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Nature Neuroscience Jun 2018Dopamine is a critical modulator of both learning and motivation. This presents a problem: how can target cells know whether increased dopamine is a signal to learn or... (Review)
Review
Dopamine is a critical modulator of both learning and motivation. This presents a problem: how can target cells know whether increased dopamine is a signal to learn or to move? It is often presumed that motivation involves slow ('tonic') dopamine changes, while fast ('phasic') dopamine fluctuations convey reward prediction errors for learning. Yet recent studies have shown that dopamine conveys motivational value and promotes movement even on subsecond timescales. Here I describe an alternative account of how dopamine regulates ongoing behavior. Dopamine release related to motivation is rapidly and locally sculpted by receptors on dopamine terminals, independently from dopamine cell firing. Target neurons abruptly switch between learning and performance modes, with striatal cholinergic interneurons providing one candidate switch mechanism. The behavioral impact of dopamine varies by subregion, but in each case dopamine provides a dynamic estimate of whether it is worth expending a limited internal resource, such as energy, attention, or time.
Topics: Animals; Dopamine; Dopaminergic Neurons; Humans; Learning; Motivation; Signal Transduction
PubMed: 29760524
DOI: 10.1038/s41593-018-0152-y -
Current Opinion in Neurobiology Aug 2019Dopamine controls motor functions, motivation, and reward-related learning through G-protein coupled receptor signaling. The current working model is that upon release,... (Review)
Review
Dopamine controls motor functions, motivation, and reward-related learning through G-protein coupled receptor signaling. The current working model is that upon release, dopamine diffuses to influence many target cells via wide-spread receptors. Recent studies, however, suggest that dopamine release is fast and generates small signaling hotspots. In this review, we summarize progress on the understanding of the dopamine release apparatus and evaluate how its properties may shape dopamine signaling during firing. We discuss how mechanisms of regulation may act through this machinery and propose that striatal architecture for dopamine signaling may have evolved to support rapid dopamine coding.
Topics: Corpus Striatum; Dopamine; Learning; Motivation; Reward
PubMed: 30769276
DOI: 10.1016/j.conb.2019.01.001 -
Experimental & Molecular Medicine Dec 2020Dopamine regulates reward-related behavior through the mesolimbic dopaminergic pathway. Stress affects dopamine levels and dopaminergic neuronal activity in the... (Review)
Review
Dopamine regulates reward-related behavior through the mesolimbic dopaminergic pathway. Stress affects dopamine levels and dopaminergic neuronal activity in the mesolimbic dopamine system. Changes in mesolimbic dopaminergic neurotransmission are important for coping with stress, as they allow adaption to behavioral responses to various environmental stimuli. Upon stress exposure, modulation of the dopaminergic reward system is necessary for monitoring and selecting the optimal process for coping with stressful situations. Aversive stressful events may negatively regulate the dopaminergic reward system, perturbing reward sensitivity, which is closely associated with chronic stress-induced depression. The mesolimbic dopamine system is excited not only by reward but also by aversive stressful stimuli, which adds further intriguing complexity to the relationship between stress and the reward system. This review focuses on lines of evidence related to how stress, especially chronic stress, affects the mesolimbic dopamine system, and discusses the role of the dopaminergic reward system in chronic stress-induced depression.
Topics: Animals; Brain; Cell Plasticity; Dopamine; Dopaminergic Neurons; Humans; Reward; Signal Transduction; Stress, Psychological
PubMed: 33257725
DOI: 10.1038/s12276-020-00532-4 -
Current Opinion in Neurobiology Apr 2021Dopamine neurons have been intensely studied for their roles in reinforcement learning. A dominant theory of how these neurons contribute to learning is through the... (Review)
Review
Dopamine neurons have been intensely studied for their roles in reinforcement learning. A dominant theory of how these neurons contribute to learning is through the encoding of a reward prediction error (RPE) signal. Recent advances in dopamine research have added nuance to RPE theory by incorporating the ideas of sensory prediction error, distributional encoding, and belief states. Further nuance is likely to be added shortly by convergent lines of research on dopamine neuron diversity. Finally, a major challenge is to reconcile RPE theory with other current theories of dopamine function to account for dopamine's role in movement, motivation, and goal-directed planning.
Topics: Dopamine; Dopaminergic Neurons; Motivation; Reinforcement, Psychology; Reward
PubMed: 33197709
DOI: 10.1016/j.conb.2020.10.012 -
Biological Psychiatry Jan 2017The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with... (Review)
Review
The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients.
