Netrin 1-Mediated Role of the Substantia Nigra Pars Compacta and Ventral Tegmental Area in the Guidance of the Medial Habenular Axons

The fasciculus retroflexus is an important fascicle that mediates reward-related behaviors and is associated with different psychiatric diseases. It is the main habenular efference and constitutes a link between forebrain regions, the midbrain, and the rostral hindbrain. The proper functional organization of habenular circuitry requires complex molecular programs to control the wiring of the habenula during development. However, the mechanisms guiding the habenular axons toward their targets remain mostly unknown. Here, we demonstrate the role of the mesodiencephalic dopaminergic neurons (substantia nigra pars compacta and ventral tegmental area) as an intermediate target for the correct medial habenular axons navigation along the anteroposterior axis. These neuronal populations are distributed along the anteroposterior trajectory of these axons in the mesodiencephalic basal plate. Using in vitro and in vivo experiments, we determined that this navigation is the result of netrin 1 attraction generated by the mesodiencephalic dopaminergic neurons. This attraction is mediated by the receptor deleted in colorectal cancer (DCC), which is strongly expressed in the medial habenular axons. The increment in our knowledge on the fasciculus retroflexus trajectory guidance mechanisms opens the possibility of analyzing if its alteration in mental health patients could account for some of their symptoms.

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Inhibition of Autophagy In Vivo Extends Methamphetamine Toxicity to Mesencephalic Cell Bodies

Pharmaceuticals ◽

10.3390/ph14101003 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1003

Author(s):

Michela Ferrucci ◽

Francesca Biagioni ◽

Carla L. Busceti ◽

Chiara Vidoni ◽

Roberta Castino ◽

...

Keyword(s):

Substantia Nigra ◽

Ventral Tegmental Area ◽

Cell Cultures ◽

Substantia Nigra Pars Compacta ◽

Systemic Injection ◽

Axon Terminals ◽

Nigrostriatal Dopamine

Methamphetamine (METH) is a widely abused psychostimulant and a stress-inducing compound, which leads to neurotoxicity for nigrostriatal dopamine (DA) terminals in rodents and primates including humans. In vitro studies indicate that autophagy is a strong modulator of METH toxicity. In detail, suppressing autophagy increases METH toxicity, while stimulating autophagy prevents METH-induced toxicity in cell cultures. In the present study, the role of autophagy was investigated in vivo. In the whole brain, METH alone destroys meso-striatal DA axon terminals, while fairly sparing DA cell bodies within substantia nigra pars compacta (SNpc). No damage to either cell bodies or axons from ventral tegmental area (VTA) is currently documented. According to the hypothesis that ongoing autophagy prevents METH-induced DA toxicity, we tested whether systemic injection of autophagy inhibitors such as asparagine (ASN, 1000 mg/Kg) or glutamine (GLN, 1000 mg/Kg), may extend METH toxicity to DA cell bodies, both within SNpc and VTA, where autophagy was found to be inhibited. When METH (5 mg/Kg × 4, 2 h apart) was administered to C57Bl/6 mice following ASN or GLN, a frank loss of cell bodies takes place within SNpc and a loss of both axons and cell bodies of VTA neurons is documented. These data indicate that, ongoing autophagy protects DA neurons and determines the refractoriness of cell bodies to METH-induced toxicity.

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Characteristics of Electrically Evoked Somatodendritic Dopamine Release in Substantia Nigra and Ventral Tegmental Area In Vitro

Journal of Neurophysiology ◽

10.1152/jn.1997.77.2.853 ◽

1997 ◽

Vol 77 (2) ◽

pp. 853-862 ◽

Cited By ~ 100

Author(s):

M. E. Rice ◽

S. J. Cragg ◽

S. A. Greenfield

Keyword(s):

