scholarly journals Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Alex Reichenbach ◽  
Rachel E Clarke ◽  
Romana Stark ◽  
Sarah H Lockie ◽  
Mathieu Mequinion ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Release ◽  
Ex Vivo ◽  
Temporal Integration ◽  
Dorsal Striatum ◽  
Glucose Sensing ◽  
Palatable Food ◽  
Operant Responding ◽  
Metabolic Sensing ◽  
Homeostatic State

Agouti-related peptide (AgRP) neurons increase motivation for food, however whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesized that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 minutes in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.

scholarly journals Glucose-sensing in AgRP neurons integrates homeostatic energy state with dopamine signalling in the striatum.

2021 ◽  
Author(s):  
Alex Reichenbach ◽  
Rachel Clarke ◽  
Romana Stark ◽  
Sarah H Lockie ◽  
Mathieu Mequinion ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Release ◽  
Energy State ◽  
Dorsal Striatum ◽  
Glucose Sensing ◽  
Low Energy ◽  
Metabolic Enzyme ◽  
Acid Oxidation ◽  
Operant Responding ◽  
Electrophysiological Studies

Hunger increases the motivation of an organism to seek out and consume highly palatable energy dense foods by acting on the midbrain dopaminergic system. Here, we identify a novel molecular mechanism through which hunger-sensing AgRP neurons detect low energy availability and modulate dopamine release to increase motivation for food reward. We tested the hypothesis that carnitine acetyltransferase (Crat), a metabolic enzyme regulating glucose and fatty acid oxidation, in AgRP neurons is necessary to sense low energy states and regulate motivation for food rewards by modulating accumbal or striatal dopamine release. In support of this, electrophysiological studies show that AgRP neurons require Crat for appropriate glucose-sensing. Intact glucose-sensing in AgRP neurons controls post-ingestive dopamine accumulation in the dorsal striatum. Fibre photometry experiments, using the dopamine sensor GRABDA, revealed that impaired glucose-sensing, in mice lacking Crat in AgRP neurons, reduces dopamine release in the nucleus accumbens to palatable food consumption and during operant responding, particularly in the fasted state. Finally, the reduced dopamine release in the nucleus accumbens of mice lacking Crat in AgRP neurons affects sucrose preference and motivated operant responding for sucrose rewards. Notably, these effects are potentiated in the hungry state and therefore highlight that glucose-sensing by Crat in AgRP neurons is required for the appropriate integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum. These studies offer a novel molecular target to control the overconsumption of palatable foods in a population of hunger-sensing AgRP neurons.

scholarly journals Kappa-opioid receptor-dependent changes in dopamine and affective behavior occur differentially across the nucleus accumbens shell rostro-caudal axis

2020 ◽  
Author(s):  
Breanne E. Pirino ◽  
Mary B. Spodnick ◽  
Andrew T. Gargiulo ◽  
Genevieve R. Curtis ◽  
Jessica R. Barson ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Opioid Receptor ◽  
Dopamine Release ◽  
Neural Circuit ◽  
Ex Vivo ◽  
Kappa Opioid Receptor ◽  
Affective Behavior ◽  
Kappa Opioid ◽  
Affective Behaviors ◽  
The Impact

ABSTRACTNeural circuit engagement within the nucleus accumbens (NAc) shell is implicated in the regulation of both negative and positive affect. Classically, the dynorphin/kappa opioid receptor (KOR) system in the NAc was believed to promote dysphoric behavior, while dopamine was viewed as interacting with reward behavior, and KOR activation was known to inhibit dopamine release. Recently, however, both the KOR and dopamine systems have, separately, been shown to have differential effects across the rostro-caudal axis of the NAc shell on hedonic responses. Whether or not this is due to interactions between KORs and dopamine, and if it extends to other affective behaviors, remains to be determined. In this study, we examined in rats the relationship between the KOR and dopamine systems in both the rostral and caudal NAc shell using ex vivo fast scan cyclic voltammetry and the impact of KOR activation on affective behavior using approach-avoidance assays. We report here that activation of KORs in the caudal NAc shell significantly inhibits dopamine release, stimulates novelty-induced rearing behavior, increases avoidance behavior, and reduces locomotor activity. In contrast, activation of KORs in the rostral NAc shell inhibits dopamine release to a lesser extent and instead increases approach behavior. Taken together, these results indicate that there is heterogeneity across the rostro-caudal axis of the NAc shell in the effects of KOR stimulation on affective behaviors, and they suggest that this might be due to differences in KOR control over dopamine release.

