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Anthony A. Grace - One of the best experts on this subject based on the ideXlab platform.
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state dependent effects of the d2 partial agonist aripiprazole on Dopamine Neuron activity in the mam neurodevelopmental model of schizophrenia
Neuropsychopharmacology, 2019Co-Authors: Susan Sonnenschein, Kathryn M Gill, Anthony A. GraceAbstract:Aripiprazole is an antipsychotic drug characterized by partial agonist activity at D2 receptors to normalize both hyperDopaminergic and hypoDopaminergic states. Traditional D2 antagonist antipsychotic drugs have been shown previously to reduce Dopamine Neuron activity through action on D2 autoreceptors to produce an overexcitation-induced cessation of cell firing, referred to as depolarization block. It is unclear whether aripiprazole reduces Dopamine Neuron activity via inhibition or, as seen following D2 antagonist administration, depolarization block. The impact of acute and repeated aripiprazole treatment was examined in the methylazoxymethanol acetate (MAM) rodent model to observe its effects on a hyperDopaminergic system, compared to normal rats. We found that administration of aripiprazole acutely or after 1 or 7 days of withdrawal from 21-day repeated treatment led to a decrease in the number of spontaneously active Dopamine Neurons in MAM rats but not in controls. This reduction was not reversed by apomorphine (100–200 µg/kg i.p. or 20 µg/kg i.v.) administration, suggesting that it was not due to depolarization block. In contrast, 1 h after induction of depolarization block of Dopamine Neurons by acute haloperidol treatment (0.6 mg/kg i.p.), aripiprazole (1 mg/kg, i.p.) reversed the depolarization block state. Therefore, aripiprazole rapidly reduced the hyperDopaminergic activity selectively in MAM rats. The reduction is unlikely due to depolarization block and persists following 7-day withdrawal from repeated treatment. Aripiprazole also removes haloperidol-induced depolarization block in MAM rats, which may underlie the acute psychotic state often observed with switching to this treatment.
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medial septum differentially regulates Dopamine Neuron activity in the rat ventral tegmental area and substantia nigra via distinct pathways
Neuropsychopharmacology, 2018Co-Authors: D M Bortz, Anthony A. GraceAbstract:The medial septum (MS) impacts hippocampal activity and the hippocampus, in turn, regulates midbrain Dopamine (DA) Neuron activity. However, it remains to be determined how MS activation impacts midbrain DA activity. This question was addressed by infusing NMDA (0.75 µg/0.2 µL) into the medial septum of anesthetized male Sprague-Dawley rats and recording Dopamine Neuron activity in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). MS activation increased (71%) the number of spontaneously active DA Neurons in the VTA, and decreased (40%) the number of active DA Neurons in the SNc. Effects in both the VTA and SNc required the ventral subiculum, but were differentially dependent on cholinergic and GABAergic mechanisms within the vSub and rostral and caudal subregions of the ventral pallidum, respectively. MS activation also decreased amphetamine-induced locomotor behavior, which was dependent on GABAergic inputs to the hippocampus. These findings demonstrate that the MS differentially regulates meso-striatal DA transmission via distinct pathways.
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sex dependent effects of stress on immobility behavior and vta Dopamine Neuron activity modulation by ketamine
The International Journal of Neuropsychopharmacology, 2017Co-Authors: Millie Rinconcortes, Anthony A. GraceAbstract:Background Stress constitutes a risk factor across several psychiatric disorders. Moreover, females are more susceptible to stress-related disorders, such as depression, than males. Although Dopamine system underactivation is implicated in the pathophysiology of depression, little is known about the female Dopamine system at baseline and post-stress. Methods The effects of chronic mild stress were examined on ventral tegmental area Dopamine Neuron activity and forced swim test immobility by comparing male and female rats. The impact of a single dose of the rapid antidepressant ketamine (10 mg/kg, i.p.) on forced swim test immobility and ventral tegmental area function was then tested. Results Baseline ventral tegmental area Dopamine activity was comparable in both sexes. At baseline, females exhibited roughly double the forced swim test immobility duration than males, which corresponded to ~50% decrease in ventral tegmental area Dopamine population activity compared with similarly treated (i.e., post-forced swim test) males. Following chronic mild stress, there was greater immobility duration in both sexes and reduced ventral tegmental area Dopamine Neuron activity by approximately 50% in males and nearly 75% in females. Ketamine restored behavior and post-forced swim test ventral tegmental area Dopamine activity for up to 7 days in females as well as in both male and female chronic mild stress-exposed rats. Conclusions These data suggest increased female susceptibility to depression-like phenotypes (i.e., greater immobility, ventral tegmental area hypofunction) is associated with higher Dopamine system sensitivity to both acute and repeated stress relative to males. Understanding the neural underpinnings of sex differences in stress vulnerability will provide insight into mechanisms of disease and optimizing therapeutic approaches in both sexes.