Electrical Stimulation ◽

Substantia Nigra ◽

Ventral Tegmental Area ◽

Dopamine Release ◽

Substantia Nigra Pars Compacta ◽

Frequency Dependent ◽

Body Regions ◽

Ventral Tegmental ◽

Da Release

Rice, M. E., S. J. Cragg, and S. A. Greenfield. Characteristics of electrically evoked somatodendritic dopamine release in substantia nigra and ventral tegmental area in vitro. J. Neurophysiol. 77: 853–862, 1997. Somatodendritic dopamine (DA) release from neurons of the midbrain represents a nonclassical form of neuronal signaling. We assessed characteristics of DA release during electrical stimulation of the substantia nigra pars compacta (SNc) in guinea pig midbrain slices. With the use of parameters optimized for this region, we compared stimulus-induced increases in extracellular DA concentration ([DA]o) in medial and lateral SNc, ventral tegmental area (VTA), and dorsal striatum in vitro. DA release was monitored directly with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. Detection of DA in SNc was confirmed by electrochemical, pharmacological, and anatomic criteria. Voltammograms of the released substance had the same peak potentials as those of DA obtained during in vitro calibration, but different from those of the indoleamine 5-hydroxytryptamine. Similar voltammograms were also obtained in the DA-rich striatum during local electrical stimulation. Contribution from the DA metabolite 3,4-dihydroxyphenylacetic acid to somatodendritic release was negligible, as indicated by the lack of effect of the monoamine oxidase inhibitor pargyline (20 μM) on the signal. Lastly, DA voltammograms could only be elicited in regions that were subsequently determined to be positive for tyrosine hydroxylase immunoreactivity (TH-ir). The frequency dependence of stimulated DA release in SNc was determined over a range of 1–50 Hz, with a constant duration of 10 s. Release was frequency dependent up to 10 Hz, with no further increase at higher frequencies. Stimulation at 10 Hz was used in all subsequent experiments. With this paradigm, DA release in SNc was tetrodotoxin insensitive, but strongly Ca2+ dependent. Stimulated [DA]o in the midbrain was also site specific. At the midcaudal level examined, DA efflux was significantly greater in VTA (1.04 ± 0.05 μM, mean ± SE) than in medial SNc (0.52 ± 0.05 μM), which in turn was higher than in lateral SNc (0.35 ± 0.03 μM). This pattern followed the apparent density of TH-ir, which was also VTA > medial SNc > lateral SNc. This report has introduced a new paradigm for the study of somatodendritic DA release. Voltammetric recording with electrodes of 2–4 μm tip diameter permitted highly localized, direct detection of endogenous DA. The Ca2+ dependence of stimulated release indicated that the process was physiologically relevant. Moreover, the findings that somatodendritic release was frequency dependent across a range characteristic of DA cell firing rates and that stimulated [DA]o varied markedly among DA cell body regions have important implications for how dendritically released DA may function in the physiology and pathophysiology of substantia nigra and VTA.

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Pedunculopontine glutamatergic neurons control spike patterning in substantia nigra dopaminergic neurons

eLife ◽

10.7554/elife.30352 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 13

Author(s):

Daniel J Galtieri ◽

Chad M Estep ◽

David L Wokosin ◽

Stephen Traynelis ◽

D James Surmeier

Keyword(s):

Substantia Nigra ◽

Dopaminergic Neurons ◽

Substantia Nigra Pars Compacta ◽

Glutamatergic Synapses ◽

Glutamatergic Neurons ◽

Oscillatory Mechanisms ◽

Goal Directed Behavior ◽

Stimulation Of

Burst spiking in substantia nigra pars compacta (SNc) dopaminergic neurons is a key signaling event in the circuitry controlling goal-directed behavior. It is widely believed that this spiking mode depends upon an interaction between synaptic activation of N-methyl-D-aspartate receptors (NMDARs) and intrinsic oscillatory mechanisms. However, the role of specific neural networks in burst generation has not been defined. To begin filling this gap, SNc glutamatergic synapses arising from pedunculopotine nucleus (PPN) neurons were characterized using optical and electrophysiological approaches. These synapses were localized exclusively on the soma and proximal dendrites, placing them in a good location to influence spike generation. Indeed, optogenetic stimulation of PPN axons reliably evoked spiking in SNc dopaminergic neurons. Moreover, burst stimulation of PPN axons was faithfully followed, even in the presence of NMDAR antagonists. Thus, PPN-evoked burst spiking of SNc dopaminergic neurons in vivo may not only be extrinsically triggered, but extrinsically patterned as well.

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Ventral pallidal GABAergic neurons control wakefulness associated with motivation through the ventral tegmental pathway

Molecular Psychiatry ◽

10.1038/s41380-020-00906-0 ◽

2020 ◽

Author(s):

Ya-Dong Li ◽

Yan-Jia Luo ◽

Wei Xu ◽

Jing Ge ◽

Yoan Cherasse ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Gabaergic Neurons ◽

