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Proceedings of the National Academy of... Mar 2023Dopamine (DA) loss in Parkinson's disease (PD) causes debilitating motor deficits. However, dopamine is also widely linked to reward prediction and learning, and the...
Dopamine (DA) loss in Parkinson's disease (PD) causes debilitating motor deficits. However, dopamine is also widely linked to reward prediction and learning, and the contribution of dopamine-dependent learning to movements that are impaired in PD-which often do not lead to explicit rewards-is unclear. Here, we used two distinct motor tasks to dissociate dopamine's acute motoric effects vs. its long-lasting, learning-mediated effects. In dopamine-depleted mice, motor task performance gradually worsened with task exposure. Task experience was critical, as mice that remained in the home cage during the same period were relatively unimpaired when subsequently probed on the task. Repeated dopamine replacement treatments acutely rescued deficits and gradually induced long-term rescue that persisted despite treatment withdrawal. Surprisingly, both long-term rescue and parkinsonian performance decline were task specific, implicating dopamine-dependent learning. D1R activation potently induced acute rescue that gradually consolidated into long-term rescue. Conversely, reduced D2R activation potently induced parkinsonian decline. In dopamine-depleted mice, either D1R activation or D2R activation prevented parkinsonian decline, and both restored balanced activation of direct vs. indirect striatal pathways. These findings suggest that reinforcement and maintenance of movements-even movements not leading to explicit rewards-are fundamental functions of dopamine and provide potential mechanisms for the hitherto unexplained "long-duration response" by dopaminergic therapies in PD.
Topics: Mice; Animals; Dopamine; Neurons; Corpus Striatum; Learning; Parkinson Disease
PubMed: 36920928
DOI: 10.1073/pnas.2213093120 -
Neuroscience Dec 2014Dopamine D2-autoreceptors play a key role in regulating the activity of dopamine neurons and control the synthesis, release and uptake of dopamine. These Gi/o-coupled... (Review)
Review
Dopamine D2-autoreceptors play a key role in regulating the activity of dopamine neurons and control the synthesis, release and uptake of dopamine. These Gi/o-coupled inhibitory receptors play a major part in shaping dopamine transmission. Found at both somatodendritic and axonal sites, autoreceptors regulate the firing patterns of dopamine neurons and control the timing and amount of dopamine released from their terminals in target regions. Alterations in the expression and activity of autoreceptors are thought to contribute to Parkinson's disease as well as schizophrenia, drug addiction and attention-deficit hyperactivity disorder (ADHD), which emphasizes the importance of D2-autoreceptors in regulating the dopamine system. This review will summarize the cellular actions of dopamine autoreceptors and discuss recent advances that have furthered our understanding of the mechanisms by which D2-receptors control dopamine transmission.
Topics: Animals; Autoreceptors; Dopamine; Dopaminergic Neurons; Receptors, Dopamine D2; Reward
PubMed: 24463000
DOI: 10.1016/j.neuroscience.2014.01.025 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2023Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the... (Review)
Review
Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc). Current therapeutic options ease the symptoms of PD; however, they have multiple undesirable effects and do not slow the disease progression. Exercise by itself has many positive impacts on general health. In this review, the positive impact of different forms of exercise were found to improve motor and non-motor symptoms in PD. Exercise effects is mediate by multiple mechanisms, including the upregulation of brain-derived neurotrophic factor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and autophagy regulating proteins; and downregulates proinflammatory cytokines. In this review, the significance of exercise in PD, as well as in the prevention and maintenance of the disease was discussed. Many questions are left unanswered in this manuscript, including potential genetic factors underlying response to exercise. Therefore, further high-quality studies on humans are needed.
Topics: Humans; Animals; Parkinson Disease; Dopamine; Exercise; Dopaminergic Neurons; Disease Models, Animal
PubMed: 36617448
DOI: 10.17712/nsj.2023.1.20220105 -
Neuron Feb 2018Many learned responses depend on the coordinated activation and inhibition of synaptic pathways in the striatum. Local dopamine neurotransmission acts in concert with a... (Review)
Review
Many learned responses depend on the coordinated activation and inhibition of synaptic pathways in the striatum. Local dopamine neurotransmission acts in concert with a variety of neurotransmitters to regulate cortical, thalamic, and limbic excitatory inputs to drive the direct and indirect striatal spiny projection neuron outputs that determine the activity, sequence, and timing of learned behaviors. We review recent advances in the characterization of stereotyped neuronal and operant responses that predict and then obtain rewards. These depend on the local release of dopamine at discrete times during behavioral sequences, which, acting with glutamate, provides a presynaptic filter to select which excitatory synapses are inhibited and which signals pass to indirect pathway circuits. This is followed by dopamine-dependent activation of specific direct pathway circuits to procure a reward. These steps may provide a means by which higher organisms learn behaviors in response to feedback from the environment.
