Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels

In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca2+) concentration, thus reducing the Ca2+-dependent potassium (K+) current. In this way, the GABA-mediated hyperpolarization replaces Ca2+-dependent K+ current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally.

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Both Estrogen and Androgen Modify the Response to Activation of Neurokinin-3 and κ-Opioid Receptors in Arcuate Kisspeptin Neurons From Male Mice

Endocrinology ◽

10.1210/en.2015-1688 ◽

2015 ◽

Vol 157 (2) ◽

pp. 752-763 ◽

Cited By ~ 17

Author(s):

Kristen A. Ruka ◽

Laura L. Burger ◽

Suzanne M. Moenter

Keyword(s):

Estrogen Receptor ◽

Firing Pattern ◽

Pulse Generator ◽

Brain Slices ◽

Gonadal Steroids ◽

Gnrh Neuron ◽

Male Mice ◽

Neurokinin B ◽

Neuron Firing ◽

Kndy Neurons

Abstract Gonadal steroids regulate the pattern of GnRH secretion. Arcuate kisspeptin (kisspeptin, neurokinin B, and dynorphin [KNDy]) neurons may convey steroid feedback to GnRH neurons. KNDy neurons increase action potential firing upon the activation of neurokinin B receptors (neurokinin-3 receptor [NK3R]) and decrease firing upon the activation of dynorphin receptors (κ-opioid receptor [KOR]). In KNDy neurons from intact vs castrated male mice, NK3R-mediated stimulation is attenuated and KOR-mediated inhibition enhanced, suggesting gonadal secretions are involved. Estradiol suppresses spontaneous GnRH neuron firing in male mice, but the mediators of the effects on firing in KNDy neurons are unknown. We hypothesized the same gonadal steroids affecting GnRH firing pattern would regulate KNDy neuron response to NK3R and KOR agonists. To test this possibility, extracellular recordings were made from KNDy neurons in brain slices from intact, untreated castrated or castrated adult male mice treated in vivo with steroid receptor agonists. As observed previously, the stimulation of KNDy neurons by the NK3R agonist senktide was attenuated in intact vs castrated mice and suppression by dynorphin was enhanced. In contrast to observations of steroid effects on the GnRH neuron firing pattern, both estradiol and DHT suppressed senktide-induced KNDy neuron firing and enhanced the inhibition caused by dynorphin. An estrogen receptor-α agonist but not an estrogen receptor-β agonist mimicked the effects of estradiol on NK3R activation. These observations suggest the steroid modulation of responses to activation of NK3R and KOR as mechanisms for negative feedback in KNDy neurons and support the contribution of these neurons to steroid-sensitive elements of a GnRH pulse generator.

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Optimization of Rhythmic Behaviors by Modulation of the Neuromuscular Transform

Journal of Neurophysiology ◽

10.1152/jn.2000.83.1.260 ◽

2000 ◽

Vol 83 (1) ◽

pp. 260-279 ◽

Cited By ~ 32

Author(s):

Vladimir Brezina ◽

Irina V. Orekhova ◽

Klaudiusz R. Weiss

Keyword(s):

