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 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 Neurexins Regulate GABA Co-release by Dopamine Neurons

2021 ◽  
Author(s):  
Charles Ducrot ◽  
Gregory de Carvalho ◽  
Benoit Delignat-Lavaud ◽  
Constantin Delmas ◽  
Nicolas Giguere ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dopamine Neurons ◽  
Electrophysiological Recording ◽  
Conditional Deletion ◽  
Synaptic Cell Adhesion Molecules ◽  
Midbrain Dopamine ◽  
Neuron Terminals ◽  
Reduced Rate ◽  
Activity Dependent ◽  
Da Release

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) revealed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings reveal that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions.

The Role of Vitamin D3 in the Development and Neuroprotection of Midbrain Dopamine Neurons

2016 ◽  
pp. 273-297 ◽  
Author(s):  
Rowan P. Orme ◽  
Charlotte Middleditch ◽  
Lauren Waite ◽  
Rosemary A. Fricker
Keyword(s):  
Vitamin D3 ◽  
Dopamine Neurons ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

scholarly journals A role of midbrain dopamine neurons in negative punishment

IBRO Reports ◽  
2019 ◽  
Vol 6 ◽  
pp. S193
Author(s):  
Constance Peng ◽  
Philip Jean-Richard Dit Bressel ◽  
Gavan Mcnally
Keyword(s):  
Dopamine Neurons ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

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.

scholarly journals Inhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice

Bone Research ◽  
2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Zuqiang Wang ◽  
Hangang Chen ◽  
Qiaoyan Tan ◽  
Junlan Huang ◽  
Siru Zhou ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Genetic Ablation ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Current Therapies ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Deficient Mice

AbstractThe intervertebral disc (IVD) is the largest avascular tissue. Hypoxia-inducible factors (HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease (DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate (EP) and annulus fibrosus (AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol (2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

scholarly journals HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Peng Zhong ◽  
Casey R Vickstrom ◽  
Xiaojie Liu ◽  
Ying Hu ◽  
Laikang Yu ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Chronic Stress ◽  
Ex Vivo ◽  
Critical Role ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Hcn Channels ◽  
Neuron Firing ◽  
Ventral Tegmental

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related 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.

Evidence for a modulatory role of Ih on the firing of a subgroup of midbrain dopamine neurons

Neuroreport ◽  
2001 ◽  
Vol 12 (2) ◽  
pp. 255-258 ◽  
Author(s):  
Vincent Seutin ◽  
Laurent Massotte ◽  
Michel-François Renette ◽  
Albert Dresse
Keyword(s):  
Dopamine Neurons ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

scholarly journals Basal forebrain mediates prosocial behavior via disinhibition of midbrain dopamine neurons

2021 ◽  
Vol 118 (7) ◽  
pp. e2019295118
Author(s):  
Jun Wang ◽  
Jie Li ◽  
Qian Yang ◽  
Ya-Kai Xie ◽  
Ya-Lan Wen ◽  
...  
Keyword(s):  
Social Interaction ◽  
Prosocial Behavior ◽  
Basal Forebrain ◽  
Social Preference ◽  
Dopamine Neurons ◽  
Inhibitory Neurons ◽  
Axon Terminals ◽  
Midbrain Dopamine ◽  
Da Release

Sociability is fundamental for our daily life and is compromised in major neuropsychiatric disorders. However, the neuronal circuit mechanisms underlying prosocial behavior are still elusive. Here we identify a causal role of the basal forebrain (BF) in the control of prosocial behavior via inhibitory projections that disinhibit the midbrain ventral tegmental area (VTA) dopamine (DA) neurons. Specifically, BF somatostatin-positive (SST) inhibitory neurons were robustly activated during social interaction. Optogenetic inhibition of these neurons in BF or their axon terminals in the VTA largely abolished social preference. Electrophysiological examinations further revealed that SST neurons predominantly targeted VTA GABA neurons rather than DA neurons. Consistently, optical inhibition of SST neuron axon terminals in the VTA decreased DA release in the nucleus accumbens during social interaction, confirming a disinhibitory action. These data reveal a previously unappreciated function of the BF in prosocial behavior through a disinhibitory circuitry connected to the brain’s reward system.

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