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.

Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

2021 ◽  
Vol 118 (40) ◽  
pp. e2111069118
Author(s):  
Theodoros Tsetsenis ◽  
Julia K. Badyna ◽  
Julianne A. Wilson ◽  
Xiaowen Zhang ◽  
Elizabeth N. Krizman ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dorsal Hippocampus ◽  
Memory Formation ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Aversive Learning ◽  
Contextual Fear ◽  
Dopaminergic Transmission ◽  
Midbrain Dopaminergic Neurons ◽  
Midbrain Dopamine

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

scholarly journals Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice

2018 ◽  
Vol 115 (49) ◽  
pp. E11532-E11541 ◽  
Author(s):  
Hui Shen ◽  
Rosa Anna M. Marino ◽  
Ross A. McDevitt ◽  
Guo-Hua Bi ◽  
Kai Chen ◽  
...  
Keyword(s):  
Glutamate Release ◽  
Glutamate Transporter ◽  
Dopamine Neurons ◽  
Therapeutic Interventions ◽  
Vesicular Glutamate Transporter ◽  
Increased Risk ◽  
Locomotor Impairment ◽  
Functional Consequences ◽  
Midbrain Dopamine ◽  
And Function

A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson’s disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.

scholarly journals Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

2018 ◽  
Author(s):  
Polina Kosillo ◽  
Natalie M. Doig ◽  
Alexander H.C.W. Agopyan-Miu ◽  
Kamran Ahmed ◽  
Lisa Conyers ◽  
...  
Keyword(s):  
Critical Role ◽  
Dopamine Neurons ◽  
Negative Regulator ◽  
Gene Encoding ◽  
Cognitive Behaviors ◽  
High Prevalence ◽  
Midbrain Dopamine ◽  
And Function ◽  
Mtor Complex 1 ◽  
Midbrain Dopamine Neurons

SummarymTOR complex 1 (mTORC1) is a central coordinator of cell growth and metabolism. Mutations in regulators of mTORC1 cause syndromic disorders with a high prevalence of cognitive and psychiatric conditions. To elucidate the cellular origins of these manifestations, we conditionally deleted the gene encoding the mTORC1 negative regulator Tsc1 from mouse midbrain dopamine neurons, which modulate motor, affective, and cognitive behaviors that are frequently affected in psychiatric disorders. Loss of Tsc1 and constitutive activation of mTORC1 strongly impacted the properties of dopamine neurons, causing somatodendritic hypertrophy, reduced intrinsic excitability, altered axon terminal ultrastructure, and severely impaired dopamine release. These perturbations were associated with selective deficits in cognitive flexibility, which could be prevented by genetic reduction of the obligatory mTORC1 protein Raptor. Our results establish a critical role for mTORC1 in setting the functional properties of midbrain dopamine neurons, and indicate that dopaminergic dysfunction may underlie cognitive inflexibility in mTOR-related syndromes.

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 An exceptionally preserved armored dinosaur reveals the morphology and allometry of osteoderms and their horny epidermal coverings

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e4066 ◽  
Author(s):  
Caleb M. Brown
Keyword(s):  
Allometric Scaling ◽  
Soft Tissues ◽  
Organic Residues ◽  
Spine Length ◽  
Relative Contribution ◽  
Specific Morphology ◽  
Allometric Analysis ◽  
Species Specific ◽  
And Function ◽  
Basal Length

Although the evolution and function of “exaggerated” bony projections in ornithischian dinosaurs has been subject to significant debate recently, our understanding of the structure and morphology of their epidermal keratinized coverings is greatly limited. The holotype ofBorealopelta, a new nodosaurid ankylosaur, preserves osteoderms and extensive epidermal structures (dark organic residues), in anatomic position across the entire precaudal length. Contrasting previous specimens, organic epiosteodermal scales, often in the form of horn-like (keratinous) sheaths, cap and exaggerate nearly all osteoderms, allowing for morphometric and allometric analyses of both the bony osteoderms and their horny sheaths. A total of 172 osteoderms were quantified, with osteoderm spine length and height being positively allometric with respect to basal length and width. Despite tight correlations between the different measures amongst all other osteoderms, the large parascapular spines represent consistent outliers. Thickness and relative contribution of the keratinized epiosteodermal scales/sheaths varies greatly by region, ranging from 2% to 6% for posterior thoracics, to ∼25% (1.3×) for the parascapular spines—similar to horn sheaths in some bovid analogues. Relative to the bony cores, the horny portions of the spines are strongly positively allometric (slope = 2.3, CI = 1.8–2.8). Strong allometric scaling, species-specific morphology, and significant keratinous extension of the cervicoscapular spines is consistent with elaboration under socio-sexual selection. This marks the first allometric analysis of ornithischian soft tissues.

scholarly journals Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Nicolas X Tritsch ◽  
Won-Jong Oh ◽  
Chenghua Gu ◽  
Bernardo L Sabatini
Keyword(s):  
Dopaminergic Neurons ◽  
De Novo ◽  
Dopamine Neurons ◽  
Gaba Uptake ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Gaba Transporters ◽  
Midbrain Dopamine ◽  
Nigrostriatal Dopamine Neurons ◽  
Midbrain Dopamine Neurons

Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.

scholarly journals Generation of a DAT-Flp mouse line for intersectional genetic targeting of dopamine neuron subpopulations

2020 ◽  
Author(s):  
Daniel J. Kramer ◽  
Polina Kosillo ◽  
Drew Friedmann ◽  
David Stafford ◽  
Liqun Luo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dopaminergic Neurons ◽  
Single Gene ◽  
Dopamine Neurons ◽  
Mouse Line ◽  
Flp Recombinase ◽  
And Function ◽  
Genetic Targeting ◽  
The Brain ◽  
Mouse Lines

AbstractDopamine neurons project to diverse regions throughout the brain to modulate various brain processes and behaviors. It is increasingly appreciated that dopamine neurons are heterogeneous in their gene expression, circuitry, physiology, and function. Current approaches to target dopamine neurons are largely based on single gene drivers, which either label all dopamine neurons, or mark a sub-set but concurrently label non-dopaminergic neurons. Here we establish a novel mouse line in which Flp recombinase is knocked-in to the endogenous Slc6a3 (dopamine active transporter, DAT) locus. DAT-Flp mice can be used with various Cre-expressing mouse lines to efficiently and selectively label dopaminergic subpopulations using Cre/Flp-dependent intersectional strategies. We demonstrate the utility of this approach by crossing DAT-Flp mice with NEX-Cre mice, to specifically label Neurod6-expressing dopamine neurons that project to the nucleus accumbens medial shell. DAT-Flp mice represent a novel tool, which will help parse the diverse functions mediated by dopaminergic circuits.

scholarly journals Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons

Science ◽  
2015 ◽  
Vol 350 (6256) ◽  
pp. 102-106 ◽  
Author(s):  
Jae-Ick Kim ◽  
Subhashree Ganesan ◽  
Sarah X. Luo ◽  
Yu-Wei Wu ◽  
Esther Park ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Dopaminergic Neurons ◽  
Dopamine Neurons ◽  
Inhibitory Neurotransmitter ◽  
Midbrain Dopaminergic Neurons ◽  
Evolutionarily Conserved ◽  
Gaba Synthesis ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.

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