A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons

Jia, Qi; Zhang, Shiliang; Wang, Huiling; Buendía, José de Jesús Aceves; Hoffman, Alexander F.; Lupica, Carl R.; Seal, Rebecca P.; Morales, Marisela

doi:10.1038/ncomms6390

Cited by 160 publications

(178 citation statements)

References 56 publications

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“…A substantial number of DR neurons express VGluT3, which constitutes a major part of the DR efferent projection to the ventral midbrain (Hioki et al, 2010;Qi et al, 2014;Watabe-Uchida et al, 2012). Dorsal raphe glutamatergic neurons also establish asymetrical synaptic connections with VM dopamine neurons (Qi et al, 2014). Altogether, these findings strongly suggest that reward can be induced by activation of DR glutamatergic afferent inputs to VM DA neurons.…”

Section: Discussionsupporting

confidence: 51%

“…Altogether, these findings strongly suggest that reward can be induced by activation of DR glutamatergic afferent inputs to VM DA neurons. Consistently, two recent optogenetic studies have shown that selective activation of DR glutamatergic releasing neurons or glutamatergic VM terminals is rewarding (Liu et al, 2014;Qi et al, 2014).…”

Section: Discussionmentioning

confidence: 63%

“…McDavitt et al, (2014) also showed that stimulation of this DR to VM pathway generates glutamatergic excitatory postsynaptic current in VM dopamine neurons, and that the rewarding effect associated with its activation is blocked by a selective dopamine D1 antagonist. A substantial number of DR neurons express VGluT3, which constitutes a major part of the DR efferent projection to the ventral midbrain (Hioki et al, 2010;Qi et al, 2014;Watabe-Uchida et al, 2012). Dorsal raphe glutamatergic neurons also establish asymetrical synaptic connections with VM dopamine neurons (Qi et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

Hernández

Khodami-Pour

Lévesque

et al. 2015

Neuropsychopharmacol

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Glutamate is a major component of the reward circuitry and recent clinical studies suggest that new molecules that would target glutamate neurotransmission are most likely to constitute more effective medications for mood disorders. It is well known that activation of N-methyl-D-aspartate glutamate receptors (NMDARs) initiates dopamine burst firing, a mode associated with reward signaling; but NMDARs also contribute to the maintenance of an inhibitory drive to dopamine neurons. Such opposite modulatory functions imply that different subtypes of NMDARs are expressed on different ventral midbrain (VM) neurons and/or afferent inputs to dopamine neurons. By using the small interfering RNA (siRNA) technique, we studied the effects of VM downregulation of NMDAR subunits GluN1, GluN2A, and GluN2D on reward induced by dorsal raphe electrical stimulation. Reward thresholds were measured before and 24 h after each of three consecutive daily bilateral microinjections of siRNA for the targeted receptor subunit(s) or non-active RNA sequence. After the last measurement, reward thresholds were reassessed following a bilateral microinjection of the preferred GluN2A-NMDA antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA). Western-blot analysis showed that siRNAs reduced GluN1-and GluN2A-containing receptors whereas behavioral tests showed that only a reduction in GluN1 produced reward attenuation. Despite NMDAR reduction, reward-enhancing effect of PPPA remained unchanged. We conclude that VM glutamate relays the reward signal initiated by dorsal raphe electrical stimulation by acting on NMDARs devoid of GluN2A/2D subunits and exerts an inhibition on this reward signal by acting on GluN2A-containing NMDARs most likely located on afferent terminals.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

Hernández

Khodami-Pour

Lévesque

et al. 2015

Neuropsychopharmacol

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“…+ 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…”

Section: Vglut3mentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Serotonergic and glutamatergic neurons of the dorsal raphe regulate many brain functions and are important for mental health. Their functional diversity is based on molecularly distinct subtypes; however, the development of this heterogeneity is poorly understood. We show that the ventral neuroepithelium of mouse anterior hindbrain is divided into specific subdomains giving rise to serotonergic neurons as well as other types of neurons and glia. The newly born serotonergic precursors are segregated into distinct subpopulations expressing vesicular glutamate transporter 3 (Vglut3) or serotonin transporter (Sert). These populations differ in their requirements for transcription factors Gata2 and Gata3, which are activated in the post-mitotic precursors. Gata2 operates upstream of Gata3 as a cell fate selector in both populations, whereas Gata3 is important for the differentiation of the Sert + precursors and for the serotonergic identity of the Vglut3 + precursors. Similar to the serotonergic neurons, the Vglut3-expressing glutamatergic neurons, located in the central dorsal raphe, are derived from neural progenitors in the ventral hindbrain and express Pet1. Furthermore, both Gata2 and Gata3 are redundantly required for their differentiation. Our study demonstrates lineage relationships of the dorsal raphe neurons and suggests that functionally significant heterogeneity of these neurons is established early during their differentiation.

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Aggression modulator: Understanding the multifaceted role of the dorsal raphe nucleus

Mitsui,

Takahashi

2024

BioEssays

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Aggressive behavior is instinctively driven behavior that helps animals to survive and reproduce and is closely related to multiple behavioral and physiological processes. The dorsal raphe nucleus (DRN) is an evolutionarily conserved midbrain structure that regulates aggressive behavior by integrating diverse brain inputs. The DRN consists predominantly of serotonergic (5‐HT:5‐hydroxytryptamine) neurons and decreased 5‐HT activity was classically thought to increase aggression. However, recent studies challenge this 5‐HT deficiency model, revealing a more complex role for the DRN 5‐HT system in aggression. Furthermore, emerging evidence has shown that non‐5‐HT populations in the DRN and specific neural circuits contribute to the escalation of aggressive behavior. This review argues that the DRN serves as a multifaceted modulator of aggression, acting not only via 5‐HT but also via other neurotransmitters and neural pathways, as well as different subsets of 5‐HT neurons. In addition, we discuss the contribution of DRN neurons in the behavioral and physiological aspects implicated in aggressive behavior, such as arousal, reward, and impulsivity, to further our understanding of DRN‐mediated aggression modulation.

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A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons

Cited by 160 publications

References 56 publications

Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

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

Aggression modulator: Understanding the multifaceted role of the dorsal raphe nucleus

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