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Involvement of Infralimbic Prefrontal Cortex but not Lateral Habenula in Dopamine Attenuation After Chronic Mild Stress
Neuropsychopharmacology, 2017Co-Authors: Jared L Moreines, Zoe L Owrutsky, Anthony A. GraceAbstract:Emerging evidence supports a role for Dopamine in major depressive disorder (MDD). We recently reported fewer spontaneously active ventral tegmental area (VTA) Dopamine Neurons (ie, reduced Dopamine Neuron population activity) in the chronic mild stress (CMS) rodent model of MDD. In this study, we examined the role of two brain regions that have been implicated in MDD in humans, the infralimbic prefrontal cortex (ILPFC)—that is, rodent homolog of Brodmann area 25 (BA25), and the lateral habenula (LHb) in the CMS-induced attenuation of Dopamine Neuron activity. The impact of activating the ILPFC or LHb was evaluated using single-unit extracellular recordings of identified VTA Dopamine Neurons. The involvement of each region in Dopamine Neuron attenuation following 5–7 weeks of CMS was then evaluated by selective inactivation. Activation of either ILPFC or LHb in normal rats potently suppressed Dopamine Neuron population activity, but in unique patterns. ILPFC activation selectively inhibited Dopamine Neurons in medial VTA, which were most impacted by CMS. Conversely, LHb activation selectively inhibited Dopamine Neurons in lateral VTA, which were unaffected by CMS. Moreover, only ILPFC inactivation restored Dopamine Neuron population activity to normal levels following CMS; LHb inactivation had no restorative effect. These data suggest that, in the CMS model of MDD, the ILPFC is the primary driver of diminished Dopamine Neuron responses. These findings support a neural substrate for ILPFC/BA25 linking affective and motivational circuitry dysfunction in MDD.
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the infralimbic cortex bidirectionally modulates mesolimbic Dopamine Neuron activity via distinct neural pathways
The Journal of Neuroscience, 2013Co-Authors: Mary H Patton, Brandon Bizup, Anthony A. GraceAbstract:The ventral tegmental area (VTA) has been implicated in a number of psychiatric disorders, including schizophrenia, depression, and bipolar disorder. One major regulator of the mesolimbic Dopaminergic system is the medial prefrontal cortex (mPFC), which makes direct and indirect connections to the hippocampus and amygdala, as well as directly to the VTA. The mPFC is comprised of two subregions: the infralimbic and prelimbic cortices (ilPFC and plPFC). However, the specific roles of these subregions in regulating VTA Dopamine activity have remained unclear. In this study, we aim to clarify this role and to examine the divergent neuranatomical circuits by which the mPFC regulates VTA activity. Using in vivo extracellular recordings in rats, we tested the effects of pharmacological activation (with NMDA) and inactivation (with TTX) of the ilPFC and plPFC on Dopamine Neuron activity, and tested the roles of the ventral subiculum (vSub) and basolateral amygdala in this process. We found that the ilPFC exerts a bidirectional control of VTA Dopamine Neurons, which are differentially modulated through the vSub and the basolateral amygdala. Specifically, activation or inactivation of the ilPFC attenuated or activated Dopamine Neuron population activity, respectively. Furthermore, Dopamine activation depended on the ventral hippocampus and inactivation on the amygdala. In contrast, only inactivation of the plPFC altered Dopamine Neuron activity. These data indicate that the mPFC has the ability to uniquely fine-tune Dopaminergic activity in the VTA. Furthermore, the data presented here suggest that the ilPFC may have a role in the pathophysiology of psychiatric disorders.
Stephen Rayport - One of the best experts on this subject based on the ideXlab platform.
