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Nature Reviews. Neurology Jan 2024Schizophrenia is a leading cause of global disability. Current pharmacotherapy for the disease predominantly uses one mechanism - dopamine D2 receptor blockade - but... (Review)
Review
Schizophrenia is a leading cause of global disability. Current pharmacotherapy for the disease predominantly uses one mechanism - dopamine D2 receptor blockade - but often shows limited efficacy and poor tolerability. These limitations highlight the need to better understand the aetiology of the disease to aid the development of alternative therapeutic approaches. Here, we review the latest meta-analyses and other findings on the neurobiology of prodromal, first-episode and chronic schizophrenia, and the link to psychotic symptoms, focusing on imaging evidence from people with the disorder. This evidence demonstrates regionally specific neurotransmitter alterations, including higher glutamate and dopamine measures in the basal ganglia, and lower glutamate, dopamine and γ-aminobutyric acid (GABA) levels in cortical regions, particularly the frontal cortex, relative to healthy individuals. We consider how dysfunction in cortico-thalamo-striatal-midbrain circuits might alter brain information processing to underlie psychotic symptoms. Finally, we discuss the implications of these findings for developing new, mechanistically based treatments and precision medicine for psychotic symptoms, as well as negative and cognitive symptoms.
Topics: Humans; Schizophrenia; Dopamine; Neurochemistry; Psychotic Disorders; Glutamic Acid
PubMed: 38110704
DOI: 10.1038/s41582-023-00904-0 -
Neuron Jan 2024The pathophysiology of affective disorders-particularly circuit-level mechanisms underlying bidirectional, periodic affective state transitions-remains poorly...
The pathophysiology of affective disorders-particularly circuit-level mechanisms underlying bidirectional, periodic affective state transitions-remains poorly understood. In patients, disruptions of sleep and circadian rhythm can trigger transitions to manic episodes, whereas depressive states are reversed. Here, we introduce a hybrid automated sleep deprivation platform to induce transitions of affective states in mice. Acute sleep loss causes mixed behavioral states, featuring hyperactivity, elevated social and sexual behaviors, and diminished depressive-like behaviors, where transitions depend on dopamine (DA). Using DA sensor photometry and projection-targeted chemogenetics, we reveal that elevated DA release in specific brain regions mediates distinct behavioral changes in affective state transitions. Acute sleep loss induces DA-dependent enhancement in dendritic spine density and uncaging-evoked dendritic spinogenesis in the medial prefrontal cortex, whereas optically mediated disassembly of enhanced plasticity reverses the antidepressant effects of sleep deprivation on learned helplessness. These findings demonstrate that brain-wide dopaminergic pathways control sleep-loss-induced polymodal affective state transitions.
Topics: Humans; Mice; Animals; Dopamine; Sleep Deprivation; Brain; Sleep; Emotions
PubMed: 37922904
DOI: 10.1016/j.neuron.2023.10.002 -
Brain : a Journal of Neurology Aug 2023Parkinson's disease is the second most common neurodegenerative disease and yet the early pathophysiological events of the condition and sequences of dysfunction remain... (Review)
Review
Parkinson's disease is the second most common neurodegenerative disease and yet the early pathophysiological events of the condition and sequences of dysfunction remain unclear. The loss of dopaminergic neurons and reduced levels of striatal dopamine are descriptions used interchangeably as underlying the motor deficits in Parkinson's disease. However, decades of research suggest that dopamine release deficits in Parkinson's disease do not occur only after cell death, but that there is dysfunction or dysregulation of axonal dopamine release before cell loss. Here we review the evidence for dopamine release deficits prior to neurodegeneration in Parkinson's disease, drawn from a large and emerging range of Parkinson's disease models, and the mechanisms by which these release deficits occur. The evidence indicates that impaired dopamine release can result from disruption to a diverse range of Parkinson's disease-associated genetic and molecular disturbances, and can be considered as a potential pathophysiological hallmark of Parkinson's disease.
Topics: Humans; Parkinson Disease; Dopamine; Neurodegenerative Diseases; Dopaminergic Neurons
PubMed: 36864664
DOI: 10.1093/brain/awad064 -
Translational Neurodegeneration Sep 2023A pathological feature of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars... (Review)
Review
A pathological feature of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. DA is the neurotransmitter of dopaminergic neurons. Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products, including reactive oxygen species, DA quinones, and 3,4-dihydroxyphenylacetaldehyde. Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways, and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.
Topics: Humans; Dopamine; Parkinson Disease; Brain; Dopaminergic Neurons
PubMed: 37718439
DOI: 10.1186/s40035-023-00378-6 -
Neuron Oct 2023GABAergic neurons in the laterodorsal tegmental nucleus (LDT) encode aversion by directly inhibiting mesolimbic dopamine (DA). Yet, the detailed cellular and circuit...
