scholarly journals Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2

2021 ◽  
Author(s):  
Polina Kosillo ◽  
Kamran M. Ahmed ◽  
Bradley M. Roberts ◽  
Stephanie J. Cragg ◽  
Helen S. Bateup
Keyword(s):  
Therapeutic Strategies ◽  
Structure And Function ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Intrinsic Excitability ◽  
Brain Disorders ◽  
Neuron Morphology ◽  
Midbrain Dopamine ◽  
And Function ◽  
Specific Deletion

The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties and whether they act together or independently is unknown. Here we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. As mTOR is involved in several brain disorders caused by dopaminergic dysregulation including Parkinson's disease and addiction, our results have implications for understanding the pathophysiology and potential therapeutic strategies for these diseases.

scholarly journals Deletion of the alternative splice variant KChIP4a in midbrain dopamine neurons selectively enhances extinction learning

2018 ◽  
Author(s):  
Kauê Machado Costa ◽  
Jochen Roeper
Keyword(s):  
Splice Variant ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Prediction Errors ◽  
Β Subunit ◽  
Extinction Learning ◽  
Negative Prediction ◽  
Midbrain Dopamine ◽  
Specific Deletion ◽  
Midbrain Dopamine Neurons

AbstractInhibition of midbrain dopamine neurons is thought to underlie the signaling of events that are less rewarding than expected and drive learning based on these negative prediction errors. It has recently been shown that Kv4.3 channels influence the integration of inhibitory inputs in specific subpopulations of dopamine neurons. The functional properties of Kv4.3 channels are themselves strongly determined by the binding of auxiliary β-subunits; among them KChIP4a stands-out for its unique combination of modulatory effects. These include decreasing surface membrane trafficking and slowing inactivation kinetics. Therefore, we hypothesized that KChIP4a expression in dopamine neurons could play a crucial role in behavior, in particular by affecting the computation of negative prediction errors. We developed a mouse line where the alternative exon that codes for the KChIP4a splice variant was selectively deleted in midbrain dopamine neurons. In a reward-based reinforcement learning task, we observed that dopamine neuron-specific KChIP4a deletion selectively accelerated the rate of extinction learning, without impacting the acquisition of conditioned responses. We further found that this effect was due to a faster decrease in the initiation rate of goal-directed behaviors, and not faster increases in action disengagement. Furthermore, computational fitting of the behavioral data with a Rescorla-Wagner model confirmed that the observed phenotype was attributable to a selective increase in the learning rate from negative prediction errors. Finally, KChIP4a deletion did not affect performance in other dopamine-sensitive behavioral tasks that did not involve learning from disappointing events, including an absence of effects on working memory, locomotion and novelty preference. Taken together, our results demonstrate that an exon- and midbrain dopamine neuron-specific deletion of an A-type K+ channel β-subunit leads to a selective gain of function in extinction learning.One Sentence SummaryExon- and midbrain dopamine neuron-specific deletion of the Kv4 channel β-subunit KChIP4a selectively accelerates extinction learning

scholarly journals Endogenous Mammalian Cardiotonic Steroids—A New Cardiovascular Risk Factor?—A Mini-Review

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 727
Author(s):  
Natalia Słabiak-Błaż ◽  
Grzegorz Piecha
Keyword(s):  
Adenosine Triphosphatase ◽  
Therapeutic Strategies ◽  
Structure And Function ◽  
Sodium Potassium ◽  
Sodium Homeostasis ◽  
Cardiovascular Tissue ◽  
Ancient Times ◽  
And Function ◽  
Regulation Of Blood Pressure

The role of endogenous mammalian cardiotonic steroids (CTS) in the physiology and pathophysiology of the cardiovascular system and the kidneys has interested researchers for more than 20 years. Cardiotonic steroids extracted from toads or plants, such as digitalis, have been used to treat heart disease since ancient times. CTS, also called endogenous digitalis-like factors, take part in the regulation of blood pressure and sodium homeostasis through their effects on the transport enzyme called sodium–potassium adenosine triphosphatase (Na/K-ATPase) in renal and cardiovascular tissue. In recent years, there has been increasing evidence showing deleterious effects of CTS on the structure and function of the heart, vasculature and kidneys. Understanding the role of CTS may be useful in the development of potential new therapeutic strategies.