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Dopamine Neuron synaptic connectivity defines physiological striatal domains
2020Co-Authors: Nao Chuhma, Stephen RayportAbstract:Dopamine Neurons projecting to the striatum control movement, cognition, and motivation. They do so via slower, Dopamine volume transmission and also via faster synaptic Dopamine, glutamate and GABA transmission. To define the scope of these synaptic actions, we recorded Dopamine Neuron synaptic currents in the four major classes of striatal Neurons. This revealed that Dopaminergic and GABAergic synaptic actions are widespread; glutamatergic synaptic actions are robust in the medial nucleus accumbens and the anterolateral dorsal striatum, mediating fast and slow excitation, respectively. Dopamine Neuron synaptic actions in cholinergic interNeurons are the strongest and most complex, involving all three transmitters, their multiple receptors, and are the most regionally heterogeneous. The caudal striatum forms a single domain with overall weak Dopamine Neuron synaptic actions. This synaptic mapping reveals that Dopamine Neuron synaptic actions extend across the entire striatum, are regionally heterogeneous and organized in physiological domains, determined mainly by their excitatory actions.
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Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia
Biological Psychiatry, 2017Co-Authors: Nao Chuhma, Susana Mingote, Abigail Kalmbach, Leora Yetnikoff, Stephen RayportAbstract:Brain imaging has revealed alterations in Dopamine uptake, release, and receptor levels in patients with schizophrenia that have been resolved on the scale of striatal subregions. However, the underlying synaptic mechanisms are on a finer scale. Dopamine Neuron synaptic actions vary across the striatum, involving variations not only in Dopamine release but also in Dopamine Neuron connectivity, cotransmission, modulation, and activity. Optogenetic studies have revealed that Dopamine Neurons release Dopamine in a synaptic signal mode, and that the Neurons also release glutamate and gamma-aminobutyric acid as cotransmitters, with striking regional variation. Fast glutamate and gamma-aminobutyric acid cotransmission convey discrete patterns of Dopamine Neuron activity to striatal Neurons. Glutamate may function not only in a signaling role at a subset of Dopamine Neuron synapses, but also in mediating vesicular synergy, contributing to regional differences in loading of Dopamine into synaptic vesicles. Regional differences in Dopamine Neuron signaling are likely to be differentially involved in the schizophrenia disease process and likely determine the subregional specificity of the action of psychostimulants that exacerbate the disorder, and antipsychotics that ameliorate the disorder. Elucidating Dopamine Neuron synaptic signaling offers the potential for achieving greater pharmacological specificity through intersectional pharmacological actions targeting subsets of Dopamine Neuron synapses.
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Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions.
Journal of Neuroscience, 2015Co-Authors: Susana Mingote, Nao Chuhma, Sheila V. Kusnoor, Bianca C. Field, Ariel Y. Deutch, Stephen RayportAbstract:In the ventral tegmental area (VTA), a subpopulation of Dopamine Neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) Neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize Dopamine Neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA Neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DATIREScre mice to restrict expression to Dopamine Neurons. ChR2-EYFP-expressing Neurons almost invariably stained for tyrosine hydroxylase, identifying them as Dopaminergic. Dopamine Neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal Neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all Dopamine Neuron terminals impinging on recorded Neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA Dopamine Neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the Dopamine Neuron excitatory functional connectome. SIGNIFICANCE STATEMENT Dopamine Neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain Dopamine Neurons are capable of glutamate cotransmission. With conditional expression of channelrhodopsin in Dopamine Neurons, we systematically explored Dopamine Neuron connections in the forebrain and identified regionally specific Dopamine Neuron excitatory connections. Establishing that only a subset of forebrain regions receive excitatory connections from Dopamine Neurons will help to determine the function of Dopamine Neuron glutamate cotransmission, which likely involves transmission of precise temporal signals and enhancement of the dynamic range of Dopamine Neuron signals.