scholarly journals Differences in Nicotine Encoding Dopamine Release between the Striatum and Shell Portion of the Nucleus Accumbens

2018 ◽  
Vol 28 (3) ◽  
pp. 248-261 ◽  
Author(s):  
Yuan-Hao Chen ◽  
Bon-Jour Lin ◽  
Tsung-Hsun Hsieh ◽  
Tung-Tai Kuo ◽  
Jonathan Miller ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
High Frequency ◽  
Dopamine Release ◽  
Brain Slices ◽  
Dorsal Striatum ◽  
High Frequency Stimulation ◽  
Sprague Dawley ◽  
Frequency Stimulation ◽  
Da Release

The aim of this work was to determine the effect of nicotine desensitization on dopamine (DA) release in the dorsal striatum and shell of the nucleus accumbens (NAc) from brain slices. In vitro fast-scan cyclic voltammetry analysis was used to evaluate dopamine release in the dorsal striatum and the NAc shell of Sprague–Dawley rats after infusion of nicotine, a nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (Mec), and an α4β2 cholinergic receptor antagonist (DHβe). DA release related to nicotine desensitization in the striatum and NAc shell was compared. In both structures, tonic release was suppressed by inhibition of the nicotine receptor (via Mec) and the α4β2 receptor (via DHβe). Paired-pulse ratio (PPR) was facilitated in both structures after nicotine and Mec infusion, and this facilitation was suppressed by increasing the stimulation interval. After variable frequency stimulation (simulating phasic burst), nicotine infusion induced significant augmentation of DA release in the striatum that was not seen in the absence of nicotine. In contrast, nicotine reduced phasic DA release in NAc, although frequency augmentation was seen both with and without nicotine. Evaluation of DA release evoked by various trains (high-frequency stimulation (HFS) 100 Hz) of high-frequency stimulation revealed significant enhancement after a train of three or more pulses in the striatum and NAc. The concentration differences between tonic and phasic release related to nicotine desensitization were more pronounced in the NAc shell. Nicotine desensitization is associated with suppression of tonic release of DA in both the striatum and NAc shell that may occur via the α4β2 subtype of nAChR, whereas phasic frequency-dependent augmentation and HFS-related gating release is more pronounced in the striatum than in the NAc shell. Differences between phasic and tonic release associated with nicotine desensitization may underlie processing of reward signals in the NAc shell, and this may have major implications for addictive behavior.

scholarly journals Plasticity in striatal dopamine release is governed by release-independent depression and the dopamine transporter

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Mark D. Condon ◽  
Nicola J. Platt ◽  
Yan-Feng Zhang ◽  
Bradley M. Roberts ◽  
Michael A. Clements ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Dopaminergic Neurons ◽  
Action Potentials ◽  
Dopamine Release ◽  
Ex Vivo ◽  
Dorsal Striatum ◽  
Short Term ◽  
Fast Scan Cyclic Voltammetry ◽  
Short Term Plasticity ◽  
Initial Release

Abstract Mesostriatal dopaminergic neurons possess extensively branched axonal arbours. Whether action potentials are converted to dopamine output in the striatum will be influenced dynamically and critically by axonal properties and mechanisms that are poorly understood. Here, we address the roles for mechanisms governing release probability and axonal activity in determining short‐term plasticity of dopamine release, using fast‐scan cyclic voltammetry in the ex vivo mouse striatum. We show that brief short‐term facilitation and longer short term depression are only weakly dependent on the level of initial release, i.e. are release insensitive. Rather, short-term plasticity is strongly determined by mechanisms which govern axonal activation, including K+‐gated excitability and the dopamine transporter, particularly in the dorsal striatum. We identify the dopamine transporter as a master regulator of dopamine short‐term plasticity, governing the balance between release‐dependent and independent mechanisms that also show region‐specific gating.