GABAergic neurons in the laterodorsal tegmental nucleus (LDT) encode aversion by directly inhibiting mesolimbic dopamine (DA). Yet, the detailed cellular and circuit mechanisms by which these cells relay unpleasant stimuli to DA neurons and regulate behavioral output remain largely unclear. Here, we show that LDT neurons bidirectionally respond to rewarding and aversive stimuli in mice. Activation of LDT neurons promotes aversion and reduces DA release in the lateral nucleus accumbens. Furthermore, we identified two molecularly distinct LDT cell populations. Somatostatin-expressing (Sst) LDT neurons indirectly regulate the mesolimbic DA system by disinhibiting excitatory hypothalamic neurons. In contrast, Reelin-expressing LDT neurons directly inhibit downstream DA neurons. The identification of separate GABAergic subpopulations in a single brainstem nucleus that relay unpleasant stimuli to the mesolimbic DA system through direct and indirect projections is critical for establishing a circuit-level understanding of how negative valence is encoded in the mammalian brain.
Topics: Mice; Animals; Ventral Tegmental Area; Dopamine; Nucleus Accumbens; Dopaminergic Neurons; gamma-Aminobutyric Acid; Mammals
PubMed: 37499661
DOI: 10.1016/j.neuron.2023.06.021 -
Neuron Feb 2024Striatal dopamine (DA) release has long been linked to reward processing, but it remains controversial whether DA release reflects costs or benefits and how these...
Striatal dopamine (DA) release has long been linked to reward processing, but it remains controversial whether DA release reflects costs or benefits and how these signals vary with motivation. Here, we measure DA release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) while independently varying costs and benefits and apply behavioral economic principles to determine a mouse's level of motivation. We reveal that DA release in both structures incorporates both reward magnitude and sunk cost. Surprisingly, motivation was inversely correlated with reward-evoked DA release. Furthermore, optogenetically evoked DA release was also heavily dependent on sunk cost. Our results reconcile previous disparate findings by demonstrating that striatal DA release simultaneously encodes cost, benefit, and motivation but in distinct manners over different timescales. Future work will be necessary to determine whether the reduction in phasic DA release in highly motivated animals is due to changes in tonic DA levels.
Topics: Mice; Animals; Dopamine; Motivation; Corpus Striatum; Neostriatum; Nucleus Accumbens; Reward
PubMed: 38016471
DOI: 10.1016/j.neuron.2023.10.038 -
International Journal of Medical... 2023Repeated low-level red-light (RLRL), characterized by increased energy supply and cellular metabolism, thus enhancing metabolic repair processes, has gained persistent... (Review)
Review
Repeated low-level red-light (RLRL), characterized by increased energy supply and cellular metabolism, thus enhancing metabolic repair processes, has gained persistent worldwide attention in recent years as a new novel scientific approach for therapeutic application in myopia. This therapeutic revolution led by RLRL therapy is due to significant advances in bioenergetics and photobiology, for instance, enormous progresses in photobiomodulation regulated by cytochrome oxidase, the primary photoreceptor of the light in the red to near infrared regions of the electromagnetic spectrum, as the primary mechanism of action in RLRL therapy. This oxidase is also a key mitochondrial enzyme for cellular bioenergetics, especially for the nerve cells in the retina and brain. In addition, dopamine (DA)-enhanced release of nitric oxide may also be involved in controlling myopia by activation of nitric oxide synthase, enhancing cGMP signaling. Recent evidence has also suggested that RLRL may inhibit myopia progression by inhibiting spherical equivalent refraction (SER) progression and axial elongation without adverse effects. In this review, we provide scientific evidence for RLRL therapy as a unique paradigm to control myopia and support the theory that targeting neuronal energy metabolism may constitute a major target for the neurotherapeutics of myopia, with emphasis on its molecular, cellular, and nervous tissue levels, and the potential benefits of RLRL therapy for myopia.
Topics: Humans; Myopia; Retina; Refraction, Ocular; Dopamine; Low-Level Light Therapy
PubMed: 37786442
DOI: 10.7150/ijms.85746 -
Cell Reports Oct 2023Dopamine synapses play a crucial role in volitional movement and reward-related behaviors, while dysfunction of dopamine synapses causes various psychiatric and...
