scholarly journals A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Ian D Blum ◽  
Lei Zhu ◽  
Luc Moquin ◽  
Maia V Kokoeva ◽  
Alain Gratton ◽  
...  
Keyword(s):  
Mammalian Species ◽  
Dopamine Neurons ◽  
Mammalian Brain ◽  
Behavioral Arousal ◽  
Dopaminergic Tone ◽  
Activity Cycles ◽  
Midbrain Dopamine ◽  
Locomotor Rhythms ◽  
Underlying Mechanisms ◽  
Period Lengthening

Ultradian (∼4 hr) rhythms in locomotor activity that do not depend on the master circadian pacemaker in the suprachiasmatic nucleus have been observed across mammalian species, however, the underlying mechanisms driving these rhythms are unknown. We show that disruption of the dopamine transporter gene lengthens the period of ultradian locomotor rhythms in mice. Period lengthening also results from chemogenetic activation of midbrain dopamine neurons and psychostimulant treatment, while the antipsychotic haloperidol has the opposite effect. We further reveal that striatal dopamine levels fluctuate in synchrony with ultradian activity cycles and that dopaminergic tone strongly predicts ultradian period. Our data indicate that an arousal regulating, dopaminergic ultradian oscillator (DUO) operates in the mammalian brain, which normally cycles in harmony with the circadian clock, but can desynchronize when dopamine tone is elevated, thereby producing aberrant patterns of arousal which are strikingly similar to perturbed sleep-wake cycles comorbid with psychopathology.

scholarly journals Implications of cellular models of dopamine neurons for disease

2016 ◽  
Vol 116 (6) ◽  
pp. 2815-2830 ◽  
Author(s):  
Carmen C. Canavier ◽  
Rebekah C. Evans ◽  
Andrew M. Oster ◽  
Eleftheria K. Pissadaki ◽  
Guillaume Drion ◽  
...  
Keyword(s):  
Firing Pattern ◽  
Dopamine Neurons ◽  
Cell Models ◽  
Analytical Technique ◽  
Cellular Models ◽  
Single Compartment ◽  
Midbrain Dopamine ◽  
Underlying Mechanisms ◽  
Neural Signaling ◽  
Midbrain Dopamine Neurons

This review addresses the present state of single-cell models of the firing pattern of midbrain dopamine neurons and the insights that can be gained from these models into the underlying mechanisms for diseases such as Parkinson's, addiction, and schizophrenia. We will explain the analytical technique of separation of time scales and show how it can produce insights into mechanisms using simplified single-compartment models. We also use morphologically realistic multicompartmental models to address spatially heterogeneous aspects of neural signaling and neural metabolism. Separation of time scale analyses are applied to pacemaking, bursting, and depolarization block in dopamine neurons. Differences in subpopulations with respect to metabolic load are addressed using multicompartmental models.

scholarly journals Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

2021 ◽  
pp. 1-24
Author(s):  
Juho-Matti Renko ◽  
Arun Kumar Mahato ◽  
Tanel Visnapuu ◽  
Konsta Valkonen ◽  
Mati Karelson ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Disease Modifying Therapy ◽  
Immortalized Cells ◽  
Midbrain Dopamine ◽  
6 Hydroxydopamine

Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP +-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD.

Deletion of VGLUT2 in midbrain dopamine neurons attenuates dopamine and glutamate responses to methamphetamine in mice

2021 ◽  
Vol 202 ◽  
pp. 173104
Author(s):  
Hui Shen ◽  
Kai Chen ◽  
Rosa Anna M. Marino ◽  
Ross A. McDevitt ◽  
Zheng-Xiong Xi
Keyword(s):  
Dopamine Neurons ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons
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