scholarly journals In vivo functional diversity of midbrain dopamine neurons within identified axonal projections

2019 ◽  
Author(s):  
Navid Farassat ◽  
Kauê M. Costa ◽  
Stefan Albert ◽  
Lora Kovacheva ◽  
Josef Shin ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Functional Diversity ◽  
Multiple Scales ◽  
Dopamine Neurons ◽  
Unit Recording ◽  
Data Set ◽  
Midbrain Dopamine ◽  
Firing Properties

AbstractThe functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and synaptic connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and juxtacellular labelling in mouse brain to create the first single cell-resolved in vivo functional topography of the midbrain DA system. We identified surprising differences in burst firing among those DA neurons projecting to dorsolateral striatum, which were organized along the medio-lateral substantia nigra (SN) axis. Furthermore, burst properties also differentiated DA neurons in the medial SN that projected either to dorsal or ventral striatum. In contrast, DA neurons projecting to lateral shell of nucleus accumbens displayed identical firing properties, irrespective of whether they were located in the SN or ventral tegmental area (VTA), thus breaching classical anatomical boundaries. Finally, we found robust differences in mean firing rates and pause durations among VTA DA neurons projecting to either lateral or medial shell of nucleus accumbens. Together, our data set establishes a high-resolution functional landscape of midbrain DA neurons, which will facilitate the identification of selective functions and pathophysiological changes within the midbrain DA system.

scholarly journals In vivo functional diversity of midbrain dopamine neurons within identified axonal projections

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Navid Farassat ◽  
Kauê Machado Costa ◽  
Strahinja Stojanovic ◽  
Stefan Albert ◽  
Lora Kovacheva ◽  
...  
Keyword(s):  
Functional Diversity ◽  
Multiple Scales ◽  
Dopamine Neurons ◽  
Unit Recording ◽  
Axonal Projections ◽  
Intact Brain ◽  
Functional Topography ◽  
Midbrain Dopamine

Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create an in vivo functional topography of the midbrain DA system. We identified differences in burst firing among DA neurons projecting to dorsolateral striatum. Bursting also differentiated DA neurons in the medial substantia nigra (SN) projecting either to dorsal or ventral striatum. We found differences in mean firing rates and pause durations among ventral tegmental area (VTA) DA neurons projecting to lateral or medial shell of nucleus accumbens. Our data establishes a high-resolution functional in vivo landscape of midbrain DA neurons.

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.

scholarly journals Author response: In vivo functional diversity of midbrain dopamine neurons within identified axonal projections

2019 ◽  
Author(s):  
Navid Farassat ◽  
Kauê Machado Costa ◽  
Strahinja Stojanovic ◽  
Stefan Albert ◽  
Lora Kovacheva ◽  
...  
Keyword(s):  
Functional Diversity ◽  
Dopamine Neurons ◽  
Author Response ◽  
Axonal Projections ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

Hyperlocomotion during Recovery from Isoflurane Anesthesia Is Associated with Increased Dopamine Turnover in the Nucleus Accumbens and Striatum in Mice

1997 ◽  
Vol 86 (2) ◽  
pp. 464-475 ◽  
Author(s):  
Masahiro Irifune ◽  
Tomoaki Sato ◽  
Takashige Nishikawa ◽  
Takashi Masuyama ◽  
Masahiro Nomoto ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Nucleus Accumbens ◽  
High Performance ◽  
Gas Flow ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Dopamine Turnover