Topics: Animals; Behavior, Animal; Cerebral Cortex; Conditioning, Operant; Corpus Striatum; Dopamine; Neural Pathways; Neurons; Receptors, Dopamine D1; Receptors, Dopamine D2; Reward; Synapses
PubMed: 29420932
DOI: 10.1016/j.neuron.2018.01.006 -
Cognitive, Affective & Behavioral... Jun 2019Despite dopamine's significant role in models of value-based decision-making and findings demonstrating loss of dopamine function in aging, evidence of systematic... (Review)
Review
Despite dopamine's significant role in models of value-based decision-making and findings demonstrating loss of dopamine function in aging, evidence of systematic changes in decision-making over the life span remains elusive. Previous studies attempting to resolve the neural basis of age-related alteration in decision-making have typically focused on physical age, which can be a poor proxy for age-related effects on neural systems. There is growing appreciation that aging has heterogeneous effects on distinct components of the dopamine system within subject in addition to substantial variability between subjects. We propose that some of the conflicting findings in age-related effects on decision-making may be reconciled if we can observe the underlying dopamine components within individuals. This can be achieved by incorporating in vivo imaging techniques including positron emission tomography (PET) and neuromelanin-sensitive MR. Further, we discuss how affective factors may contribute to individual differences in decision-making performance among older adults. Specifically, we propose that age-related shifts in affective attention ("positivity effect") can, in some cases, counteract the impact of altered dopamine function on specific decision-making processes, contributing to variability in findings. In an effort to provide clarity to the field and advance productive hypothesis testing, we propose ways in which in vivo dopamine imaging can be leveraged to disambiguate dopaminergic influences on decision-making, and suggest strategies for assessing individual differences in the contribution of affective attentional focus.
Topics: Affect; Aging; Attention; Brain; Decision Making; Dopamine; Humans; Magnetic Resonance Imaging; Melanins; Neuroimaging; Positron-Emission Tomography
PubMed: 30536205
DOI: 10.3758/s13415-018-00678-9 -
PLoS Computational Biology Jul 2022Studying the brain circuits that control behavior is challenging, since in addition to their structural complexity there are continuous feedback interactions between...
Studying the brain circuits that control behavior is challenging, since in addition to their structural complexity there are continuous feedback interactions between actions and sensed inputs from the environment. It is therefore important to identify mathematical principles that can be used to develop testable hypotheses. In this study, we use ideas and concepts from systems biology to study the dopamine system, which controls learning, motivation, and movement. Using data from neuronal recordings in behavioral experiments, we developed a mathematical model for dopamine responses and the effect of dopamine on movement. We show that the dopamine system shares core functional analogies with bacterial chemotaxis. Just as chemotaxis robustly climbs chemical attractant gradients, the dopamine circuit performs 'reward-taxis' where the attractant is the expected value of reward. The reward-taxis mechanism provides a simple explanation for scale-invariant dopaminergic responses and for matching in free operant settings, and makes testable quantitative predictions. We propose that reward-taxis is a simple and robust navigation strategy that complements other, more goal-directed navigation mechanisms.
Topics: Dopamine; Learning; Motivation; Neurons; Reward
PubMed: 35877694
DOI: 10.1371/journal.pcbi.1010340 -
Brain Research Jun 2019Using environmental cues to acquire good and avoid harmful things is critical for survival. Rewarding and aversive outcomes both drive behavior through reinforcement... (Review)
Review
Using environmental cues to acquire good and avoid harmful things is critical for survival. Rewarding and aversive outcomes both drive behavior through reinforcement learning and sometimes occur together in the environment, but it remains unclear how these signals are encoded within the brain and if signals for positive and negative reinforcement are encoded similarly. Recent studies demonstrate that the dopaminergic system and interconnected brain regions process both positive and negative reinforcement necessary for approach and avoidance behaviors, respectively. Here, we review these data with a special focus on behavioral paradigms that manipulate both expected reward and the avoidability of aversive events to reveal neural correlates related to value, prediction error encoding, motivation, and salience.
Topics: Animals; Appetitive Behavior; Avoidance Learning; Cues; Dopamine; Humans; Motivation; Neurons; Nucleus Accumbens; Reinforcement, Psychology; Reward
PubMed: 30300635
DOI: 10.1016/j.brainres.2018.10.008 -
The Journal of Physiology Dec 2023Agonists of dopamine D2 receptors (D2R), 5-hydroxytryptamine (5-HT, serotonin) receptors (5-HTR) and ghrelin receptors (GHSR) activate neurons in the lumbosacral...