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Dopamine Neurons Control Striatal Cholinergic Neurons via Regionally Heterogeneous Dopamine and Glutamate Signaling
Neuron, 2014Co-Authors: Nao Chuhma, Susana Mingote, Holly Moore, Stephen RayportAbstract:Midbrain Dopamine Neurons fire in bursts conveying salient information. Bursts are associated with pauses in tonic firing of striatal cholinergic interNeurons. Although the reciprocal balance of Dopamine and acetylcholine in the striatum is well known, how Dopamine Neurons control cholinergic Neurons has not been elucidated. Here, we show that Dopamine Neurons make direct fast Dopaminergic and glutamatergic connections with cholinergic interNeurons, with regional heterogeneity. Dopamine Neurons drive a burst-pause firing sequence in cholinergic interNeurons in the medial shell of the nucleus accumbens, mixed actions in the accumbens core, and a pause in the dorsal striatum. This heterogeneity is due mainly to regional variation in Dopamine-Neuron glutamate cotransmission. A single dose of amphetamine attenuates Dopamine Neuron connections to cholinergic interNeurons with dose-dependent regional specificity. Overall, the present data indicate that Dopamine Neurons control striatal circuit function via discrete, plastic connections with cholinergic interNeurons.
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Dopamine Neuron glutamate cotransmission frequency dependent modulation in the mesoventromedial projection
Neuroscience, 2009Co-Authors: Nao Chuhma, Susana Mingote, Won Yung Choi, Stephen RayportAbstract:Mesoventromedial Dopamine Neurons projecting from the medial ventral tegmental area to the ventromedial shell of the nucleus accumbens play a role in attributing incentive salience to environmental stimuli that predict important events, and appear to be particularly sensitive to the effects of psychostimulant drugs. Despite the observation that these Dopamine Neurons make up almost the entire complement of Neurons in the projection, stimulating their cell bodies evokes a fast glutamatergic response in accumbens Neurons. This is apparently due to Dopamine Neuron glutamate cotransmission, suggested by the extensive coexpression of vesicular glutamate transporter 2 (VGLUT2) in the Neurons. To examine the interplay between the Dopamine and glutamate signals, we used acute quasi-horizontal brain slices made from DAT-YFP mice in which the intact mesoventromedial projection can be visualized. Under current clamp, when Dopamine Neurons were stimulated repeatedly, Dopamine Neuron glutamate transmission showed Dopamine-mediated facilitation, solely at higher, burst-firing frequencies. Facilitation was diminished under voltage clamp and flipped to inhibition by intracellular Cs+ or GDPβS, indicating that it was mediated postsynaptically. Postsynaptic facilitation was D1 mediated, required activation of NMDA receptors and closure of voltage gated K+-channels. When postsynaptic facilitation was blocked, D2-mediated presynaptic inhibition became apparent. These counterbalanced pre- and postsynaptic actions determine the frequency dependence of Dopamine modulation; at lower firing frequencies Dopamine modulation is not apparent, while at burst firing frequency postsynaptic facilitation dominates and Dopamine becomes facilitatory. Dopamine Neuron glutamate cotransmission may play an important role in encoding the incentive salience value of conditioned stimuli that activate goal-directed behaviors, and may be an important subtract for enduring drug-seeking behaviors.
Nao Chuhma - One of the best experts on this subject based on the ideXlab platform.
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Dopamine Neuron synaptic connectivity defines physiological striatal domains
2020Co-Authors: Nao Chuhma, Stephen RayportAbstract:Dopamine Neurons projecting to the striatum control movement, cognition, and motivation. They do so via slower, Dopamine volume transmission and also via faster synaptic Dopamine, glutamate and GABA transmission. To define the scope of these synaptic actions, we recorded Dopamine Neuron synaptic currents in the four major classes of striatal Neurons. This revealed that Dopaminergic and GABAergic synaptic actions are widespread; glutamatergic synaptic actions are robust in the medial nucleus accumbens and the anterolateral dorsal striatum, mediating fast and slow excitation, respectively. Dopamine Neuron synaptic actions in cholinergic interNeurons are the strongest and most complex, involving all three transmitters, their multiple receptors, and are the most regionally heterogeneous. The caudal striatum forms a single domain with overall weak Dopamine Neuron synaptic actions. This synaptic mapping reveals that Dopamine Neuron synaptic actions extend across the entire striatum, are regionally heterogeneous and organized in physiological domains, determined mainly by their excitatory actions.