scholarly journals Age-dependent effects of protein restriction on dopamine release

2020 ◽  
Vol 46 (2) ◽  
pp. 394-403
Author(s):  
Fabien Naneix ◽  
Kate Z. Peters ◽  
Andrew M. J. Young ◽  
James E. McCutcheon
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Release ◽  
Physiological State ◽  
Brain Slices ◽  
Dorsal Striatum ◽  
Protein Restriction ◽  
Fast Scan Cyclic Voltammetry ◽  
Health And Development ◽  
Late Maturation ◽  
The Impact

AbstractDespite the essential role of protein intake for health and development, very little is known about the impact of protein restriction on neurobiological functions, especially at different stages of the lifespan. The dopamine system is a central actor in the integration of food-related processes and is influenced by physiological state and food-related signals. Moreover, it is highly sensitive to dietary effects during early life periods such as adolescence due to its late maturation. In the present study, we investigated the impact of protein restriction either during adolescence or adulthood on the function of the mesolimbic (nucleus accumbens) and nigrostriatal (dorsal striatum) dopamine pathways using fast-scan cyclic voltammetry in rat brain slices. In the nucleus accumbens, protein restriction in adults increased dopamine release in response to low and high frequency trains of stimulation (1–20 Hz). By contrast, protein restriction during adolescence decreased nucleus accumbens dopamine release. In the dorsal striatum, protein restriction at adulthood has no impact on dopamine release but the same diet during adolescence induced a frequency-dependent increase in stimulated dopamine release. Taken together, our results highlight the sensitivity of the different dopamine pathways to the effect of protein restriction, as well as their vulnerability to deleterious diet effects at different life stages.

scholarly journals Kinetic features of the dopamine release and uptake in the dorsal and ventral striatum of rats

2020 ◽  
Vol 19 (4) ◽  
pp. 47-54
Author(s):  
Valery N. Mukhin ◽  
Ivan R. Borovets ◽  
Vadim V. Sizov ◽  
Konstantin I. Pavlov ◽  
Victor M. Klimenko
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Release ◽  
Ventral Striatum ◽  
Dorsal Striatum ◽  
Principal Component ◽  
Dopamine Uptake ◽  
Rat Striatum ◽  
The Core ◽  
Kinetics Of

Kinetics of the evoked dopamine release and subsequent uptake in the parts of the rat striatum has not been studied sufficiently. The aim of this study is to fill this gap and to investigate kinetics of dopamine release and uptake in vivo so that comparison can be made between the dorsal and the parts of the ventral striatum and with taking into account the overlapping electrochemical factors during the subsequent analysis of voltammetry recordings. Materials and methods. The evoked wave of dopamine release and uptake in the dorsal striatum, core, and shell of the nucleus accumbens in the different groups of rats was recorded by the fast-scan cyclic voltammetry. Voltammetry recordings were subjected to principal component analysis and only the components associated with dopamine were taken for further analysis. The values of the parameters of the curves of dopamine release and uptake were defined. Then factor and variance analyses of the parameters were carried out. Results. Factor analysis showed that the set of parameters of the dopamine wave can be reduced to the 4 factors that are comparable with the variables of the known from the literature mathematical model that describes the dopamine wave based on the MichaelisMenten equation. Two of the factors and the corresponding parameters of the dopamine curve differ within the dorsal and ventral striatum. Factor 1 is associated with the parameters HL, T80_20, T20_0, slope_T20T0, which are significantly larger in the core of the nucleus accumbens. Factor 3 is associated with the parameters T50_2, AUC, FWHH, T100_80 which are significantly less in the dorsal striatum. Conclusions. The parameters of the curve of dopamine release and uptake are determined by 4 factors. Among the dopamine curve parameters, the best measures of the factors are T50_1, DAC, T100_80 и T20_0. The kinetics of stimulated dopamine release and uptake varies within the dorsal and ventral striatum. The final phase of dopamine uptake is slowed in the core of the nucleus accumbens in comparison to the shell, and the dorsal striatum. The slope of initial phase of dopamine uptake in the dorsal striatum is steeper.

