scholarly journals Withdrawal From Intermittent Ethanol Exposure Increases Probability of Burst Firing in VTA Neurons In Vitro

2007 ◽  
Vol 98 (4) ◽  
pp. 2297-2310 ◽  
Author(s):  
F. Woodward Hopf ◽  
Miquel Martin ◽  
Billy T. Chen ◽  
M. Scott Bowers ◽  
Maysha M. Mohamedi ◽  
...  
Keyword(s):  
Ethanol Exposure ◽  
Burst Firing ◽  
Dopamine Neurons ◽  
Calcium Dependent ◽  
Physiological Properties ◽  
Seeking Behavior ◽  
Delayed Recovery ◽  
Small Conductance

Changing the activity of ventral tegmental area (VTA) dopamine neurons from pacemaker to burst firing is hypothesized to increase the salience of stimuli, such as an unexpected reward, and likely contributes to withdrawal-associated drug-seeking behavior. Accordingly, pharmacological, behavioral, and electrophysiological data suggest an important role of the VTA in mediating alcohol-dependent behaviors. However, the effects of repeated ethanol exposure on VTA dopamine neuron ion channel function are poorly understood. Here, we repeatedly exposed rats to ethanol (2 g/kg ethanol, ip, twice per day for 5 days), then examined the firing patterns of VTA dopamine neurons in vitro after 7 days withdrawal. Compared with saline-treated animals, the function of the small conductance calcium-dependent potassium channel (SK) was reduced in ethanol-treated animals. Consistent with a role for SK in regulation of burst firing, NMDA applied during firing facilitated the transition to bursting in ethanol-treated but not saline-treated animals; NMDA consistently induced bursting only in saline-treated animals when SK was inhibited. Also, enhanced bursting in ethanol-treated animals was not a result of differences in NMDA-induced depolarization. Further, Ih was also reduced in ethanol-treated animals, which delayed recovery from hyperpolarization, but did not account for the increased NMDA-induced bursting in ethanol-treated animals. Finally, repeated ethanol exposure and withdrawal also enhanced the acute locomotor-activating effect of cocaine (15 mg/kg, ip). Thus withdrawal after repeated ethanol exposure produced several alterations in the physiological properties of VTA dopamine neurons, which could ultimately increase the ability of VTA neurons to produce burst firing and thus might contribute to addiction-related behaviors.

scholarly journals Calcium dynamics control K-ATP channel-mediated bursting in substantia nigra dopamine neurons: a combined experimental and modeling study

2018 ◽  
Vol 119 (1) ◽  
pp. 84-95 ◽  
Author(s):  
Christopher Knowlton ◽  
Sylvie Kutterer ◽  
Jochen Roeper ◽  
Carmen C. Canavier
Keyword(s):  
Substantia Nigra ◽  
Activity Patterns ◽  
Receptor Activation ◽  
Burst Firing ◽  
Dopamine Neurons ◽  
Open Probability ◽  
Midbrain Dopamine

Burst firing in medial substantia nigra (mSN) dopamine (DA) neurons has been selectively linked to novelty-induced exploration behavior in mice. Burst firing in mSN DA neurons, in contrast to lateral SN DA neurons, requires functional ATP-sensitive potassium (K-ATP) channels both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is unknown. We show experimentally that L-type calcium channel activity in mSN DA neurons enhances open probability of K-ATP channels. We then generate a mathematical model to study the role of Ca2+ dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca2+ influx leads to local accumulation of ADP due to Ca-ATPase activity, which in turn activates K-ATP channels. If K-ATP channel activation reaches levels sufficient to terminate spiking, rhythmic bursting occurs. The model explains the experimental observation that, in vitro, coapplication of NMDA and a selective K-ATP channel opener, NN414, is required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca2+ influx, which increases the activation of K-ATP. The model suggests that additional sources of hyperpolarization, such as GABAergic synaptic input, are recruited in vivo for burst termination or rebound burst discharge. The model predicts that NN414 increases the sensitivity of the K-ATP channel to ADP, promoting burst firing in vitro, and that that high levels of Ca2+ buffering, as might be expected in the calbindin-positive SN DA neuron subpopulation, promote rhythmic bursting pattern, consistent with experimental observations in vivo. NEW & NOTEWORTHY Recently identified distinct subpopulations of midbrain dopamine neurons exhibit differences in their two primary activity patterns in vivo: tonic (single spike) firing and phasic bursting. This study elucidates the biophysical basis of bursts specific to dopamine neurons in the medial substantia nigra, enabled by ATP-sensitive K+ channels and necessary for novelty-induced exploration. A better understanding of how dopaminergic signaling differs between subpopulations may lead to therapeutic strategies selectively targeted to specific subpopulations.

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.

The Role of the cAMP-Response Element in the Bcl-2 Promoter in the Regulation of Endogenous Bcl-2 Expression and Apoptosis in Murine B Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2987-2987
Author(s):  
Hong Xiang ◽  
Linda M. Boxer
Keyword(s):  
B Cells ◽  
Wild Type ◽  
Camp Response Element ◽  
Response Element ◽  
Calcium Dependent ◽  
Flow Cytometric ◽  
Immature B Cells