Dopamine synapses play a crucial role in volitional movement and reward-related behaviors, while dysfunction of dopamine synapses causes various psychiatric and neurological disorders. Despite this significance, the true biological nature of dopamine synapses remains poorly understood. Here, we show that dopamine transmission is strongly correlated with GABA co-transmission across the brain and dopamine synapses are structured and function like GABAergic synapses with marked regional heterogeneity. In addition, GABAergic-like dopamine synapses are clustered on the dendrites, and GABA transmission at dopamine synapses has distinct physiological properties. Interestingly, the knockdown of neuroligin-2, a key postsynaptic protein at GABAergic synapses, unexpectedly does not weaken GABA co-transmission but instead facilitates it at dopamine synapses in the striatal neurons. More importantly, the attenuation of GABA co-transmission precedes deficits in dopaminergic transmission in animal models of Parkinson's disease. Our findings reveal the spatial and functional nature of GABAergic-like dopamine synapses in health and disease.
Topics: Animals; Dopamine; Brain; Synapses; Neurons; gamma-Aminobutyric Acid; Receptors, GABA-A
PubMed: 37819757
DOI: 10.1016/j.celrep.2023.113239 -
Function (Oxford, England) 2023We are constantly bombarded by sensory information and constantly making decisions on how to act. In order to optimally adapt behavior, we must judge which sequences of... (Review)
Review
We are constantly bombarded by sensory information and constantly making decisions on how to act. In order to optimally adapt behavior, we must judge which sequences of sensory inputs and actions lead to successful outcomes in specific circumstances. Neuronal circuits of the basal ganglia have been strongly implicated in action selection, as well as the learning and execution of goal-directed behaviors, with accumulating evidence supporting the hypothesis that midbrain dopamine neurons might encode a reward signal useful for learning. Here, we review evidence suggesting that midbrain dopaminergic neurons signal reward prediction error, driving synaptic plasticity in the striatum underlying learning. We focus on phasic increases in action potential firing of midbrain dopamine neurons in response to unexpected rewards. These dopamine neurons prominently innervate the dorsal and ventral striatum. In the striatum, the released dopamine binds to dopamine receptors, where it regulates the plasticity of glutamatergic synapses. The increase of striatal dopamine accompanying an unexpected reward activates dopamine type 1 receptors (D1Rs) initiating a signaling cascade that promotes long-term potentiation of recently active glutamatergic input onto striatonigral neurons. Sensorimotor-evoked glutamatergic input, which is active immediately before reward delivery will thus be strengthened onto neurons in the striatum expressing D1Rs. In turn, these neurons cause disinhibition of brainstem motor centers and disinhibition of the motor thalamus, thus promoting motor output to reinforce rewarded stimulus-action outcomes. Although many details of the hypothesis need further investigation, altogether, it seems likely that dopamine signals in the striatum might underlie important aspects of goal-directed reward-based learning.
Topics: Dopamine; Learning; Reward; Dopaminergic Neurons; Ventral Striatum
PubMed: 37841525
DOI: 10.1093/function/zqad056 -
Environmental Pollution (Barking, Essex... Nov 2023Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to...
Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) on dopamine metabolism and underling molecular basis in nematodes. The dopamine content was reduced by 6-PPDQ (1 and 10 μg/L). Meanwhile, dopamine related behaviors (basal slowing response and area restricted searching) were changed by 6-PPDQ (1 and 10 μg/L). Exposure to 6-PPDQ (1 and 10 μg/L) decreased expressions of genes (cat-2 and bas-1) encoding enzymes governing dopamine synthesis and cat-1 encoding dopamine transporter. Development of dopaminergic neurons was also affected by 10 μg/L 6-PPDQ as reflected by decrease in fluorescence intensity, neuronal loss, and defect in dendrite development. Exposure to 6-PPDQ (1 and 10 μg/L) altered expressions of ast-1 and rcat-1 encoding upregulators of cat-2 and bas-1. The dopamine content and expressions of cat-2 and bas-1 were inhibited by RNAi of ast-1 and increased by RNAi of rcat-1 in 6-PPDQ exposed nematodes. Using endpoints of locomotion behavior and brood size, in 6-PPDQ exposed nematodes, the susceptibility to toxicity was caused by RNAi of ast-1, cat-2, bas-1, and cat-1, and the resistance to toxicity was induced by RNAi of rcat-1. Therefore, 6-PPDQ exposure disrupted dopamine metabolism and the altered molecular basis for dopamine metabolism was associated with 6-PPDQ toxicity induction. Moreover, the defects in dopamine related behaviors and toxicity on locomotion and reproduction could be rescued by treatment with 0.1 mM dopamine.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dopamine; Oxidative Stress; Phenylenediamines; Benzoquinones
PubMed: 37777057
DOI: 10.1016/j.envpol.2023.122649