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Dopamine Neuron glutamate cotransmission evokes a delayed excitation in lateral dorsal striatal cholinergic interNeurons
eLife, 2018Co-Authors: Nao Chuhma, Susana Mingote, Abigail Kalmbach, Leora Yetnikoff, Thong C, Samira Ztaou, Anna Claire Sienna, Sophia Tepler, Jeanfrancois PoulinAbstract:Dopamine Neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr Dopamine Neuron terminals in mouse brain slices pauses the firing of cholinergic interNeurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by Dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7. DA Neurons do not signal to spiny projection Neurons in the medial dStr, while they elicit ionotropic glutamate responses in the lateral dStr. The DA Neurons mediating these excitatory signals are in the substantia nigra (SN). Thus, SN Dopamine Neurons engage different receptors in different postsynaptic Neurons in different dStr subregions to convey strikingly different signals. Editorial note This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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Dopamine Neuron dependent behaviors mediated by glutamate cotransmission.
eLife, 2017Co-Authors: Susana Mingote, Nao Chuhma, Abigail Kalmbach, Gretchen M. Thomsen, Yvonne Wang, Andra Mihali, Caroline E. Sferrazza, Ilana Zucker-scharff, Anna-claire Siena, Martha G. WelchAbstract:Dopamine Neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a Dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their Dopamine Neurons, Dopamine Neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling a selective focus on the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic Neurons. Thus, a reduction in Dopamine Neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.
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Dopamine Neuron dependent behaviors mediated by glutamate cotransmission
2017Co-Authors: Susana Mingote, Nao Chuhma, Abigail Kalmbach, Gretchen M. Thomsen, Yvonne Wang, Andra Mihali, Caroline E. Sferrazza, Ilana Zucker-scharff, Anna-claire Siena, Martha G. WelchAbstract:Dopamine Neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene GLS1). In mice with a DAT-driven conditional heterozygous (cHET) reduction of GLS1 in their Dopamine Neurons, Dopamine Neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling focusing the cotransmission. DAT GLS1 cHET mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic Neurons. Thus, a reduction in Dopamine Neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.
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Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia
Biological Psychiatry, 2017Co-Authors: Nao Chuhma, Susana Mingote, Abigail Kalmbach, Leora Yetnikoff, Stephen RayportAbstract:Brain imaging has revealed alterations in Dopamine uptake, release, and receptor levels in patients with schizophrenia that have been resolved on the scale of striatal subregions. However, the underlying synaptic mechanisms are on a finer scale. Dopamine Neuron synaptic actions vary across the striatum, involving variations not only in Dopamine release but also in Dopamine Neuron connectivity, cotransmission, modulation, and activity. Optogenetic studies have revealed that Dopamine Neurons release Dopamine in a synaptic signal mode, and that the Neurons also release glutamate and gamma-aminobutyric acid as cotransmitters, with striking regional variation. Fast glutamate and gamma-aminobutyric acid cotransmission convey discrete patterns of Dopamine Neuron activity to striatal Neurons. Glutamate may function not only in a signaling role at a subset of Dopamine Neuron synapses, but also in mediating vesicular synergy, contributing to regional differences in loading of Dopamine into synaptic vesicles. Regional differences in Dopamine Neuron signaling are likely to be differentially involved in the schizophrenia disease process and likely determine the subregional specificity of the action of psychostimulants that exacerbate the disorder, and antipsychotics that ameliorate the disorder. Elucidating Dopamine Neuron synaptic signaling offers the potential for achieving greater pharmacological specificity through intersectional pharmacological actions targeting subsets of Dopamine Neuron synapses.
Patricia H Janak - One of the best experts on this subject based on the ideXlab platform.
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Dopamine Neurons create Pavlovian conditioned stimuli with circuit-defined motivational properties.
Nature Neuroscience, 2018Co-Authors: Benjamin T Saunders, Jocelyn M. Richard, Elyssa B. Margolis, Patricia H JanakAbstract:Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals toward the acquisition of rewards (for example, food) that are necessary for survival. We tested the fundamental role of midbrain Dopamine Neurons in conferring predictive and motivational properties to cues, independent of external rewards. We found that brief phasic optogenetic excitation of Dopamine Neurons, when presented in temporal association with discrete sensory cues, was sufficient to instantiate those cues as conditioned stimuli that subsequently both evoked Dopamine Neuron activity on their own and elicited cue-locked conditioned behavior. Notably, we identified highly parcellated functions for Dopamine Neuron subpopulations projecting to different regions of striatum, revealing dissociable Dopamine systems for the generation of incentive value and conditioned movement invigoration. Our results indicate that Dopamine Neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to create, gate, and shape cue-controlled behaviors.
