scholarly journals Divergent mesolimbic dopamine circuits support alcohol-seeking triggered by discrete cues and contexts

2018 ◽  
Author(s):  
M.D. Valyear ◽  
I. Glovaci ◽  
A. Zaari ◽  
S. Lahlou ◽  
I. Trujillo-Pisanty ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Ventral Tegmental Area ◽  
Neural Mechanisms ◽  
Dopamine Neurons ◽  
Environmental Cues ◽  
Contextual Cues ◽  
Mesolimbic Dopamine ◽  
Neutral Context ◽  
Dopamine Circuits ◽  
Alcohol Seeking

ABSTRACTDiscrete and contextual cues that predict alcohol trigger alcohol-seeking. However, the extent to which context influences alcohol-seeking triggered by discrete cues, and the neural mechanisms underlying these responses, are not well known. We show that, relative to a neutral context, a context associated with alcohol persistently elevated alcohol-seeking triggered by a discrete cue, and supported higher levels of priming-induced reinstatement. Alcohol-seeking triggered by a discrete cue in a neutral context was reduced by designer receptor-mediated inhibition of ventral tegmental area (VTA) dopamine neurons in TH::Cre rats. Inhibiting terminals of VTA dopamine neurons in the nucleus accumbens (NAc) core reduced alcohol-seeking triggered by a discrete cue, irrespective of context, whereas inhibiting VTA dopamine terminals in the NAc shell selectively reduced the elevation of alcohol-seeking triggered by a discrete cue in an alcohol context. This dissociation highlights unique roles for divergent mesolimbic dopamine circuits in alcohol-seeking driven by discrete and contextual environmental cues.

scholarly journals Dissociable mesolimbic dopamine circuits control responding triggered by alcohol-predictive discrete cues and contexts

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Milan D. Valyear ◽  
Iulia Glovaci ◽  
Audrey Zaari ◽  
Soraya Lahlou ◽  
Ivan Trujillo-Pisanty ◽  
...  
Keyword(s):  
Animal Model ◽  
Substance Use ◽  
Nucleus Accumbens ◽  
Conditioned Stimulus ◽  
Substance Use Disorder ◽  
Dopamine Neurons ◽  
Environmental Cues ◽  
Mesolimbic Dopamine ◽  
Dopamine Circuits ◽  
Alcohol Seeking

Abstract Context can influence reactions to environmental cues and this elemental process has implications for substance use disorder. Using an animal model, we show that an alcohol-associated context elevates entry into a fluid port triggered by a conditioned stimulus (CS) that predicted alcohol (CS-triggered alcohol-seeking). This effect persists across multiple sessions and, after it diminishes in extinction, the alcohol context retains the capacity to augment reinstatement. Systemically administered eticlopride and chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons reduce CS-triggered alcohol-seeking. Chemogenetically silencing VTA dopamine terminals in the nucleus accumbens (NAc) core reduces CS-triggered alcohol-seeking, irrespective of context, whereas silencing VTA dopamine terminals in the NAc shell selectively reduces the elevation of CS-triggered alcohol-seeking in an alcohol context. This dissociation reveals new roles for divergent mesolimbic dopamine circuits in the control of responding to a discrete cue for alcohol and in the amplification of this behaviour in an alcohol context.

scholarly journals The mesolimbic dopamine signatures of relapse to alcohol-seeking

2020 ◽  
Author(s):  
Yu Liu ◽  
Philip Jean-Richard-dit-Bressel ◽  
Joanna Oi-Yue Yau ◽  
Alexandra Willing ◽  
Asheeta A. Prasad ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Ventral Tegmental Area ◽  
Activity Patterns ◽  
Mesolimbic Dopamine ◽  
Self Administration ◽  
Dopamine System ◽  
Mesolimbic Dopamine System ◽  
Ventral Tegmental ◽  
Alcohol Seeking

AbstractThe mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. Here we show how different forms of relapse to alcohol-seeking are assembled from activity across the ventral tegmental area and the nucleus accumbens. Using gCaMP and dLight fibre photometry, we show that self-administration and two forms of relapse (renewal/context-induced reinstatement and reacquisition) are associated with recruitment across the mesolimbic dopamine system. Using a variety of interventions, we show that this activity is causal to both forms of relapse. Finally, we use dissimilarity matrices to identify mesolimbic dopamine signatures of self-administration, extinction, and relapse. We show that signatures of relapse can be identified from heterogeneous activity profiles across the mesolimbic dopamine system and that these signatures differ for different forms of relapse.

scholarly journals Supramammillary neurons projecting to the septum regulate dopamine and motivation for environmental interaction in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrew J. Kesner ◽  
Rick Shin ◽  
Coleman B. Calva ◽  
Reuben F. Don ◽  
Sue Junn ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Theta Oscillations ◽  
Mesolimbic Dopamine ◽  
Sucrose Consumption ◽  
Behavioral Interaction ◽  
Hypothalamic Structure ◽  
Hippocampal Theta ◽  
Substances Of Abuse ◽  
Stimulation Of

