scholarly journals Pain is so close to pleasure: the same dopamine neurons can mediate approach and avoidance in Drosophila

2021 ◽  
Author(s):  
Christian Rohrsen ◽  
Aida Kumpf ◽  
Kader Semiz ◽  
Ferruh Aydin ◽  
Benjamin deBivort ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Neuronal Population ◽  
Dopamine Neurons ◽  
Common Currency ◽  
Approach And Avoidance ◽  
Aversive Stimuli ◽  
Appetitive Stimuli ◽  
Self Stimulation ◽  
Transgenic Drosophila

In mammals, dopamine is considered a central neuromodulator involved in all kinds of rewarding experiences ('common currency' hypothesis). In insects, the role of dopaminergic neurons in aversive stimuli was discovered before dopaminergic neurons were found to also be involved in processing appetitive stimuli. Here, we screened about 50 transgenic Drosophila lines, representing different subpopulations of dopaminergic neurons for their ability to sustain approach or avoidance behavior, when activated optogenetically in four different operant self-stimulation paradigms. None of the lines sustain consistent behavioral valence in all experiments. Individual lines sustain approach in one experiment and avoidance in another. One line mediated strong avoidance early in the experiment and weak approach in later stages. The evidence presented here appears to contradict a 'common currency' dopamine function in flies. Instead, different dopaminergic neurons convey valence in a context-dependent and flexible manner, reflecting the genetic heterogeneity of the dopaminergic neuronal population.

scholarly journals Tcf4 Is Involved in Subset Specification of Mesodiencephalic Dopaminergic Neurons

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 317
Author(s):  
Simone Mesman ◽  
Iris Wever ◽  
Marten P. Smidt
Keyword(s):  
Neuronal Differentiation ◽  
Dopaminergic Neurons ◽  
Neuronal Development ◽  
Neuronal Population ◽  
Minor Role ◽  
Initial Increase ◽  
E Box ◽  
A Minor ◽  
Bhlh Factor

During development, mesodiencephalic dopaminergic (mdDA) neurons form into different molecular subsets. Knowledge of which factors contribute to the specification of these subsets is currently insufficient. In this study, we examined the role of Tcf4, a member of the E-box protein family, in mdDA neuronal development and subset specification. We show that Tcf4 is expressed throughout development, but is no longer detected in adult midbrain. Deletion of Tcf4 results in an initial increase in TH-expressing neurons at E11.5, but this normalizes at later embryonic stages. However, the caudal subset marker Nxph3 and rostral subset marker Ahd2 are affected at E14.5, indicating that Tcf4 is involved in correct differentiation of mdDA neuronal subsets. At P0, expression of these markers partially recovers, whereas expression of Th transcript and TH protein appears to be affected in lateral parts of the mdDA neuronal population. The initial increase in TH-expressing cells and delay in subset specification could be due to the increase in expression of the bHLH factor Ascl1, known for its role in mdDA neuronal differentiation, upon loss of Tcf4. Taken together, our data identified a minor role for Tcf4 in mdDA neuronal development and subset specification.

scholarly journals Modeling Uncertainty-Seeking Behavior Mediated by Cholinergic Influence on Dopamine

2019 ◽  
Author(s):  
Marwen Belkaid ◽  
Jeffrey L. Krichmar
Keyword(s):  
Decision Making ◽  
Dopaminergic Neurons ◽  
Cholinergic System ◽  
Dopamine Neurons ◽  
Comprehensive Understanding ◽  
Dopaminergic Activity ◽  
Integrate And Fire ◽  
Major Implication ◽  
Seeking Behavior

AbstractRecent findings suggest that acetylcholine mediates uncertainty-seeking behaviors through its projection to dopamine neurons – another neuromodulatory system known for its major implication in reinforcement learning and decision-making. In this paper, we propose a leaky-integrate-and-fire model of this mechanism. It implements a softmax-like selection with an uncertainty bonus by a cholinergic drive to dopaminergic neurons, which in turn influence synaptic currents of downstream neurons. The model is able to reproduce experimental data in two decision-making tasks. It also predicts that i) in the absence of cholinergic input, dopaminergic activity would not correlate with uncertainty, and that ii) the adaptive advantage brought by the implemented uncertainty-seeking mechanism is most useful when sources of reward are not highly uncertain. Moreover, this modeling work allows us to propose novel experiments which might shed new light on the role of acetylcholine in both random and directed exploration. Overall, this study thus contributes to a more comprehensive understanding of the roles of the cholinergic system and its involvement in decision-making in particular.

scholarly journals Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3022
Author(s):  
Maria Vizziello ◽  
Linda Borellini ◽  
Giulia Franco ◽  
Gianluca Ardolino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Gene Mutations ◽  
Neuronal Population ◽  
In Vivo Models ◽  
Mitochondrial Homeostasis

The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.

