Cue-Evoked Dopamine Release Rapidly Modulates D2 Neurons in the Nucleus Accumbens During Motivated Behavior - PubMed (original) (raw)
Cue-Evoked Dopamine Release Rapidly Modulates D2 Neurons in the Nucleus Accumbens During Motivated Behavior
Catarina Owesson-White et al. J Neurosci. 2016.
Abstract
Dopaminergic neurons that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) fire in response to unpredicted rewards or to cues that predict reward delivery. Although it is well established that reward-related events elicit dopamine release in the NAc, the role of rapid dopamine signaling in modulating NAc neurons that respond to these events remains unclear. Here, we examined dopamine's actions in the NAc in the rat brain during an intracranial self-stimulation task in which a cue predicted lever availability for electrical stimulation of the VTA. To distinguish actions of dopamine at select receptors on NAc neurons during the task, we used a multimodal sensor that probes three aspects of neuronal communication simultaneously: neurotransmitter release, cell firing, and identification of dopamine receptor type. Consistent with prior studies, we first show dopamine release events in the NAc both at cue presentation and after lever press (LP). Distinct populations of NAc neurons encode these behavioral events at these same locations selectively. Using our multimodal sensor, we found that dopamine-mediated responses after the cue involve exclusively a subset of D2-like receptors (D2Rs), whereas dopamine-mediated responses proximal to the LP are mediated by both D1-like receptors (D1R) and D2Rs. These results demonstrate for the first time that dopamine-mediated responses after cues that predict reward availability are specifically linked to its actions at a subset of neurons in the NAc containing D2Rs.
Significance statement: Successful reward procurement typically involves the completion of a goal-directed behavior in response to appropriate environmental cues. Although numerous studies link the mesolimbic dopamine system with these processes, how dopamine's effects are mediated on the receptor level within a key neural substrate, the nucleus accumbens, remains elusive. Here, we used a unique multimodal sensor that reveals three aspects of neuronal interactions: neurotransmitter release, cell firing, and dopamine-receptor type. We identified a key role of D2-like receptor (D2R)-expressing neurons in response to a reward-predicting cue, whereas both the D2R and D1R types modulate responses of neurons proximal to the goal-directed action. This work provides novel insight into the unique role of D2R-mediated neuronal activity to reward-associated cues, a fundamental aspect of motivated behaviors.
Keywords: dopamine; dopamine receptors; electrophysiology; iontophoresis; reward anticipation; voltammetry.
Copyright © 2016 the authors 0270-6474/16/366011-11$15.00/0.
Figures
Figure 1.
Dopamine response and single-unit events in the NAc during ICSS from a single anatomical location. A, Average dopamine concentration measured during 30 LPs in a single representative experiment. Left, Traces aligned to the cue (red line). Right, Same traces but aligned to LP (blue line). Corresponding set of cyclic voltammograms are given in the 2D color plots that show data collected for a 10 s period before and after the cue or LP. _y_-axis: applied voltage (_E_app); _x_-axis: time (s), current is shown in false color. B, Raster plots of single-unit activity and histograms recorded at the same site in a single representative experiment. Left, Rasters aligned to the cue (red symbols). Right, Same traces aligned to LP (blue symbols).
Figure 2.
MSN cell-firing patterns and dopamine traces in the core and shell. A, Averaged dopamine concentration responses in the shell (n = 33 locations) and core (n = 20 locations), ***p < 0.001. B, Histograms of firing responses of cue-responsive cells in core (n = 5) and shell (n = 6). C, Histograms from LP-excitatory cells sorted by region, core (n = 10), and shell (n = 15). Inset: Single MSN waveform during ICSS. D, Histograms from LP-inhibitory cells in core (n = 13) and shell (n = 18). In B–D, the average dopamine concentration at the sites where the cells were recorded is shown in green. E–G, Timing relationship between cell-firing rate (black lines) and dopamine release (green shaded) for cue-responsive, LP-excitatory, and LP-inhibitory cell types, respectively. Responses are scaled so that they show the change from minimum to maximum for dopamine and firing rate shown in E and F, whereas the opposite is true for the firing rate shown in G.
Figure 3.
