Whole-Brain Mapping of Direct Inputs to Midbrain Dopamine Neurons

Watabe-Uchida, Mitsuko; Zhu, Lihua; Ogawa, Shuji; Vamanrao, Archana; Uchida, Naoshige

doi:10.1016/j.neuron.2012.03.017

Cited by 1,041 publications

(1,111 citation statements)

References 94 publications

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“…More likely, dopamine from the VTA regulates interhemispheric and intrahemispheric communication between the OFC and BLA via D1-like receptor stimulation in the OFC. This interpretation is supported by anatomical evidence from previous studies (Berger et al, 1991;Dunnett and Robbins, 1992;Frankle et al, 2006;Reynolds et al, 2006;Sesack and Grace, 2010;Watabe-Uchida et al, 2012) and from our retrograde tracing experiment indicating that the VTA (Figure 4a), but not the SN (Figure 4b), projects to the OFC. Moreover, the OFC and BLA share direct, reciprocal intrahemispheric and interhemispheric connections (Figure 4c and d; Carmichael and Price, 1995a;Ghashghaei and Barbas, 2002;Krettek and Price, 1977;McDonald, 1991) as well as indirect connections relayed through the mediodorsal thalamus (Cavada et al, 2000;Demeter et al, 1990;Ghashghaei and Barbas, 2002;Macey et al, 2003;Miyashita et al, 2007).…”

Section: Discussionsupporting

confidence: 88%

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Lasseter

Xie

Arguello

et al. 2013

Neuropsychopharmacol

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Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra-and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior.

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Section: Discussionsupporting

confidence: 88%

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Lasseter

Xie

Arguello

et al. 2013

Neuropsychopharmacol

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“…Intra-VTA neurotensin activates dopamine neurons and contributes to behavioral sensitization after administration of psychostimulants (47). The parabrachial nucleus is one source of neurotensinergic projections to the VTA (48) and projects bilaterally to midbrain dopamine neurons (49). Regardless of the mechanism, the synchronicity in dopamine release between hemispheres uncovered here establishes that chemical signaling, like physiological activity (50), is tightly coupled across the brain.…”

Section: Discussionmentioning

confidence: 81%

Cross-hemispheric dopamine projections have functional significance

Fox

Mikhailova

Bass

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dopamine signaling occurs on a subsecond timescale, and its dysregulation is implicated in pathologies ranging from drug addiction to Parkinson's disease. Anatomic evidence suggests that some dopamine neurons have cross-hemispheric projections, but the significance of these projections is unknown. Here we report unprecedented interhemispheric communication in the midbrain dopamine system of awake and anesthetized rats. In the anesthetized rats, optogenetic and electrical stimulation of dopamine cells elicited physiologically relevant dopamine release in the contralateral striatum. Contralateral release differed between the dorsal and ventral striatum owing to differential regulation by D2-like receptors. In the freely moving animals, simultaneous bilateral measurements revealed that dopamine release synchronizes between hemispheres and intact, contralateral projections can release dopamine in the midbrain of 6-hydroxydopamine-lesioned rats. These experiments are the first, to our knowledge, to show cross-hemispheric synchronicity in dopamine signaling and support a functional role for contralateral projections. In addition, our data reveal that psychostimulants, such as amphetamine, promote the coupling of dopamine transients between hemispheres.dopamine | voltammetry | synchrony | nucleus accumbens | dorsal striatum D opamine neurotransmission modulates arousal and motivation, and is important to the expression of reward-seeking behavior. Dopamine is released on a subsecond timescale during unexpected reward (1, 2), and becomes time-locked to cues that predict reward (3-7). Dopamine transients in the nucleus accumbens (NAc) occur as a result of cell firing in the ventral tegmental area (VTA) (8, 9), and in rats reach concentrations of 50-200 nM before returning to baseline (10, 11). Striatal dopamine transients also occur spontaneously during periods of rest (10, 11), reflecting endogenous dopamine modulation. The magnitude and frequency of dopamine transients increase in response to drugs of abuse (12, 13), which is thought to contribute to their reinforcing properties (14). Although numerous studies have summarized the function of dopamine circuits in reward-based behaviors (15, 16) and motor control (17-19), anatomic descriptions of dopamine projections are conflicting (20-23). Recent evidence suggests that some dopamine neurons project contralateral to their origin (22, 23), contradictory to the uncrossed dopamine system described previously (20, 21). To date, the significance of contralaterally projecting dopamine neurons, and how they may contribute to cross-hemispheric signaling, have not been established.A potential role for contralateral dopamine projections emerged in a recent study on brain stimulation reward (24). When rats were trained to self-stimulate the VTA, infusion of dopamine receptor antagonists in the NAc suppressed stimulation. This effect was seen whether the infusion was contralateral or ipsilateral to the stimulation site, reflecting cross-hemispheric modulation of the behavior. Furthe...

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“…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%

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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Whole-Brain Mapping of Direct Inputs to Midbrain Dopamine Neurons

Cited by 1,041 publications

References 94 publications

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Cross-hemispheric dopamine projections have functional significance

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

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