dopaminergic activity
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2021 ◽  
Vol 23 (1) ◽  
pp. 453
Author(s):  
Andrea Stofkova ◽  
Miloslav Zloh ◽  
Dominika Andreanska ◽  
Ivana Fiserova ◽  
Jan Kubovciak ◽  
...  

The gateway reflex is a mechanism by which neural inputs regulate chemokine expression at endothelial cell barriers, thereby establishing gateways for the invasion of autoreactive T cells into barrier-protected tissues. In this study, we hypothesized that rod photoreceptor dysfunction causes remodeling of retinal neural activity, which influences the blood–retinal barrier and the development of retinal inflammation. We evaluated this hypothesis using Gnat1rd17 mice, a model of night blindness with late-onset rod-cone dystrophy, and experimental autoimmune uveoretinitis (EAU). Retinal remodeling and its effect on EAU development were investigated by transcriptome profiling, target identification, and functional validation. We showed that Gnat1rd17 mice primarily underwent alterations in their retinal dopaminergic system, triggering the development of an exacerbated EAU, which was counteracted by dopamine replacement with L-DOPA administered either systemically or locally. Remarkably, dopamine acted on retinal endothelial cells to inhibit NF-κB and STAT3 activity and the expression of downstream target genes such as chemokines involved in T cell recruitment. These results suggest that rod-mediated dopamine release functions in a gateway reflex manner in the homeostatic control of immune cell entry into the retina, and the loss of retinal dopaminergic activity in conditions associated with rod dysfunction increases the susceptibility to autoimmune uveitis.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Allison E Hamilos ◽  
Giulia Spedicato ◽  
Ye Hong ◽  
Fangmiao Sun ◽  
Yulong Li ◽  
...  

Clues from human movement disorders have long suggested that the neurotransmitter dopamine plays a role in motor control, but how the endogenous dopaminergic system influences movement is unknown. Here we examined the relationship between dopaminergic signaling and the timing of reward-related movements in mice. Animals were trained to initiate licking after a self-timed interval following a start-timing cue; reward was delivered in response to movements initiated after a criterion time. The movement time was variable from trial-to-trial, as expected from previous studies. Surprisingly, dopaminergic signals ramped-up over seconds between the start-timing cue and the self-timed movement, with variable dynamics that predicted the movement/reward time on single trials. Steeply rising signals preceded early lick-initiation, whereas slowly rising signals preceded later initiation. Higher baseline signals also predicted earlier self-timed movements. Optogenetic activation of dopamine neurons during self-timing did not trigger immediate movements, but rather caused systematic early-shifting of movement initiation, whereas inhibition caused late-shifting, as if modulating the probability of movement. Consistent with this view, the dynamics of the endogenous dopaminergic signals quantitatively predicted the moment-by-moment probability of movement initiation on single trials. We propose that ramping dopaminergic signals, likely encoding dynamic reward expectation, can modulate the decision of when to move.


2021 ◽  
Author(s):  
Maciej M Jankowski ◽  
Bogna M Ignatowska-Jankowska ◽  
Wojciech Glac ◽  
Marek Wiergowski ◽  
Paulina Kazmierska-Grebowska ◽  
...  

Modulation of dopamine transmission evokes strong behavioral effects that can be achieved by psychoactive drugs such as haloperidol or cocaine. Cocaine non-specifically increases dopamine transmission by blocking dopamine active transporter (DAT) and evokes behavioral arousal, while haloperidol is a non-specific dopamine D2 receptor antagonist with sedative effects. Interestingly, dopamine has been found to affect immune cells in addition to its action in the central nervous system. Here we address the possible interactions between haloperidol and cocaine and their effects on both immune cells and behavior in freely moving rats. We use an intravenous model of haloperidol and binge cocaine administration to evaluate the drugs' impact on the distribution of lymphocyte subsets in both the peripheral blood and the spleen. We assess the drugs' behavioral effects by measuring locomotor activity. Cocaine evoked a pronounced locomotor response and stereotypic behaviors, both of which were completely blocked after pretreatment with haloperidol. The results suggest that blood lymphopenia which was induced by haloperidol and cocaine (except for NKT cells), is independent of dopaminergic activity and most likely results from the massive secretion of corticosterone. Haloperidol pretreatment prevented the cocaine-induced decrease in NKT cell numbers. On the other hand, the increased systemic dopaminergic activity after cocaine administration is a significant factor in retaining T CD4+ and B lymphocytes in the spleen.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Darshini Mahadevia ◽  
Rinki Saha ◽  
Alessia Manganaro ◽  
Nao Chuhma ◽  
Annette Ziolkowski-Blake ◽  
...  

AbstractSeptal-hypothalamic neuronal activity centrally mediates aggressive behavior and dopamine system hyperactivity is associated with elevated aggression. However, the causal role of dopamine in aggression and its target circuit mechanisms are largely unknown. To address this knowledge gap, we studied the modulatory role of the population- and projection-specific dopamine function in a murine model of aggressive behavior. We find that terminal activity of ventral tegmental area (VTA) dopaminergic neurons selectively projecting to the lateral septum (LS) is sufficient for promoting aggression and necessary for establishing baseline aggression. Within the LS, dopamine acts on D2-receptors to inhibit GABAergic neurons, and septal D2-signaling is necessary for VTA dopaminergic activity to promote aggression. Collectively, our data reveal a powerful modulatory influence of dopaminergic synaptic input on LS function and aggression, effectively linking the clinically pertinent hyper-dopaminergic model of aggression with the classic septal-hypothalamic aggression axis.


