Heterologous Regulation of Receptors on Target Cells of Dopamine Neurons in the Prefrontal Cortex, Nucleus Accumbens, and Striatum

AbstractOrexin neurons are involved in homeostatic regulatory processes, including arousal and feeding, and provide a major input from the hypothalamus to the ventral tegmental area (VTA) of the midbrain. VTA neurons are a central hub processing reward and motivation and target the medial prefrontal cortex (mPFC) and the shell part of nucleus accumbens (NAcs). We investigated whether subpopulations of dopamine (DA) neurons in the VTA projecting either to the mPFC or the medial division of shell part of nucleus accumbens (mNAcs) receive differential input from orexin neurons and whether orexin exerts differential electrophysiological effects upon these cells. VTA neurons projecting to the mPFC or the mNAcs were traced retrogradely by Cav2-Cre virus and identified by expression of yellow fluorescent protein (YFP). Immunocytochemical analysis showed that a higher proportion of all orexin-innervated DA neurons projected to the mNAcs (34.5%) than to the mPFC (5.2%). Of all sampled VTA neurons projecting either to the mPFC or mNAcs, the dopaminergic (68.3 vs. 79.6%) and orexin-innervated DA neurons (68.9 vs. 64.4%) represented the major phenotype. Whole-cell current clamp recordings were obtained from fluorescently labeled neurons in slices during baseline periods and bath application of orexin A. Orexin similarly increased the firing rate of VTA dopamine neurons projecting to mNAcs (1.99 ± 0.61 Hz to 2.53 ± 0.72 Hz) and mPFC (0.40 ± 0.22 Hz to 1.45 ± 0.56 Hz). Thus, the hypothalamic orexin system targets mNAcs and to a lesser extent mPFC-projecting dopaminergic neurons of the VTA and exerts facilitatory effects on both clusters of dopamine neurons.

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Mesolimbic dopamine projections mediate cue-motivated reward seeking but not reward retrieval in rats

eLife ◽

10.7554/elife.43551 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 8

Author(s):

Briac Halbout ◽

Andrew T Marshall ◽

Ali Azimi ◽

Mimi Liljeholm ◽

Stephen V Mahler ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Suppressive Effect ◽

Maladaptive Behavior ◽

Dopamine Neurons ◽

Action Sequence ◽

Reward Seeking ◽

Fixed Action ◽

Dopamine Circuits ◽

Goal Directed Behavior

Efficient foraging requires an ability to coordinate discrete reward-seeking and reward-retrieval behaviors. We used pathway-specific chemogenetic inhibition to investigate how rats’ mesolimbic and mesocortical dopamine circuits contribute to the expression and modulation of reward seeking and retrieval. Inhibiting ventral tegmental area dopamine neurons disrupted the tendency for reward-paired cues to motivate reward seeking, but spared their ability to increase attempts to retrieve reward. Similar effects were produced by inhibiting dopamine inputs to nucleus accumbens, but not medial prefrontal cortex. Inhibiting dopamine neurons spared the suppressive effect of reward devaluation on reward seeking, an assay of goal-directed behavior. Attempts to retrieve reward persisted after devaluation, indicating they were habitually performed as part of a fixed action sequence. Our findings show that complete bouts of reward seeking and retrieval are behaviorally and neurally dissociable from bouts of reward seeking without retrieval. This dichotomy may prove useful for uncovering mechanisms of maladaptive behavior.

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Dexmedetomidine Activation of Dopamine Neurons in the Ventral Tegmental Area Attenuates the Depth of Sedation in Mice

Anesthesiology ◽

10.1097/aln.0000000000003347 ◽

2020 ◽

Vol 133 (2) ◽

pp. 377-392

Author(s):

Gaolin Qiu ◽

Ying Wu ◽

Zeyong Yang ◽

Long Li ◽

Xiaona Zhu ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Ventral Tegmental Area ◽

Medial Prefrontal Cortex ◽

Repeated Measures ◽

Intraperitoneal Injection ◽

Dopamine Neurons ◽

Patch Clamp Recording ◽

Repeated Measures Anova ◽

Ventral Tegmental

Background Dexmedetomidine induces a sedative response that is associated with rapid arousal. To elucidate the underlying mechanisms, the authors hypothesized that dexmedetomidine increases the activity of dopaminergic neurons in the ventral tegmental area, and that this action contributes to the unique sedative properties of dexmedetomidine. Methods Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca2+ indicator and patch-clamp recording. Dopamine neurotransmitter dynamics in the medial prefrontal cortex and nucleus accumbens were measured by a genetically encoded dopamine sensor. Ventral tegmental area dopamine neurons were inhibited or activated by a chemogenetic approach, and the depth of sedation was estimated by electroencephalography. Results Ca2+ signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 μg/kg; dexmedetomidine, 16.917 [14.882; 21.748], median [25%; 75%], vs. saline, –0.745 [–1.547; 0.359], normalized data, P = 0.001; n = 6 mice). Dopamine transmission increased in the medial prefrontal cortex after intraperitoneal injection of dexmedetomidine (40 μg/kg; dexmedetomidine, 10.812 [9.713; 15.104], median [25%; 75%], vs. saline, –0.498 [–0.664; –0.355], normalized data, P = 0.001; n = 6 mice) and in the nucleus accumbens (dexmedetomidine, 8.543 [7.135; 11.828], median [25%; 75%], vs. saline, –0.329 [–1.220; –0.047], normalized data, P = 0.001; n = 6 mice). Chemogenetic inhibition or activation of ventral tegmental area dopamine neurons increased or decreased slow waves, respectively, after intraperitoneal injection of dexmedetomidine (40 μg/kg; delta wave: two-way repeated measures ANOVA, F[2, 33] = 8.016, P = 0.002; n = 12 mice; theta wave: two-way repeated measures ANOVA, F[2, 33] = 22.800, P < 0.0001; n = 12 mice). Conclusions Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related forebrain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Mesolimbic dopamine projections mediate cue-motivated reward seeking but not reward retrieval