AbstractThe supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal. However, recent studies reported that the stimulation of SuM neurons with neuroactive chemicals, including substances of abuse, is reinforcing. We conducted experiments to elucidate how SuM neurons mediate such effects. Using optogenetics, we found that the excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was relayed by their projections to septal GLU neurons. SuM neurons were active during exploration and approach behavior and diminished activity during sucrose consumption. Consistently, inhibition of SuM neurons disrupted approach responses, but not sucrose consumption. Such functions are similar to those of mesolimbic dopamine neurons. Indeed, the stimulation of SuM-to-septum GLU neurons and septum-to-ventral tegmental area (VTA) GLU neurons activated mesolimbic dopamine neurons. We propose that the supramammillo-septo-VTA pathway regulates arousal that reinforces and energizes behavioral interaction with the environment.

scholarly journals Characterization of orexin input to dopamine neurons of the ventral tegmental area projecting to the medial prefrontal cortex and shell of nucleus accumbens

2022 ◽  
Author(s):  
Imre Kalló ◽  
Azar Omrani ◽  
Frank J. Meye ◽  
Han de Jong ◽  
Zsolt Liposits ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Ventral Tegmental Area ◽  
Medial Prefrontal Cortex ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Dopamine Neurons ◽  
Regulatory Processes ◽  
Ventral Tegmental ◽  
Shell Part

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.

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

eLife ◽  
2019 ◽  
Vol 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.

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

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

Endogenous enkephalin modulation of dopamine neurons in ventral tegmental area

1986 ◽  
Vol 251 (2) ◽  
pp. R243-R249 ◽  
Author(s):  
P. W. Kalivas ◽  
R. Richardson-Carlson
Keyword(s):  
Nucleus Accumbens ◽  
Motor Activity ◽  
Ventral Tegmental Area ◽  
Physiological Role ◽  
Dopamine Metabolism ◽  
Dopamine Neurons ◽  
Spontaneous Motor Activity ◽  
Opioid Antagonist ◽  
Dopamine Antagonist ◽  
Ventral Tegmental

Many lines of evidence support the possibility that the opioid pentapeptides Met- and Leu-enkephalin can modulate dopamine neurons in the ventral tegmental area (VTA). Thus microinjection of enkephalin analogues into the VTA of rats produces a dopamine-dependent increase in spontaneous motor activity and an increase in dopamine metabolism in certain mesolimbic dopamine terminal fields, such as the nucleus accumbens. To determine if these effects can be produced by endogenous enkephalins, an enkephalinase A inhibitor, thiorphan, was microinjected into the VTA to inhibit enkephalin metabolism. Thiorphan produced a dose-dependent (0.3-3.33 micrograms) increase in spontaneous motor activity that was blocked by pretreatment with the opioid antagonist naloxone (2.0 mg/kg ip) or the dopamine antagonist haloperidol (0.1 mg/kg ip). Thiorphan injection into the VTA increased dopamine metabolism in the nucleus accumbens, prefrontal cortex, and septum but not in the striatum. In all brain regions the increase in dopamine metabolism was blocked by pretreatment with naloxone. These data demonstrate that endogenous enkephalin in the VTA can increase the activity of A10 dopamine neurons, supporting a physiological role for enkephalin in mesolimbic and mesocortical dopamine-mediated behaviors.

scholarly journals Differential expression of long-term potentiation among identified inhibitory inputs to dopamine neurons

2017 ◽  
Vol 118 (4) ◽  
pp. 1998-2008 ◽  
Author(s):  
DeNard V. Simmons ◽  
Alyssa K. Petko ◽  
Carlos A. Paladini
Keyword(s):  
Nucleus Accumbens ◽  
Adenylyl Cyclase ◽  
Ventral Tegmental Area ◽  
Cyclic Gmp ◽  
Long Term Potentiation ◽  
Dopamine Neurons ◽  
Gaba Neurons ◽  
Tegmental Nucleus ◽  
Term Potentiation

The in vivo firing pattern of ventral tegmental area (VTA) dopamine neurons is controlled by GABA afferents originating primarily from the nucleus accumbens (NAc), rostromedial tegmental nucleus (RMTg), and local GABA neurons within the VTA. Although different forms of plasticity have been observed from GABA inputs to VTA dopamine neurons, one dependent on cyclic GMP synthesis and the other on adenylyl cyclase activation, it is unknown whether plasticity is differentially expressed in each. Using an optogenetic strategy, we show that identified inhibitory postsynaptic currents (IPSCs) from local VTA GABA neurons and NAc afferents exhibit a cyclic GMP-dependent long-term potentiation (LTP) that is capable of inhibiting the firing activity of dopamine neurons. However, this form of LTP was not induced from RMTg afferents. Only an adenylyl cyclase-mediated increase in IPSCs was exhibited by all three inputs. Thus discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons. NEW & NOTEWORTHY We describe a mapping of plasticity expression, mediated by different mechanisms, among three distinct GABA afferents to ventral tegmental area (VTA) dopamine neurons: the rostromedial tegmental nucleus, the nucleus accumbens, and the local GABA neurons within the VTA known to synapse on VTA dopamine neurons. This work is the first demonstration that discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons.

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