Background It was recently reported that isoflurane increases dopamine release in the striatum in rats both in vivo and in vitro, and that isoflurane inhibits uptake of dopamine in the rat brain synaptosomes. However, the functional role of these effects of isoflurane on dopamine neurons is uncertain. Dopaminergic mechanisms within the nucleus accumbens and striatum play an important role in the control of locomotor activity, and a change in dopamine turnover depends essentially on a change in impulse flow in the dopamine neurons. In this study, the effects of isoflurane on locomotor activity and on dopamine turnover were investigated in discrete brain regions in mice. Methods Mice were placed in individual airtight clear plastic chambers and spontaneously breathed isoflurane in 25% oxygen and 75% nitrogen (fresh gas flow, 4 l/min). Locomotor activity was measured with an Animex activity meter. Animals were decapitated after treatments with or without isoflurane, and the concentrations of monoamines and their metabolites in different brain areas were measured by high-performance liquid chromatography. Results During the 10 min after the cessation of the 20-min exposure to isoflurane, there was a significant increase in locomotor activity in animals breathing 1.5% isoflurane but not 0.7% isoflurane. This increase in locomotor activity produced by 1.5% isoflurane was abolished by a low dose of haloperidol (0.1 mg/kg), a dopamine receptor antagonist. Regional brain monoamine assays revealed that 1.5% isoflurane significantly increased the 3,4-dihydroxyphenylacetic acid:dopamine ratio (one indicator of transmitter turnover) in the nucleus accumbens and striatum, but a concentration of 0.7% did not. This significant increase in dopamine turnover in these regions continued during 20 min after the cessation of the administration of 1.5% isoflurane. Conclusions These results suggest that isoflurane-induced hyperlocomotion during emergence may be associated with increased dopamine turnover in the nucleus accumbens and striatum.

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 Inactivation mode of sodium channels defines the different maximal firing rates of conventional versus atypical midbrain dopamine neurons

2021 ◽  
Vol 17 (9) ◽  
pp. e1009371
Author(s):  
Christopher J. Knowlton ◽  
Tabea Ines Ziouziou ◽  
Niklas Hammer ◽  
Jochen Roeper ◽  
Carmen C. Canavier
Keyword(s):  
Nucleus Accumbens ◽  
Action Potential ◽  
Sodium Channels ◽  
Dynamic Range ◽  
Dopamine Neurons ◽  
Action Potential Firing ◽  
Depolarization Block ◽  
Midbrain Dopamine

Two subpopulations of midbrain dopamine (DA) neurons are known to have different dynamic firing ranges in vitro that correspond to distinct projection targets: the originally identified conventional DA neurons project to the dorsal striatum and the lateral shell of the nucleus accumbens, whereas an atypical DA population with higher maximum firing frequencies projects to prefrontal regions and other limbic regions including the medial shell of nucleus accumbens. Using a computational model, we show that previously identified differences in biophysical properties do not fully account for the larger dynamic range of the atypical population and predict that the major difference is that originally identified conventional cells have larger occupancy of voltage-gated sodium channels in a long-term inactivated state that recovers slowly; stronger sodium and potassium conductances during action potential firing are also predicted for the conventional compared to the atypical DA population. These differences in sodium channel gating imply that longer intervals between spikes are required in the conventional population for full recovery from long-term inactivation induced by the preceding spike, hence the lower maximum frequency. These same differences can also change the bifurcation structure to account for distinct modes of entry into depolarization block: abrupt versus gradual. The model predicted that in cells that have entered depolarization block, it is much more likely that an additional depolarization can evoke an action potential in conventional DA population. New experiments comparing lateral to medial shell projecting neurons confirmed this model prediction, with implications for differential synaptic integration in the two populations.

Simvastatin Prevents Neurodegeneration in the MPTP Mouse Model of Parkinson’s Disease via Inhibition of A1 Reactive Astrocytes

2021 ◽  
pp. 1-8
Author(s):  
Ren-Wei Du ◽  
Wen-Guang Bu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Underlying Mechanism ◽  
Reactive Astrocytes ◽  
Dopamine Neurons ◽  
Neuron Death ◽  
Neurologic Disorders

Emerging evidence indicates that A1 reactive astrocytes play crucial roles in the pathogenesis of Parkinson’s disease (PD). Thus, development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat PD. Simvastatin has been touted as a potential neuroprotective agent for neurologic disorders such as PD, but the specific underlying mechanism remains unclear. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and primary astrocytes/neurons were prepared to investigate the effects of simvastatin on PD and its underlying mechanisms in vitro and in vivo. We show that simvastatin protects against the loss of dopamine neurons and behavioral deficits in the MPTP mouse model of PD. We also found that simvastatin suppressed the expression of A1 astrocytic specific markers in vivo and in vitro. In addition, simvastatin alleviated neuron death induced by A1 astrocytes. Our findings reveal that simvastatin is neuroprotective via the prevention of conversion of astrocytes to an A1 neurotoxic phenotype. In light of simvastatin favorable properties, it should be evaluated in the treatment of PD and related neurologic disorders characterized by A1 reactive astrocytes.

Sign in / Sign up

Export Citation Format

Share Document