scholarly journals Electrical and Ca2+ signaling in dendritic spines of substantia nigra dopaminergic neurons

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Travis A Hage ◽  
Yujie Sun ◽  
Zayd M Khaliq
Keyword(s):  
Dendritic Spines ◽  
Dopaminergic Neurons ◽  
Fluorescence Recovery After Photobleaching ◽  
Dopamine Neurons ◽  
Fixed Tissue ◽  
Spine Length ◽  
Relative Contribution ◽  
Midbrain Dopamine ◽  
Shaft Synapses ◽  
And Function

Little is known about the density and function of dendritic spines on midbrain dopamine neurons, or the relative contribution of spine and shaft synapses to excitability. Using Ca2+ imaging, glutamate uncaging, fluorescence recovery after photobleaching and transgenic mice expressing labeled PSD-95, we comparatively analyzed electrical and Ca2+ signaling in spines and shaft synapses of dopamine neurons. Dendritic spines were present on dopaminergic neurons at low densities in live and fixed tissue. Uncaging-evoked potential amplitudes correlated inversely with spine length but positively with the presence of PSD-95. Spine Ca2+ signals were less sensitive to hyperpolarization than shaft synapses, suggesting amplification of spine head voltages. Lastly, activating spines during pacemaking, we observed an unexpected enhancement of spine Ca2+ midway throughout the spike cycle, likely involving recruitment of NMDA receptors and voltage-gated conductances. These results demonstrate functionality of spines in dopamine neurons and reveal a novel modulation of spine Ca2+ signaling during pacemaking.

scholarly journals Purity and Enrichment of Laser-Microdissected Midbrain Dopamine Neurons

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Amanda L. Brown ◽  
Trevor A. Day ◽  
Christopher V. Dayas ◽  
Doug W. Smith
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Acid Decarboxylase ◽  
Cell Groups ◽  
Midbrain Dopamine ◽  
High Degree ◽  
Midbrain Dopamine Neurons

The ability to microdissect individual cells from the nervous system has enormous potential, as it can allow for the study of gene expression in phenotypically identified cells. However, if the resultant gene expression profiles are to be accurately ascribed, it is necessary to determine the extent of contamination by nontarget cells in the microdissected sample. Here, we show that midbrain dopamine neurons can be laser-microdissected to a high degree of enrichment and purity. The average enrichment for tyrosine hydroxylase (TH) gene expression in the microdissected sample relative to midbrain sections was approximately 200-fold. For the dopamine transporter (DAT) and the vesicular monoamine transporter type 2 (Vmat2), average enrichments were approximately 100- and 60-fold, respectively. Glutamic acid decarboxylase (Gad65) expression, a marker for GABAergic neurons, was several hundredfold lower than dopamine neuron-specific genes. Glial cell and glutamatergic neuron gene expression were not detected in microdissected samples. Additionally, SN and VTA dopamine neurons had significantly different expression levels of dopamine neuron-specific genes, which likely reflects functional differences between the two cell groups. This study demonstrates that it is possible to laser-microdissect dopamine neurons to a high degree of cell purity. Therefore gene expression profiles can be precisely attributed to the targeted microdissected cells.

Molecular mechanisms underlying midbrain dopamine neuron development and function

2003 ◽  
Vol 480 (1-3) ◽  
pp. 75-88 ◽  
Author(s):  
Marten P. Smidt ◽  
Simone M. Smits ◽  
J.Peter H. Burbach
Keyword(s):  
Molecular Mechanisms ◽  
Dopamine Neuron ◽  
Neuron Development ◽  
Midbrain Dopamine ◽  
And Function

scholarly journals Instantiation of incentive value and movement invigoration by distinct midbrain dopamine circuits