Population Activity ◽

Lateral Habenula ◽

Optogenetic Stimulation ◽

Ventral Tegmental ◽

Stimulation Of

Abstract The ventral pallidum (VP) regulates motivation, drug addiction, and several behaviors that rely on heightened arousal. However, the role and underlying neural circuits of the VP in the control of wakefulness remain poorly understood. In the present study, we sought to elucidate the specific role of VP GABAergic neurons in controlling sleep–wake behaviors in mice. Fiber photometry revealed that the population activity of VP GABAergic neurons was increased during physiological transitions from non-rapid eye movement (non-REM, NREM) sleep to either wakefulness or REM sleep. Moreover, chemogenetic and optogenetic manipulations were leveraged to investigate a potential causal role of VP GABAergic neurons in initiating and/or maintaining arousal. In vivo optogenetic stimulation of VP GABAergic neurons innervating the ventral tegmental area (VTA) strongly promoted arousal via disinhibition of VTA dopaminergic neurons. Functional in vitro mapping revealed that VP GABAergic neurons, in principle, inhibited VTA GABAergic neurons but also inhibited VTA dopaminergic neurons. In addition, optogenetic stimulation of terminals of VP GABAergic neurons revealed that they promoted arousal by innervating the lateral hypothalamus, but not the mediodorsal thalamus or lateral habenula. The increased wakefulness chemogenetically evoked by VP GABAergic neuronal activation was completely abolished by pretreatment with dopaminergic D1 and D2/D3 receptor antagonists. Furthermore, activation of VP GABAergic neurons increased exploration time in both the open-field and light–dark box tests but did not modulate depression-like behaviors or food intake. Finally, chemogenetic inhibition of VP GABAergic neurons decreased arousal. Taken together, our findings indicate that VP GABAergic neurons are essential for arousal related to motivation.

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Characterization of substantia nigra neurogenesis in homeostasis and dopaminergic degeneration: beneficial effects of the microneurotrophin BNN-20

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02398-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Theodora Mourtzi ◽

Dimitrios Dimitrakopoulos ◽

Dimitrios Kakogiannis ◽

Charalampos Salodimitris ◽

Konstantinos Botsakis ◽

...

Keyword(s):

Stem Cell ◽

Substantia Nigra ◽

Mouse Model ◽

Dopaminergic Neurons ◽

Stem Cell Niche ◽

Substantia Nigra Pars Compacta ◽

Dopaminergic Cell ◽

Cell Niche

Abstract Background Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) underlines much of the pathology of Parkinson’s disease (PD), but the existence of an endogenous neurogenic system that could be targeted as a therapeutic strategy has been controversial. BNN-20 is a synthetic, BDNF-mimicking, microneurotrophin that we previously showed to exhibit a pleiotropic neuroprotective effect on the dopaminergic neurons of the SNpc in the “weaver” mouse model of PD. Here, we assessed its potential effects on neurogenesis. Methods We quantified total numbers of dopaminergic neurons in the SNpc of wild-type and “weaver” mice, with or without administration of BNN-20, and we employed BrdU labelling and intracerebroventricular injections of DiI to evaluate the existence of dopaminergic neurogenesis in the SNpc and to assess the origin of newborn dopaminergic neurons. The in vivo experiments were complemented by in vitro proliferation/differentiation assays of adult neural stem cells (NSCs) isolated from the substantia nigra and the subependymal zone (SEZ) stem cell niche to further characterize the effects of BNN-20. Results Our analysis revealed the existence of a low-rate turnover of dopaminergic neurons in the normal SNpc and showed, using three independent lines of experiments (stereologic cell counts, BrdU and DiI tracing), that the administration of BNN-20 leads to increased neurogenesis in the SNpc and to partial reversal of dopaminergic cell loss. The newly born dopaminergic neurons, that are partially originated from the SEZ, follow the typical nigral maturation pathway, expressing the transcription factor FoxA2. Importantly, the pro-cytogenic effects of BNN-20 were very strong in the SNpc, but were absent in other brain areas such as the cortex or the stem cell niche of the hippocampus. Moreover, although the in vitro assays showed that BNN-20 enhances the differentiation of NSCs towards glia and neurons, its in vivo administration stimulated only neurogenesis. Conclusions Our results demonstrate the existence of a neurogenic system in the SNpc that can be manipulated in order to regenerate the depleted dopaminergic cell population in the “weaver” PD mouse model. Microneurotrophin BNN-20 emerges as an excellent candidate for future PD cell replacement therapies, due to its area-specific, pro-neurogenic effects.

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Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain

10.7287/peerj.preprints.26547v2 ◽

2018 ◽

Author(s):

Tatiana V Tarasova ◽

Olga A Lytkina ◽

Valeria V Goloborshcheva ◽

Larisa N Skuratovskaya ◽

Alexandr I Antohin ◽

...