Motor Neuron ◽

Firing Pattern ◽

Critical Role ◽

Neuron Firing ◽

Functional Behavior ◽

Rhythmic Behavior ◽

Multiple Behaviors ◽

Intrinsic Plasticity ◽

Rhythmic Behaviors

We conclude our study of the properties and the functional role of the neuromuscular transform (NMT). The NMT is an input-output relation that formalizes the processes by which patterns of motor neuron firing are transformed to muscle contractions. Because the NMT acts as a dynamic, nonlinear, and modifiable filter, the transformation is complex. In the two preceding papers we developed a framework for analysis of the NMT and identified with it principles by which the NMT transforms different firing patterns to contractions. We then saw that, with fixed properties, the NMT significantly constrains the production of functional behavior. Many desirable behaviors are not possible with any firing pattern. Here we examine, theoretically as well as experimentally in the accessory radula closer (ARC) neuromuscular system of Aplysia, how this constraint is alleviated by making the properties of the NMT variable by neuromuscular plasticity and modulation. These processes dynamically tune the properties of the NMT to match the desired behavior, expanding the range of behaviors that can be produced. For specific illustration, we continue to focus on the relation between the speed of the NMT and the speed of cyclical, rhythmic behavior. Our analytic framework emphasizes the functional distinction between intrinsic plasticity or modulation of the NMT, dependent, like the contraction itself, on the motor neuron firing pattern, and extrinsic modulation, independent of it. The former is well suited to automatically optimizing the performance of a single behavior; the latter, to multiplying contraction shapes for multiple behaviors. In any case, to alleviate the constraint of the NMT, the plasticity and modulation must be peripheral. Such processes are likely to play a critical role wherever the nervous system must command, through the constraint of the NMT, a broad range of functional behaviors.

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GABAA and GABAB antagonists differentially affect the firing pattern of substantia nigra dopaminergic neurons in vivo

Synapse ◽

10.1002/(sici)1098-2396(19990601)32:3<165::aid-syn3>3.0.co;2-n ◽

1999 ◽

Vol 32 (3) ◽

pp. 165-176 ◽

Cited By ~ 103

Author(s):

Carlos A. Paladini ◽

James M. Tepper

Keyword(s):

Substantia Nigra ◽

Dopaminergic Neurons ◽

Firing Pattern ◽

Gabab Antagonists

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Camptothecin regulates microglia polarization and exerts neuroprotective effects via the AKT/Nrf2/HO-1-NF-κB signal axis in vivo and in vitro

10.21203/rs.3.rs-27607/v1 ◽

2020 ◽

Author(s):

dewei he ◽

dianfeng liu ◽

ang zhou ◽

xiyu gao ◽

yufei zhang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Cell Line ◽

Dopaminergic Neuron ◽

Inflammatory Responses ◽

Neuroprotective Effects ◽

Microglia Polarization

Abstract Background Parkinson's disease (PD), the second largest neurodegenerative disease seriously affects human health. Microglia, the main immune cells in the brain participate in the innate immune response in the central nervous system (CNS). Studies have shown that microglia can be polarized into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. Accumulated evidences suggest that over-activated M1 microglia release pro-inflammatory mediators that damage neurons and lead to Parkinson's disease (PD). In contrast, M2 microglia release neuroprotective factors and exert the effects of neuroprotection. Camptothecin (CPT), an extract of the plant Camptotheca acuminate, has been reported to have anti-inflammation and antitumor effects. However the effect of CPT on microglia polarization and microglia-mediated inflammation responses has not been reported. Therefore, we aim to explore the effect of CPT on microglia polarization and its underlying mechanism on neuroinflammation. Methods C57BL/6 mice (25–30 g) were injected LPS or PBS into the substantia nigra (SN). Open-Field Test and Immunohistochemistry were performed to test the dyskinesia of mice and the loss of neurons in the substantia nigra (SN). Microglia cell line BV-2, the neuroblastoma SH-SY5Y and dopaminergic neuron MN9D cell were cultured. Cytotoxicity assay, reverse transcription quantitative real-time polymerase chain reaction (RT-PCR), Western blot, ELISA and Immunofluorescence staining were performed. All results were presented with mean ± SD. Results In vivo, CPT improved dyskinesia of mice, reduced the loss of neurons in the substantia nigra (SN) and inhibited neuro-inflammatory responses in LPS-injected mice. In vitro, CPT inhibited M1 polarization of microglia and promotes M2 polarization via the AKT/Nrf2/HO-1-NF-κB signal axis. Furthermore, CPT protected the neuroblastoma cell line SH-SY5Y and dopaminergic neuron cell line MN9D from neurotoxicity of mediated by microglia activation. Conclusion CPT regulates the microglia polarization phenotype via the AKT/Nrf2/HO-1-NF-κB signal axis, inhibits neuro-inflammatory responses and exerts neuroprotective effects in vivo and in vitro.

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