Multimodal sensor and controlled iontophoresis. A, Electron micrograph of a multimodal sensor with three iontophoretic barrels and carbon-fiber electrode. B, Timing diagram of the iontophoresis injection period and subsequent ICSS behavioral paradigm. Each trial (n = 30) consists of a 15 s ejection period (BL if no drugs were ejected, denoted by the blue shaded region) that ends 1 s before cue onset. The lever is extended (LE) 2 s after cue onset and remains available for 15 s or until the rat presses the lever, whichever occurs first. C, Histogram showing single-unit activity of a representative cell before iontophoretic drug ejection (averaged over 30 trials). Vertical dashed lines indicate beginning and ending of the BL collection period. D, Single-unit activity of the same cell during iontophoretic ejection of SCH (with ACP) at the same location (averaged over 30 ejections). The orange line shows the average local ACP concentration during the 30 ejections. E, Average firing rates of the D1 cell shown in C and D during the period (indicated by dashed lines) before (BL) and during ejections (***p < 0.001). F, Single-unit activity of another representative cell before iontophoretic drug ejection (averaged over 30 trials). G, Single-unit activity of the same cell shown in F during iontophoretic ejection of RAC (with ACP) at the same location (averaged over 30 ejections). Ejected drug concentration monitored by ACP current (blue line, average of 30 ejections). H, Average firing rates for the D2 cell shown in F and G during the period (indicated by dashed lines) before (BL) and during ejections. ***p < 0.001.
Figure 4.
Receptor identification via the multimodal sensor. A, Average firing rates recorded during 15 s periods before (BL) or during iontophoretic ejection of SCH or RAC during the ITI for all cells. Cell firing changes during iontophoresis relative to BL were used to determine D1R or D2R chemotype. Cell-firing changes to the agonists Q and SKF were used to verify the sorting into D1-responsive MSNs (n = 15) and D2-responsive MSNs (n = 32s). N in the column refers to how many locations in which each drug was tested; the barrels contained the two antagonist (SCH and RAC) and one agonist (either SKF or Q). Dots show the individual responses to each drug. B, Latency to LP after lever extension in the presence of iontophoresed drugs (CTRL without iontophoresed drug, n = 47; RAC, n = 40; SCH, n = 34; Q, n = 17; SKF, n = 24).
Figure 5.
D2-mediated responses after the cue. A, Raster plots and histograms of firing rate from a single cue-responsive MSN during the ICSS task. Traces are aligned to cue onset (time 0). CTRL, Without iontophoresed drug; Q, in the presence of iontophoresed Q; RAC, in the presence of iontophoresed RAC. B, Summary histogram of all D2R cue-responsive cells (n = 23). C, Drug effects on task baseline and cue response firing on D2 cue cells. ***p < 0.001 for task baseline RAC compared task baseline CTRL and /+++p < 0.001 cue response CTRL compared with/task CTRL. D, Effects on cue-evoked and electrically evoked dopamine release after LP during ICSS (cue, ns; LP response, *p < 0.05).
Figure 6.
Excitatory D1 responses around LP. A, Example histograms and raster plots showing firing rates from a single LP-excitatory MSN. CTRL, Without added drug; SKF, in the presence of SKF; SCH, in the presence of SCH. B, Summary histogram of all D1R LP-excitatory cells (n = 10). C, Drug effects on baseline and task response firing on D1-like LP-excitatory cells. ***p < 0.001 for task baseline SCH compared with task baseline CTRL and /+++p < 0.001 LP response CTRL compared with/task CTRL.
Figure 7.
Inhibitory LP responses and recording sites. A, Reinforced inhibitory cells at LP that responded to D2 drugs (***p < 0.001). B, Reinforced inhibitory cells that responded to D1 drugs (**p < 0.01). C, Coronal sections ranging from 1.2 to 2.2 anterior to bregma, adapted from Paxinos and Watson (2007). Approximate recording sites are displayed by black circles; for clarity and due to overlapping sites, all sites are not shown.
Figure 8.
Overview of temporal sequence of MSN cell-firing patterns and neural pathways activated during the ICSS task. Shown is a schematic diagram of the major cell-firing patterns and relationship to MSNs containing specific dopamine receptors during the ICSS behavioral sequence. After the cue, excitatory input activates D2-containing MSNs. Dopamine release in response to the cue suppresses this activation via D2Rs. The net result is that the inhibitory projection to the ventral pallidum (VP) described by Kupchik et al. (2015) is suppressed. Shortly before the rat presses the lever for the electrical stimulation, a separate population of MSNs that contains D1Rs is excited. Dopamine release triggered by the cue is still present and promotes this excitation. The net result of this is that the inhibitory actions of the MSNs that project to the VTA (Kupchik et al., 2015) are enhanced.
References
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