Topics: Animals; Brain; Corpus Striatum; Dopamine; Humans; Polymorphism, Single Nucleotide; Psychotic Disorders; Receptors, Dopamine D2; Risk Factors; Schizophrenia; Schizophrenic Psychology; Stress, Psychological
PubMed: 27720198
DOI: 10.1016/j.biopsych.2016.07.014 -
Molecules (Basel, Switzerland) Dec 2017: Parkinson's disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement... (Review)
Review
: Parkinson's disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement therapy, mainly through actual dopamine and its original prodrug l-dopa (LD), faces many challenges such as poor blood brain barrier penetration and decreased response to therapy with time. : The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and made by chemical means, and their bioavailability was studied in animals. A promising ester prodrug for intranasal delivery has been developed. LD methyl ester is currently in Phase III clinical trials. A series of amide prodrugs were synthesized with better stability than ester prodrugs. Both amide and dimeric amide prodrugs offer enhanced blood brain barrier (BBB) penetration and better pharmacokinetics. Attaching LD to sugars has been used to exploit glucose transport mechanisms into the brain. : Till now, no DA prodrug has reached the pharmaceutical market, nevertheless, the future of utilizing prodrugs for the treatment of PD seems to be bright. For instance, LD ester prodrugs have demonstrated an adequate intranasal delivery of LD, thus enabling the absorption of therapeutic agents to the brain. Most of the amide, cyclic, peptidyl or chemical delivery systems of DA prodrugs demonstrated enhanced pharmacokinetic properties.
Topics: Animals; Dopamine; Drug Carriers; Humans; Levodopa; Parkinson Disease; Prodrugs
PubMed: 29295587
DOI: 10.3390/molecules23010040 -
Cells Mar 2021Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward... (Review)
Review
Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson's disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical and subcortical areas. Finally, we will delineate how the effect of DA on dendritic spines places this molecule at the interface between the motor and the cognitive systems. Specifically, we will be focusing on PD, vascular dementia, and schizophrenia.
Topics: Animals; Cognition; Dopamine; Humans; Movement; Neuronal Plasticity; Neurotransmitter Agents; Reward
PubMed: 33810328
DOI: 10.3390/cells10040735 -
Neuroscience and Biobehavioral Reviews Apr 2016Relatively little is known about the neuropathophysiology of binge-eating disorder (BED). Here, the evidence from neuroimaging, neurocognitive, genetics, and animal... (Review)
Review
Relatively little is known about the neuropathophysiology of binge-eating disorder (BED). Here, the evidence from neuroimaging, neurocognitive, genetics, and animal studies are reviewed to synthesize our current understanding of the pathophysiology of BED. Binge-eating disorder may be conceptualized as an impulsive/compulsive disorder, with altered reward sensitivity and food-related attentional biases. Neuroimaging studies suggest there are corticostriatal circuitry alterations in BED similar to those observed in substance abuse, including altered function of prefrontal, insular, and orbitofrontal cortices and the striatum. Human genetics and animal studies suggest that there are changes in neurotransmitter networks, including dopaminergic and opioidergic systems, associated with binge-eating behaviors. Overall, the current evidence suggests that BED may be related to maladaptation of the corticostriatal circuitry regulating motivation and impulse control similar to that found in other impulsive/compulsive disorders. Further studies are needed to understand the genetics of BED and how neurotransmitter activity and neurocircuitry function are altered in BED and how pharmacotherapies may influence these systems to reduce BED symptoms.
Topics: Animals; Attention; Binge-Eating Disorder; Brain; Cognition; Decision Making; Dopamine; Female; Humans; Impulsive Behavior; Male; Motivation; Receptors, Dopamine D2; Reward
PubMed: 26850211
DOI: 10.1016/j.neubiorev.2016.01.013 -
Neuron Nov 2022Animals both explore and avoid novel objects in the environment, but the neural mechanisms that underlie these behaviors and their dynamics remain uncharacterized. Here,...
Animals both explore and avoid novel objects in the environment, but the neural mechanisms that underlie these behaviors and their dynamics remain uncharacterized. Here, we used multi-point tracking (DeepLabCut) and behavioral segmentation (MoSeq) to characterize the behavior of mice freely interacting with a novel object. Novelty elicits a characteristic sequence of behavior, starting with investigatory approach and culminating in object engagement or avoidance. Dopamine in the tail of the striatum (TS) suppresses engagement, and dopamine responses were predictive of individual variability in behavior. Behavioral dynamics and individual variability are explained by a reinforcement-learning (RL) model of threat prediction in which behavior arises from a novelty-induced initial threat prediction (akin to "shaping bonus") and a threat prediction that is learned through dopamine-mediated threat prediction errors. These results uncover an algorithmic similarity between reward- and threat-related dopamine sub-systems.
Topics: Animals; Mice; Dopamine; Corpus Striatum; Reinforcement, Psychology; Reward; Learning
PubMed: 36130595
DOI: 10.1016/j.neuron.2022.08.022 -
Science (New York, N.Y.) Dec 2022Learning to predict rewards based on environmental cues is essential for survival. It is believed that animals learn to predict rewards by updating predictions whenever...
Learning to predict rewards based on environmental cues is essential for survival. It is believed that animals learn to predict rewards by updating predictions whenever the outcome deviates from expectations, and that such reward prediction errors (RPEs) are signaled by the mesolimbic dopamine system-a key controller of learning. However, instead of learning prospective predictions from RPEs, animals can infer predictions by learning the retrospective cause of rewards. Hence, whether mesolimbic dopamine instead conveys a causal associative signal that sometimes resembles RPE remains unknown. We developed an algorithm for retrospective causal learning and found that mesolimbic dopamine release conveys causal associations but not RPE, thereby challenging the dominant theory of reward learning. Our results reshape the conceptual and biological framework for associative learning.
Topics: Animals; Dopamine; Reward; Limbic System; Association Learning; Cues; Mice
PubMed: 36480599
DOI: 10.1126/science.abq6740