2021 ◽  
Vol 12 ◽  
Author(s):  
Julien Cabé ◽  
Georges Brousse ◽  
Bruno Pereira ◽  
Nicolas Cabé ◽  
Emily Karsinti ◽  
...  

Background: During cocaine withdrawal, transient depressive symptoms that do not meet the criteria for depression, but promote relapse, are frequently observed. Their temporality could evoke a role of dopamine, especially since the underlying mechanism of these depressive symptoms is not well understood. We hypothesized that variation in the dopaminergic activity profile, modeled from clinical markers, could be implicated in the development of depressive symptoms during cocaine withdrawal.Methods: We compared patients reporting depressive symptoms (RDS+) or not (RDS–) during cocaine withdrawal. We evaluated dopaminergic activity through indirect clinical markers based on the known dopaminergic behaviors. A combined criterion was constructed for hyper and hypo dopaminergic models according to the O'Brien method and illustrated by the Hedges' effect-size and forest-plot graph. A multidimensional factorial analysis was carried out to determine which parameters discriminate RDS+/RDS– patients.Results: 313 patients were included, and 77% reported depressive symptoms during cocaine withdrawal. Hyperdopaminergic variables used to discriminate the two groups had a large overall effect size (−0.669) and included psychotic symptoms (−0.524), hallucinations (−0.548), and delusions (−0.528). The overall effect of the hypodopaminergic component was considerable (−0.604) with a large effect size for the severity of dependence (−0.616), withdrawal symptoms (−0.578), and anhedonia (−0.528). The combined model including hyperdopaminergic and hypodopaminergic components had the largest effect size (−0.785).Conclusion: The dopaminergic activities profile, assessed by indirect clinical markers, seems to characterize patients with depressive symptoms very well during cocaine withdrawal. RDS+ patients reported moreover higher levels of psychotic symptoms and more severe cocaine use disorder than RDS–.


2021 ◽  
Author(s):  
Silvia Papalini ◽  
Neefs Laura ◽  
Tom Beckers ◽  
Lukas Van Oudenhove ◽  
Bram Vervliet

Prolonged fasting influences threat and reward processing, two fundamental systems underpinning adaptive behaviors. In animals, overnight fasting sensitizes the mesolimbic-dopaminergic activity governing avoidance, reward, and fear-extinction learning. Despite evidence that overnight fasting may also affect reward and fear learning in humans, effects on human avoidance learning have not been studied yet. Here, we examined the effects of 16h-overnight fasting on instrumental avoidance and relief from threat omission. To this end, 50 healthy women were randomly assigned to a fasting (N=25) or a re-feeding group (N=25) and performed an Avoidance-Relief Task. We found that fasting decreases unnecessary avoidance during signaled safety; this effect was mediated via a reduction in relief pleasantness during signaled absence of threat. A fasting-induced reduction in relief was also found during fear extinction learning. We conclude that fasting optimizes avoidance and safety learning. Future studies should test whether these effects also hold for anxious individuals.


2021 ◽  
Author(s):  
Michel Schultz ◽  
Beatrice Hanusch ◽  
Veronika Matschke ◽  
Carsten Theiss ◽  
Thomas Lücke ◽  
...  

2021 ◽  
Vol 118 (42) ◽  
pp. e2023674118
Author(s):  
Jia Jia ◽  
Lei He ◽  
Junfei Yang ◽  
Yichun Shuai ◽  
Jingjing Yang ◽  
...  

Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster. The chronic stress–induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/β neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress–induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.


Author(s):  
Simo Nuuttila ◽  
Mikael Eklund ◽  
Juho Joutsa ◽  
Elina Jaakkola ◽  
Elina Mäkinen ◽  
...  

AbstractGlabellar tap or reflex (GR) is an old bedside clinical test used in the diagnostics of Parkinson’s disease (PD), but its diagnostic value is unclear. This study examines the diagnostic validity and reliability of GR in PD in relation to brain dopaminergic activity. GR was performed on 161 patients with PD, 47 patients with essential tremor (ET) and 40 healthy controls immediately prior to dopamine transporter (DAT) [123I]FP-CIT SPECT scanning. The binding ratios were investigated with consideration of the GR result (normal/abnormal). In addition, the consistency of the GR was investigated with 89 patients after a mean follow-up of 2.2 years. PD and ET patients had higher GR scores than healthy controls (p < 0.001), but there was no difference in GR between PD and ET patients (p = 0.09). There were no differences in the ratio of abnormal to normal GRs between the PD and ET groups (73% vs. 64% abnormal, respectively, p = 0.13) or in DAT binding between PD patients with abnormal and normal GRs (p > 0.36). Over follow-up, the GR changed from abnormal to normal in 20% of PD patients despite the presence of clinically typical disease. The sensitivity and specificity of GR for differentiating PD from ET were 78.3% and 36.2%, respectively. Although GR has been used by clinicians in the diagnostics of PD, it does not separate PD from ET. It also shows considerable inconsistency over time, and abnormal GR has no relationship with dopamine loss. Its usefulness should be tested for other clinical diagnostic purposes.


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