Dopamine neurons coding prediction errors in reward space, but not in aversive space: a matter of location?

2014 ◽  
Vol 112 (5) ◽  
pp. 1021-1024 ◽  
Author(s):  
Joachim Morrens
Keyword(s):  
Prediction Error ◽  
Dopamine Neurons ◽  
Prediction Errors ◽  
Neurotransmitter Systems ◽  
Aversive Stimuli ◽  
Midbrain Neurons ◽  
Appetitive Stimuli ◽  
Error Coding ◽  
Potential Issue

Dopamine midbrain neurons are well known for prediction error coding in a reward context. A recent report by Christopher Fiorillo ( Science 341: 546–549, 2013), however, suggests that these neurons behave markedly different when subjects get confronted with aversive, rather than appetitive, stimuli. Despite his findings being in line with indications of appetitive and aversive stimuli being processed by distinct neurotransmitter systems, they should still be interpreted with some caution due to a potential issue of recording location.

scholarly journals Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons

Science ◽  
2015 ◽  
Vol 350 (6256) ◽  
pp. 102-106 ◽  
Author(s):  
Jae-Ick Kim ◽  
Subhashree Ganesan ◽  
Sarah X. Luo ◽  
Yu-Wei Wu ◽  
Esther Park ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Dopaminergic Neurons ◽  
Dopamine Neurons ◽  
Inhibitory Neurotransmitter ◽  
Midbrain Dopaminergic Neurons ◽  
Evolutionarily Conserved ◽  
Gaba Synthesis ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.

Dopamine and inverse incentive learning

2018 ◽  
Author(s):  
Richard J. Beninger
Keyword(s):  
Dopamine Neurons ◽  
Incentive Learning ◽  
Repeated Presentation ◽  
Aversive Stimuli ◽  
Incentive Value ◽  
Conditioned Incentive Stimuli

Dopamine and inverse incentive learning explains that dopamine determines an incentive–value continuum. Novel and intense stimuli innately produce rapid dopamine neurons activation followed by inhibition. The repeated presentation of novel stimuli leads to a loss of this effect. Aversive stimuli, biologically important by definition, often deactivate dopamine neurons and may produce inverse incentive learning, leading to conditioned inverse incentive stimuli with decreased ability to elicit approach and other responses. The offset of aversion may increase the firing of dopamine neurons producing incentive learning about safety-related stimuli. Habituation to stimuli enhances their ability to produce inverse incentive learning, suggesting that inverse incentive learning may occur during habituation. In the end, there may be no “neutral” stimuli, only stimuli that lie on a continuum of incentive value from strong conditioned incentive stimuli to strong conditioned inverse incentive stimuli with most of the things we encounter in day-to-day life falling in between.

scholarly journals α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Abeer Dagra ◽  
Douglas R. Miller ◽  
Min Lin ◽  
Adithya Gopinath ◽  
Fatemeh Shaerzadeh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Activity ◽  
Dopaminergic Neurons ◽  
Prolonged Exposure ◽  
D2 Receptor ◽  
Neuronal Firing ◽  
Dopamine Neurons ◽  
Loss Of Function ◽  
Therapeutic Implications

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

scholarly journals Chemical and Biological Molecules Involved in Differentiation, Maturation, and Survival of Dopaminergic Neurons in Health and Parkinson’s Disease: Physiological Aspects and Clinical Implications

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 754
Author(s):  
Giulia Gaggi ◽  
Andrea Di Credico ◽  
Pascal Izzicupo ◽  
Giovanni Iannetti ◽  
Angela Di Baldassarre ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Potential Role ◽  
High Efficiency ◽  
Biological Molecules ◽  
Alternative Approach ◽  
Non Coding Rnas ◽  
Set Up

Parkinson’s disease (PD) is one of the most common neurodegenerative disease characterized by a specific and progressive loss of dopaminergic (DA) neurons and dopamine, causing motor dysfunctions and impaired movements. Unfortunately, available therapies can partially treat the motor symptoms, but they have no effect on non-motor features. In addition, the therapeutic effect reduces gradually, and the prolonged use of drugs leads to a significative increase in the number of adverse events. For these reasons, an alternative approach that allows the replacement or the improved survival of DA neurons is very appealing for the treatment of PD patients and recently the first human clinical trials for DA neurons replacement have been set up. Here, we review the role of chemical and biological molecules that are involved in the development, survival and differentiation of DA neurons. In particular, we review the chemical small molecules used to differentiate different type of stem cells into DA neurons with high efficiency; the role of microRNAs and long non-coding RNAs both in DA neurons development/survival as far as in the pathogenesis of PD; and, finally, we dissect the potential role of exosomes carrying biological molecules as treatment of PD.

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