Agonists of dopamine D2 receptors (D2R), 5-hydroxytryptamine (5-HT, serotonin) receptors (5-HTR) and ghrelin receptors (GHSR) activate neurons in the lumbosacral defecation centre, and act as 'colokinetics', leading to increased propulsive colonic motility, in vivo. In the present study, we investigated which neurons in the lumbosacral defecation centre express the receptors and whether dopamine, serotonin and ghrelin receptor agonists act on the same lumbosacral preganglionic neurons (PGNs). We used whole cell electrophysiology to record responses from neurons in the lumbosacral defecation centre, following colokinetic application, and investigated their expression profiles and the chemistries of their neural inputs. Fluorescence in situ hybridisation revealed Drd2, Ghsr and Htr2C transcripts were colocalised in lumbosacral PGNs of mice, and immunohistochemistry showed that these neurons have closely associated tyrosine hydroxylase and 5-HT boutons. Previous studies showed that they do not receive ghrelin inputs. Whole cell electrophysiology in adult mice spinal cord revealed that dopamine, serotonin, α-methylserotonin and capromorelin each caused inward, excitatory currents in overlapping populations of lumbosacral PGNs. Furthermore, dopamine caused increased frequency of both IPSCs and EPSCs in a cohort of D2R neurons. Tetrodotoxin blocked the IPSCs and EPSCs, revealing a post-synaptic excitatory action of dopamine. In lumbosacral PGNs of postnatal day 7-14 rats, only dopamine's postsynaptic effects were observed. Furthermore, inward, excitatory currents evoked by dopamine were reduced by the GHSR antagonist, YIL781. We conclude that lumbosacral PGNs are the site where the action of endogenous ligands of D2R and 5-HT2R converge, and that GHSR act as a cis-modulator of D2R expressed by the same neurons. KEY POINTS: Dopamine, 5-hydroxytryptamine (5-HT, serotonin) and ghrelin (GHSR) receptor agonists increase colorectal motility and have been postulated to act at receptors on parasympathetic preganglionic neurons (PGNs) in the lumbosacral spinal cord. We aimed to determine which neurons in the lumbosacral spinal cord express dopamine, serotonin and GHSR receptors, their neural inputs, and whether agonists at these receptors excite them. We show that dopamine, serotonin and ghrelin receptor transcripts are contained in the same PGNs and that these neurons have closely associated tyrosine hydroxylase and serotonin boutons. Whole cell electrophysiology revealed that dopamine, serotonin and GHSR receptor agonists induce an inward excitatory current in overlapping populations of lumbosacral PGNs. Dopamine-induced excitation was reversed by GHSR antagonism. The present study demonstrates that lumbosacral PGNs are the site at which actions of endogenous ligands of dopamine D2 receptors and 5-HT type 2 receptors converge. Ghrelin receptors are functional, but their role appears to be as modulators of dopamine effects at D2 receptors.
Topics: Humans; Rats; Animals; Mice; Dopamine; Serotonin; Receptors, Ghrelin; Rats, Sprague-Dawley; Rodentia; Defecation; Ghrelin; Tyrosine 3-Monooxygenase; Receptors, Serotonin; Receptors, Dopamine D2
PubMed: 37772438
DOI: 10.1113/JP285217 -
Toxicology Mar 2005Nitric oxide (*NO) is a ubiquitous diffusible messenger in the central nervous system. *NO and derived nitrogen species may interact with catecholamines, thus, modifying... (Review)
Review
Nitric oxide (*NO) is a ubiquitous diffusible messenger in the central nervous system. *NO and derived nitrogen species may interact with catecholamines, thus, modifying not only its regulatory actions but also producing oxidants and free radicals that are likely to trigger toxic pathways in the nervous system. Oxidative pathways and chain oxidation reactions triggered by catecholamines may be broken by ascorbate and glutathione, of which there is ample supply in the brain. At the subcellular level, mitochondria and cytosolic dopamine storage vesicles are likely to provide site-specific settings for *NO and catecholamines interactions. Thus, a complex picture emerges in which the steady- state levels of the individual reactants, the rate constants of the reactions involved, the oxygen tension, and the compartmentalization of reactions determine the biological significance of the redox interactions between *NO and dopamine metabolism in the brain. The physiological relevance of *NO-driven chemical modifications of dopamine and its derivatives and the ensuing free radical production are discussed in connection with the neurodegeneration inherent in Parkinson's disease.
Topics: Brain; Dopamine; Free Radicals; Humans; Nitric Oxide; Oxidation-Reduction; Parkinson Disease; Structure-Activity Relationship
PubMed: 15691585
DOI: 10.1016/j.tox.2004.11.033 -
Nature Communications Jul 2022Optimal behavior requires interpreting environmental cues that indicate when to perform actions. Dopamine is important for learning about reward-predicting events, but...
Optimal behavior requires interpreting environmental cues that indicate when to perform actions. Dopamine is important for learning about reward-predicting events, but its role in adapting to inhibitory cues is unclear. Here we show that when mice can earn rewards in the absence but not presence of an auditory cue, dopamine level in the ventral striatum accurately reflects reward availability in real-time over a sustained period (80 s). In addition, unpredictable transitions between different states of reward availability are accompanied by rapid (~1-2 s) dopamine transients that deflect negatively at the onset and positively at the offset of the cue. This Dopamine encoding of reward availability and transitions between reward availability states is not dependent on reward or activity evoked dopamine release, appears before mice learn the task and is sensitive to motivational state. Our findings are consistent across different techniques including electrochemical recordings and fiber photometry with genetically encoded optical sensors for calcium and dopamine.
Topics: Animals; Cues; Dopamine; Mice; Nucleus Accumbens; Reward; Ventral Striatum
PubMed: 35778414
DOI: 10.1038/s41467-022-31377-2