and addiction.

SUBMITTER: Browne CJ

PROVIDER: S-EPMC6372654 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition.

Browne Caleb J CJ Abela Andrew R AR Chu Duong D Li Zhaoxia Z Ji Xiaodong X Lambe Evelyn K EK Fletcher Paul J PJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20181112 4

The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant ...[more]

PMID: 30420603

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Project description:Besides its "classical" neurotransmitter function, serotonin (5-HT) has been found to also act as a neurodevelopmental signal. During development, the 5-HT projection system, besides an external placental source, represents one of the earliest neurotransmitter systems to innervate the brain. One of the targets of the 5-HT projection system, originating in the brainstem raphe nuclei, is the medial prefrontal cortex (mPFC), an area involved in higher cognitive functions and important in the etiology of many neurodevelopmental disorders. Little is known, however, about the exact role of 5-HT and its signaling molecules in the formation of the raphe-prefrontal network. Using explant essays, we here studied the role of the 5-HT transporter (5-HTT), an important modulator of the 5-HT signal, in rostral raphe-prefrontal network formation. We found that the chemotrophic nature of the interaction between the origin (rostral raphe cluster) and a target (mPFC) of the 5-HT projection system was affected in rats lacking the 5-HTT (5-HTT(-/-)). While 5-HTT deficiency did not affect the dorsal raphe 5-HT-positive outgrowing neurites, the median raphe 5-HT neurites switched from a strong repulsive to an attractive interaction when co-cultured with the mPFC. Furthermore, the fasciculation of the mPFC outgrowing neurites was dependent on the amount of 5-HTT. In the mPFC of 5-HTT(-/-) pups, we observed clear differences in 5-HT innervation and the identity of a class of projection neurons of the mPFC. In the absence of the 5-HTT, the 5-HT innervation in all subareas of the early postnatal mPFC increased dramatically and the number of Satb2-positive callosal projection neurons was decreased. Together, these results suggest a 5-HTT dependency during early development of these brain areas and in the formation of the raphe-prefrontal network. The tremendous complexity of the 5-HT projection system and its role in several neurodevelopmental disorders highlights the need for further research in this largely unexplored area.

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Dataset Information

Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition.

Publications

Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition.

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