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positive reinforcement mediated by midbrain Dopamine Neurons requires d1 and d2 receptor activation in the nucleus accumbens
PLOS ONE, 2014Co-Authors: Elizabeth E Steinberg, Josiah R Boivin, Benjamin T Saunders, Ilana B Witten, Karl Deisseroth, Patricia H JanakAbstract:The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) Dopamine Neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA Dopamine Neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of Dopamine Neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether Dopamine Neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of Dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of Dopamine Neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining Dopamine Neuron-specific ICSS, identify receptor subtypes through which Dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.
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a causal link between prediction errors Dopamine Neurons and learning
Nature Neuroscience, 2013Co-Authors: Elizabeth E Steinberg, Josiah R Boivin, Ilana B Witten, Karl Deisseroth, Ronald Keiflin, Patricia H JanakAbstract:Unexpected rewards activate midbrain Dopamine Neurons, and this response is proposed to support learning by signaling discrepancies between actual and expected outcomes. Here the authors use optogenetic stimulation to demonstrate a causal role for temporally precise Dopamine Neuron signaling in cue-reward learning.
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A causal link between prediction errors, Dopamine Neurons and learning
Nature Neuroscience, 2013Co-Authors: Elizabeth E Steinberg, Josiah R Boivin, Ilana B Witten, Karl Deisseroth, Ronald Keiflin, Patricia H JanakAbstract:Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain Dopamine Neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether Dopamine Neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated Dopamine Neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of Dopamine Neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise Dopamine Neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks.
Deborah K. Hyslop - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Dopamine Neuron firing by pramipexole, a Dopamine D3 receptor-preferring agonist: comparison to other Dopamine receptor agonists
European Journal of Pharmacology, 1996Co-Authors: Montford F. Piercey, William E. Hoffmann, M. W. Smith, Deborah K. HyslopAbstract:Abstract Pramipexole, an amino-benzathiazole [( S )-4,5,6,7-tetrahydro- N -6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate] direct-acting Dopamine receptor agonist effective in treating Parkinson's disease, bound selectively and with high affinity to Dopamine D2-like receptors, with highest affinity at Dopamine D 3 receptors. Ergot Dopamine receptor agonists (bromocriptine, lisuride, pergolide) bound to both Dopamine and non-Dopamine receptors. Although all agonists depressed Dopamine Neuron firing, only pramipexole and quinpirole completely silenced firing when administered in slowly-accumulating doses. High-dose pergolide, but not other ergots, completely suppressed firing when given by a prompt bolus i.v. injection, suggesting efficacy limitations may have involved receptor desensitization for pergolide, but not for bromocriptine and lisuride. We conclude that pramipexole differs from ergot Dopamine receptor agonists currently used in the treatment of Parkinson's disease by virtue of its selectivity for Dopamine receptors, its preferential affinity for the Dopamine D 3 receptor subtype, and its greater efficacy for stimulating Dopamine receptors, as indicated in these electrophysiology assays.
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Inhibition of Dopamine Neuron firing by pramipexole, a Dopamine D3 receptor-preferring agonist: comparison to other Dopamine receptor agonists
European Journal of Pharmacology, 1996Co-Authors: Montford F. Piercey, William E. Hoffmann, M. W. Smith, Deborah K. HyslopAbstract:Abstract Pramipexole, an amino-benzathiazole [( S )-4,5,6,7-tetrahydro- N -6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate] direct-acting Dopamine receptor agonist effective in treating Parkinson's disease, bound selectively and with high affinity to Dopamine D2-like receptors, with highest affinity at Dopamine D 3 receptors. Ergot Dopamine receptor agonists (bromocriptine, lisuride, pergolide) bound to both Dopamine and non-Dopamine receptors. Although all agonists depressed Dopamine Neuron firing, only pramipexole and quinpirole completely silenced firing when administered in slowly-accumulating doses. High-dose pergolide, but not other ergots, completely suppressed firing when given by a prompt bolus i.v. injection, suggesting efficacy limitations may have involved receptor desensitization for pergolide, but not for bromocriptine and lisuride. We conclude that pramipexole differs from ergot Dopamine receptor agonists currently used in the treatment of Parkinson's disease by virtue of its selectivity for Dopamine receptors, its preferential affinity for the Dopamine D 3 receptor subtype, and its greater efficacy for stimulating Dopamine receptors, as indicated in these electrophysiology assays.