10.1101/272963 ◽

2018 ◽

Author(s):

Briac Halbout ◽

Andrew T. Marshall ◽

Ali Azimi ◽

Mimi Liljeholm ◽

Stephen V. Mahler ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Suppressive Effect ◽

Maladaptive Behavior ◽

Dopamine Neurons ◽

Action Sequence ◽

Reward Seeking ◽

Fixed Action ◽

Dopamine Circuits ◽

Goal Directed Behavior

AbstractEfficient foraging requires an ability to coordinate discrete reward-seeking and reward-retrieval behaviors. We used pathway-specific chemogenetic inhibition to investigate how mesolimbic and mesocortical dopamine circuits contribute to the expression and modulation of reward seeking and retrieval. Inhibiting ventral tegmental area dopamine neurons disrupted the tendency for reward-paired cues to motivate reward seeking, but spared their ability to increase attempts to retrieve reward. Similar effects were produced by inhibiting dopamine inputs to nucleus accumbens, but not medial prefrontal cortex. Inhibiting dopamine neurons spared the suppressive effect of reward devaluation on reward seeking, an assay of goal-directed behavior. Attempts to retrieve reward persisted after devaluation, indicating they were habitually performed as part of a fixed action sequence. Our findings show that complete bouts of reward seeking and retrieval are behaviorally and neurally dissociable from bouts of reward seeking without retrieval. This dichotomy may prove useful for uncovering mechanisms of maladaptive behavior.

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The galanin receptor-3 antagonist, SNAP 37889, inhibits cue-induced reinstatement of alcohol-seeking and increases c-Fos expression in the nucleus accumbens shell of alcohol-preferring rats

Journal of Psychopharmacology ◽

10.1177/0269881118780015 ◽

2018 ◽

Vol 32 (8) ◽

pp. 911-921 ◽

Cited By ~ 2

Author(s):

Kira-Elise Wilson ◽

Sigrid Limburg ◽

Melissa K Duggan ◽

Adam J Lawther ◽

Spencer J Williams ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Medial Prefrontal Cortex ◽

Dopamine Neurons ◽

Nucleus Accumbens Shell ◽

Nucleus Accumbens Core ◽

Fos Protein ◽

Fos Expression ◽

Dual Label ◽

Alcohol Seeking

Introduction: This study aimed to investigate the effects of the galanin-3 receptor antagonist, SNAP 37889, on c-Fos protein expression after cue-induced reinstatement of alcohol-seeking in the brains of alcohol-preferring rats. Methods: Eighteen alcohol-preferring rats were trained to self-administer 10% v/v ethanol in the presence of response-contingent cues, which was followed by extinction. Rats were then treated with SNAP 37889 (30 mg/kg, i.p.) or vehicle, before being tested for cue-induced reinstatement. Administration of SNAP 37889 reduced cue-induced reinstatement of ethanol-seeking behaviour. To examine the effect of SNAP 37889 and cue-induced reinstatement on neuronal activation, c-Fos expression was measured in subregions of the medial prefrontal cortex and nucleus accumbens. Results: SNAP 37889 administration increased c-Fos immunoreactivity in the nucleus accumbens shell, but was without effect in the nucleus accumbens core and the medial prefrontal cortex. Dual-label Fos/tyrosine hydroxylase immunohistochemistry was used to examine the effects of SNAP 37889 on dopamine neurons in the ventral tegmental area; however, no differences between SNAP 37889 and vehicle-treated rats were found. Conclusions: These data support previous findings of galanin-3 receptor involvement in cue-induced reinstatement of alcohol-seeking behaviour, and provide novel evidence that the ability of galanin-3 receptor antagonism to attenuate cue-induced reinstatement relates to activation of the nucleus accumbens shell.

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Burst activation of dopamine neurons produces prolonged post-burst availability of actively released dopamine

10.1101/125062 ◽

2017 ◽

Cited By ~ 1

Author(s):

Sweyta Lohani ◽

Adria K. Martig ◽

Suzanne M. Underhill ◽

Alicia DeFrancesco ◽

Melanie J. Roberts ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Cognitive Functions ◽

Dopamine Release ◽

Dopamine Neurons ◽

Dopamine Antagonists ◽

Burst Stimulation ◽

Multiple Timescales ◽

Impulse Flow ◽

Stimulation Of

SummaryBoth phasic and tonic modes of neurotransmission are implicated in critical functions assigned to dopamine. In learning, for example, sub-second phasic responses of ventral tegmental area (VTA) dopamine neurons to salient events serve as teaching signals, but learning is also interrupted by dopamine antagonists administered minutes after training. Our findings bridge the multiple timescales of dopamine neurotransmission by demonstrating that burst stimulation of VTA dopamine neurons produces a prolonged post-burst increase (> 20 min) of extracellular dopamine in nucleus accumbens and prefrontal cortex. This elevation is not due to spillover from the stimulation surge but depends on impulse flow-mediated dopamine release. We identified Rho-mediated internalization of dopamine transporter as a mechanism responsible for prolonged availability of actively released dopamine. These results demonstrate that phasic and tonic dopamine neurotransmission can be a continuum and may explain why both modes of signaling are critical for motivational and cognitive functions associated with dopamine.

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