Abstract We have previously shown in B cell lines that the cAMP-response element (CRE) is a major positive regulatory site in the bcl-2 promoter. This element is not only essential for bcl-2 deregulation in t(14;18) cells, but it is also responsible for the positive regulation of bcl-2 expression during the activation of mature B cells and the rescue of immature B cells from calcium-dependent apoptosis in vitro. However, the role of the CRE in the regulation of endogenous bcl-2 expression in vivo has not been characterized. We used gene targeting to generate knock-in mice in which a mutant CRE site was introduced into the bcl-2 promoter region. The mutant CRE reduced the expression of bcl-2 mRNA in several tissues, including thymus, kidney, lung, liver, brain and heart. The levels of bcl-2 mRNA and protein were also significantly lower in splenic B cells from the knock-in mice. Consistent with these results, the activation of B cells from the knock-in mice by anti-CD 40, lipopolysaccharide (LPS) or anti-IgM was reduced as compared to B cells from wild-type littermates. B cells with the mutant CRE were more susceptible to the induction of apoptosis with several different agents consistent with the decreased expression of bcl-2. Preliminary flow cytometric studies suggest that the number of B cells is decreased in the knock-in mice at 8 weeks of age. Quantitative chromatin immunoprecipitation assays revealed essentially no binding of CREB or ATF-2 and decreased binding of CBP and c-Rel to the mutant CRE site in the bcl-2 promoter. Our previous studies have shown that the CRE site in the bcl-2 promoter is linked to the mediation of signal transduction pathways in B cells, so we investigated the effect of forskolin, a cAMP-elevating agent. We found that treatment of the B cells from the knock-in mice with forskolin led to significantly more cell death than observed with wild-type B cells. Taken together, these findings indicate that the CRE site in the bcl-2 promoter has a functional role in the regulation of endogenous bcl-2 expression and plays an important role in the regulation of apoptosis in B cells.

The role of 5-HT2A receptor antagonism in amphetamine-induced inhibition of A10 dopamine neurons in vitro

2005 ◽  
Vol 520 (1-3) ◽  
pp. 77-85 ◽  
Author(s):  
Johanna E. Olijslagers ◽  
Benny Perlstein ◽  
Taco R. Werkman ◽  
Andrew C. McCreary ◽  
Richard Siarey ◽  
...  
Keyword(s):  
Dopamine Neurons ◽  
Receptor Antagonism

scholarly journals Pharmacological Antagonism of Kainate Receptor Rescues Dysfunction and Loss of Dopamine Neurons in a Mouse Model of Human Parkin-induced Toxicity

2020 ◽  
Author(s):  
Maria Regoni ◽  
Stefano Cattaneo ◽  
Daniela Mercatelli ◽  
Salvatore Novello ◽  
Alice Passoni ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neuroprotective Effect ◽  
Chronic Administration ◽  
Dopamine Neurons ◽  
Kainate Receptors ◽  
Substantia Nigra Pars Compacta ◽  
Gene Encoding ◽  
Neuroprotective Therapy

Abstract BackgroundMutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP), a neurodegenerative disease characterized by dysfunction and death of dopamine (DA) neurons in the substantia nigra pars compacta. Since a neuroprotective therapy for ARJP does not exist, research efforts aimed at discovering potential targets for neuroprotection are critically needed.A previous study demonstrated that loss of parkin function or expression of parkin mutants associated with ARJP causesan accumulation of glutamate kainate receptors (KARs) in human brain tissues and an increase of KAR-mediated currents in neuronsin vitro. MethodsBased on the hypothesisthat such KAR hyper-activation may contribute to the death of nigralDA neurons, we investigated the effect of KAR antagonism on the DA neuron dysfunction and death that occur in the parkinQ311X mouse, a model of human parkin-induced toxicity. ResultsWe found that early accumulation of KARs occurs in the DA neurons of the parkinQ311X mouse model and that chronic administration of the KAR antagonist UBP310 prevents DA neuron loss. This neuroprotective effect was associated with rescue of the abnormal firing rate of nigral DA neurons and downregulation of GluK2, the key KAR subunit. ConclusionsThis study provides novel evidence ofa causal role of glutamate KARs in the DA neuron dysfunction and loss occurring in a mouse model of human parkin-induced toxicity. Our results support KAR as a potential target in the development of a neuroprotective therapy for ARJP.

scholarly journals The Stemness of Human Ovarian Granulosa Cells and the Role of Resveratrol in the Differentiation of MSCs—A Review Based on Cellular and Molecular Knowledge

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1418 ◽  
Author(s):  
Malgorzata Jozkowiak ◽  
Greg Hutchings ◽  
Maurycy Jankowski ◽  
Katarzyna Kulcenty ◽  
Paul Mozdziak ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Granulosa Cells ◽  
Current Knowledge ◽  
Biological Activities ◽  
Primordial Follicle ◽  
Biochemical Processes ◽  
Ovarian Granulosa Cells ◽  
Physiological Properties

Ovarian Granulosa Cells (GCs) are known to proliferate in the developing follicle and undergo several biochemical processes during folliculogenesis. They represent a multipotent cell population that has been differentiated to neuronal cells, chondrocytes, and osteoblasts in vitro. However, progression and maturation of GCs are accompanied by a reduction in their stemness. In the developing follicle, GCs communicate with the oocyte bidirectionally via gap junctions. Together with neighboring theca cells, they play a crucial role in steroidogenesis, particularly the production of estradiol, as well as progesterone following luteinization. Many signaling pathways are known to be important throughout the follicle development, leading either towards luteinization and release of the oocyte, or follicular atresia and apoptosis. These signaling pathways include cAMP, PI3K, SMAD, Hedgehog (HH), Hippo and Notch, which act together in a complex manner to control the maturation of GCs through regulation of key genes, from the primordial follicle to the luteal phase. Small molecules such as resveratrol, a phytoalexin found in grapes, peanuts and other dietary constituents, may be able to activate/inhibit these signaling pathways and thereby control physiological properties of GCs. This article reviews the current knowledge about granulosa stem cells, the signaling pathways driving their development and maturation, as well as biological activities of resveratrol and its properties as a pro-differentiation agent.

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