2017 ◽  
Author(s):  
Benjamin T. Saunders ◽  
Jocelyn M. Richard ◽  
Elyssa B. Margolis ◽  
Patricia H. Janak
Keyword(s):  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Temporal Association ◽  
Conditioned Stimuli ◽  
Incentive Value ◽  
Pavlovian Learning ◽  
Midbrain Dopamine ◽  
Dopamine Circuits

Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals towards the acquisition of “rewards” (i.e., food) that are necessary for survival. Here, we test the fundamental role of midbrain dopamine neurons in conferring predictive or motivational properties to cues, independent of external rewards. We demonstrate that phasic optogenetic excitation of dopamine neurons throughout the midbrain, when presented in temporal association with discrete sensory cues, is sufficient to instantiate those cues as conditioned stimuli that subsequently both evoke dopamine neuron activity on their own, and elicit cue-locked conditioned behaviors. Critically, we identify highly parcellated behavioral functions for dopamine neuron subpopulations projecting to discrete regions of striatum, revealing dissociable mesostriatal systems for the generation of incentive value and movement invigoration. These results show that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to shape cue-controlled behavior.

scholarly journals Dopamine neuron-derived IGF-1 controls dopamine neuron firing, skill learning, and exploration

2019 ◽  
Vol 116 (9) ◽  
pp. 3817-3826 ◽  
Author(s):  
Alessandro Pristerà ◽  
Craig Blomeley ◽  
Emanuel Lopes ◽  
Sarah Threlfell ◽  
Elisa Merlini ◽  
...  
Keyword(s):  
Cognitive Processes ◽  
Skill Learning ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Firing ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Dopamine Content ◽  
Midbrain Dopamine

Midbrain dopamine neurons, which can be regulated by neuropeptides and hormones, play a fundamental role in controlling cognitive processes, reward mechanisms, and motor functions. The hormonal actions of insulin-like growth factor 1 (IGF-1) produced by the liver have been well described, but the role of neuronally derived IGF-1 remains largely unexplored. We discovered that dopamine neurons secrete IGF-1 from the cell bodies following depolarization, and that IGF-1 controls release of dopamine in the ventral midbrain. In addition, conditional deletion of dopamine neuron-derived IGF-1 in adult mice leads to decrease of dopamine content in the striatum and deficits in dopamine neuron firing and causes reduced spontaneous locomotion and impairments in explorative and learning behaviors. These data identify that dopamine neuron-derived IGF-1 acts as a regulator of dopamine neurons and regulates dopamine-mediated behaviors.

scholarly journals Dopamine Neuron Responses Depend Exponentially on Pacemaker Interval

2009 ◽  
Vol 101 (2) ◽  
pp. 926-933 ◽  
Author(s):  
Ilva Putzier ◽  
Paul H. M. Kullmann ◽  
John P. Horn ◽  
Edwin S. Levitan
Keyword(s):  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Inhibitory Synapses ◽  
Neuron Activity ◽  
Exponential Dependence ◽  
Mathematical Form ◽  
Short And Long Term ◽  
Midbrain Dopamine ◽  
Cell Variation ◽  
The Impact

Midbrain dopamine neuron activity results from the integration of the responses to metabo- and ionotropic receptors with the postsynaptic excitability of these intrinsic pacemakers. Interestingly, intrinsic pacemaker rate varies greatly between individual dopamine neurons and is subject to short- and long-term regulation. Here responses of substantia nigra dopamine neurons to defined dynamic-clamp stimuli were measured to quantify the impact of cell-to-cell variation in intrinsic pacemaker rate. Then this approach was repeated in single dopamine neurons in which pacemaker rate was altered by activation of muscarinic receptors or current injection. These experiments revealed a dramatic exponential dependence on pacemaker interval for the responses to voltage-gated A-type K+ channels, voltage-independent cation channels and ionotropic synapses. Likewise, responses to native metabotropic (GABAb and mGluR1) inhibitory synapses depended steeply on pacemaker interval. These results show that observed variations in dopamine neuron pacemaker rate are functionally significant because they produce a >10-fold difference in responses to diverse stimuli. Both the magnitude and the mathematical form of the relationship between pacemaker interval and responses were not previously anticipated.

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