scholarly journals Plasticity in striatal dopamine release is governed by release-independent depression and the dopamine transporter

2018 ◽  
Author(s):  
Mark D. Condon ◽  
Nicola J. Platt ◽  
Yan-Feng Zhang ◽  
Bradley M. Roberts ◽  
Michael A. Clements ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Dopamine Release ◽  
Ex Vivo ◽  
Dorsal Striatum ◽  
List Type ◽  
Short Term ◽  
Fast Scan Cyclic Voltammetry ◽  
Short Term Plasticity ◽  
Initial Release ◽  
Axonal Excitability

AbstractMesostriatal DA neurons possess extensively branched axonal arbours. Whether action potentials are converted to DA output in striatum will be influenced dynamically and critically by axonal properties and mechanisms that are poorly understood. We addressed the roles for mechanisms governing release probability and axonal activity in determining short-term plasticity of DA release, using fast-scan cyclic voltammetry in ex vivo mouse striatum. Brief short-term facilitation (STF) and longer short-term depression (STD) were only weakly dependent on the level of initial release, i.e. were release-insensitive. Rather, short-term plasticity was strongly determined by mechanisms which governed axonal activation, including K+-gated excitability and the dopamine transporter (DAT), particularly in dorsal striatum. We identify the DAT as a master regulator of DA short-term plasticity, governing the balance between release-dependent and independent mechanisms that also show region-specific gating.Key FindingsShort-term plasticity in dopamine release is only weakly governed by initial releaseShort-term depression is strongly dependent on axonal excitability and activationThe dopamine transporter controls short-term plasticity and drives short-term depressionDopamine transporters govern the balance between release-dependent and -independent mechanisms

scholarly journals Dopamine release in nucleus accumbens is under tonic inhibition by adenosine A1 receptors regulated by astrocytic ENT1 and dysregulated by ethanol

2021 ◽  
Author(s):  
Bradley M Roberts ◽  
Elizabeth Lambert ◽  
Jessica A Livesey ◽  
Zhaofa Wu ◽  
Yulong Li ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Release ◽  
Ex Vivo ◽  
Tonic Inhibition ◽  
Nucleoside Transporter ◽  
Striatal Neurons ◽  
Nucleus Accumbens Core ◽  
Striatal Slices ◽  
Adenosine A1 ◽  
Activity Dependent

Striatal adenosine A1 receptor (A1R) activation can inhibit dopamine release. A1Rs on other striatal neurons are activated by an adenosine tone that is limited by equilibrative nucleoside transporter 1 (ENT1) that is enriched on astrocytes and is ethanol-sensitive. We explored whether dopamine release in nucleus accumbens core is under tonic inhibition by A1Rs, and is regulated by astrocytic ENT1 and ethanol. In ex vivo striatal slices from male and female mice, A1R agonists inhibited dopamine release evoked electrically or optogenetically and detected using fast-scan cyclic voltammetry, most strongly for lower stimulation frequencies and pulse numbers, thereby enhancing the activity-dependent contrast of dopamine release. Conversely, A1R antagonists reduced activity-dependent contrast but enhanced evoked dopamine release levels, even for single optogenetic pulses indicating an underlying tonic inhibition. The ENT1 inhibitor NBTI reduced dopamine release and promoted A1R-mediated inhibition, and conversely, virally-mediated astrocytic overexpression of ENT1 enhanced dopamine release and relieved A1R-mediated inhibition. By imaging the genetically encoded fluorescent adenosine sensor GRAB-Ado, we identified a striatal extracellular adenosine tone that was elevated by the ENT1 inhibitor and sensitive to gliotoxin fluorocitrate. Finally, we identified that ethanol (50 mM) promoted A1R-mediated inhibition of dopamine release, through diminishing adenosine uptake via ENT1. Together, these data reveal that dopamine output dynamics are gated by a striatal adenosine tone, limiting amplitude but promoting contrast, regulated by ENT1, and promoted by ethanol. These data add to the diverse mechanisms through which ethanol modulates striatal dopamine, and to emerging datasets supporting astrocytic transporters as important regulators of striatal function.

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