Keyword(s):

Substantia Nigra ◽

Embryonic Development ◽

Ventral Tegmental Area ◽

Knockout Mice ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Nigrostriatal System ◽

Ventral Tegmental

Lesion of the dopaminergic neurons of the nigrostriatal system is a key feature of Parkinson's disease (PD). Alpha-synuclein is a protein that is a major component of Lewy bodies, histopathological hallmarks of PD, and is involved in regulation of dopamine (DA) neurotransmission. Previous studies of knockout mice have shown that inactivation of alpha-synuclein gene can lead to the reduction in number of DA neurons in the substantia nigra (SN). DA neurons of the SN are known to be the most affected in PD patients whereas DA neurons of neighboring ventral tegmental area (VTA) are much less susceptible to degeneration. Here we have studied the dynamics of changes in TH-positive cell numbers in the SN and VTA during a critical period of their embryonic development in alpha-synuclein knockout mice. This precise study of DA neurons during development of the SN revealed that not only is the number of DA neurons reduced by the end of the period of ontogenic selection, but that the way these neurons are formed is altered in alpha-synuclein knockout mice. At the same time, DA neurons in the VTA are not affected. Alpha-synuclein exerts a modulating effect on the formation of DA neurons in the SN and has no effect on the formation of DA neurons in VTA, the structure that is much less susceptible to degeneration in PD brain, suggesting a potential role of alpha-synuclein in the development of the population of DA neurons in substantia nigra.

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Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain

10.7287/peerj.preprints.26547 ◽

2018 ◽

Author(s):

Tatiana V Tarasova ◽

Olga A Lytkina ◽

Valeria V Goloborshcheva ◽

Larisa N Skuratovskaya ◽

Alexandr I Antohin ◽

...

Keyword(s):

Substantia Nigra ◽

Embryonic Development ◽

Ventral Tegmental Area ◽

Knockout Mice ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Nigrostriatal System ◽

Ventral Tegmental

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Differential contribution of Ih to the integration of excitatory synaptic inputs in substantia nigra pars compacta and ventral tegmental area dopaminergic neurons

European Journal of Neuroscience ◽

10.1111/ejn.13066 ◽

2015 ◽

Vol 42 (9) ◽

pp. 2699-2706 ◽

Cited By ~ 15

Author(s):

Alessio Masi ◽

Roberto Narducci ◽

Francesco Resta ◽

Carmen Carbone ◽

Kazuto Kobayashi ◽

...

Keyword(s):

Substantia Nigra ◽

Ventral Tegmental Area ◽

Dopaminergic Neurons ◽

Substantia Nigra Pars Compacta ◽

Synaptic Inputs ◽

Ventral Tegmental ◽

Differential Contribution

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Physiological Properties of Zebra Finch Ventral Tegmental Area and Substantia Nigra Pars Compacta Neurons

Journal of Neurophysiology ◽

10.1152/jn.01040.2005 ◽

2006 ◽

Vol 96 (5) ◽

pp. 2295-2306 ◽

Cited By ~ 43

Author(s):

Samuel D. Gale ◽

David J. Perkel

Keyword(s):

Substantia Nigra ◽

Ventral Tegmental Area ◽

Zebra Finch ◽

Dopaminergic Neurons ◽

Brain Slices ◽

Membrane Properties ◽

Substantia Nigra Pars Compacta ◽

D2 Dopamine Receptors ◽

Physiological Properties ◽

Ventral Tegmental

The neurotransmitter dopamine plays important roles in motor control, learning, and motivation in mammals and probably other animals as well. The strong dopaminergic projection to striatal regions and more moderate dopaminergic projections to other regions of the telencephalon predominantly arise from midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Homologous dopaminergic cell groups in songbirds project anatomically in a manner that may allow dopamine to influence song learning or song production. The electrophysiological properties of SNc and VTA neurons have not previously been studied in birds. Here we used whole cell recordings in brain slices in combination with tyrosine-hydroxylase immunolabeling as a marker of dopaminergic neurons to determine electrophysiological and pharmacological properties of dopaminergic and nondopaminergic neurons in the zebra finch SNc and VTA. Our results show that zebra finch dopaminergic neurons possess physiological properties very similar to those of mammalian dopaminergic neurons, including broad action potentials, calcium- and apamin-sensitive membrane-potential oscillations underlying pacemaker firing, powerful spike-frequency adaptation, and autoinhibition via D2 dopamine receptors. Moreover, the zebra finch SNc and VTA also contain nondopaminergic neurons with similarities (fast-firing, inhibition by the μ-opioid receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO)) and differences (strong h-current that contributes to spontaneous firing) compared with GABAergic neurons in the mammalian SNc and VTA. Our results provide insight into the intrinsic membrane properties that regulate the activity of dopaminergic neurons in songbirds and add to strong evidence for anatomical, physiological, and functional similarities between the dopaminergic systems of mammals and birds.

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