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During development, dopaminergic neurons born in the substantia nigra extend their axons toward the striatum. However, the mechanisms by which the dopaminergic axons extend the striatum to innervate their targets remain unclear. We previously showed that paired-cultivation of mesencephalic cells containing dopaminergic neurons with striatal cells leads to the extension of dopaminergic neurites from the mesencephalic cell region to the striatal cell region. The present study shows that dopaminergic neurites extended along striatal neurons in the paired-cultures of mesencephalic cells with striatal cells. The extension of dopaminergic neurites was suppressed by the pharmacological inhibition of integrin α5β1. Using lentiviral vectors, short hairpin RNA (shRNA)-mediated knockdown of integrin α5 in dopaminergic neurons suppressed the neurite outgrowth to the striatal cell region. In contrast, the knockdown of integrin α5 in non-dopaminergic mesencephalic and striatal cells had no effect. Furthermore, overexpression of integrin α5 in dopaminergic neurons differentiated from embryonic stem cells enhanced their neurite outgrowth on striatal cells. These results indicate that integrin α5β1 expression on dopaminergic neurons plays an important role in the dopaminergic neurite outgrowth on striatal neurons.
Dopaminergic local circuit neurons in the retina (DA cells) show robust, spontaneous, tetrodotoxin-sensitive pacemaking. To investigate the mechanism underlying this behavior, we characterized the sodium current and a subset of the potassium currents in the cells in voltage-clamp experiments. We found that there is a persistent component of the sodium current in DA cells which activates at more depolarized potentials than the transient component of the current. The transient component was completely inactivated at -50 mV, but DA cells remained able to fire spontaneous action potentials when potassium channels were partially blocked and the membrane potential remained above -40 mV. Based on these electrophysiological data, we developed a reduced computer model that reproduced the major features of DA cells. In simulations at the physiological resting potential, the persistent component of the sodium current was both necessary and sufficient to account for spontaneous activity, and the major contribution of the transient component of the sodium current was to initiate the depolarization of the model cell during the interspike interval. When tonic inhibition was simulated by lowering the input impedance of the model cell, the transient component played a larger role.
Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson's disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range (5-30 μM) elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson's disease.
Oxidative stress could lead to dopaminergic neuronal cell death. SC79 is a novel, selective and highly-efficient Akt activator. The current study tested its effect in dopaminergic neurons with oxidative stress. In both SH-SY5Y cells and primary murine dopaminergic neurons, pre-treatment with SC79 largely inhibited hydrogen peroxide (H2O2)-induced cell viability reduction, apoptosis and necrosis. SC79 activated Akt in the neuronal cells, which was required for its neuroprotection against H2O2. Inhibition of Akt activation (by MK-2206 or AT7867) or expression (by targeted short hairpin RNA) largely attenuated SC79-induced neuroprotection. Further, CRISPR-Cas9-mediated Akt1 knockout in SH-SY5Y cells abolished SC79-induced neuroprotective function against H2O2. Reversely, forced activation of Akt by the constitutively-active Akt1 mimicked SC79-induced anti-H2O2 activity. Together, we conclude that activation of Akt by SC79 protects dopaminergic neurons from H2O2.
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.
Treatment of psychostimulants leads to the development of behavioral sensitization, an augmented behavioral response to drug re-administration. The induction of behavioral sensitization to psychostimulants such as amphetamine and cocaine occurs at the ventral tegmental area's dopaminergic neurons (VTA-DA). Currently, there is limited experimental data about the physiological properties of methylphenidate (MPD) on VTA-DA neurons. Behavioral and electrophysiological experiments using male rats were performed before and after MPD treatment. The behavioral experiment included dose-response (0.6, 2.5, and 10.0 mg/kg MPD) study to select the most effective dose for the electrophysiological study. Methylphenidate increased locomotion in typical dose response characteristics. Based on this experiment, the 10.0 mg/kg MPD was used in two types of electrophysiological recordings: 1) intracellular recording of neuronal activity performed on horizontal 275-300 microm brain slices and 2) whole-cell patch clamping before and after electrical stimulation to study post-synaptic currents on neurophysiologically identified VTA-DA neurons. Methylphenidate suppressed the neuronal activity of these neurons for 210 +/- 30 sec. Stimulation of the prefrontal cortex afferent fibers to these VTA-DA neurons in the presence of TTX, saclofen, and picrotoxin led to the conclusion that this input is mediated via NMDA and kainate/AMPA receptors and may participate to induce behavioral sensitization to psychostimulants.
Mitochondria are essential for neuronal survival and function, and mitochondrial dysfunction plays a critical role in the pathological development of Parkinson's disease (PD). Mitochondrial quality control is known to contribute to the survival of dopaminergic (DA) neurons, with mitophagy being a key regulator of the quality control system. In this study, we show that mitophagy is impaired in the substantia nigra pars compacta (SNc) of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Treatment with the sigma-1 receptor (Sig 1R) agonist 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (PRE-084) reduced loss of DA neurons, restored motor ability and MPTP-induced damage to mitophagy activity in the SNc of PD-like mice. Additionally, knockdown of Sig 1R in SH-SY5Y DA cells inhibited mitophagy and enhanced 1-methyl-4-phenylpyridinium ion (MPP+) neurotoxicity, whereas application of the Sig 1R selective agonist SKF10047 promoted clearance of damaged mitochondria. Moreover, knockdown of Sig 1R in SH-SY5Y cells resulted in decreased levels of p-ULK1 (Unc-51 Like Autophagy Activating Kinase 1) (Ser555), p-TBK1 (TANK Binding Kinase 1) (Ser172), p-ubiquitin (Ub) (Ser65), Parkin recruitment, and stabilization of PTEN-induced putative kinase 1 (PINK1) in mitochondria. The present data provide the first evidence for potential roles of PINK1/Parkin in Sig 1R-modulated mitophagy in DA neurons.
The dopaminergic neurons of the ventral tegmental area (VTA) have been identified with the ability to co-release dopamine and glutamate. This ability was first documented in the nucleus accumbens but showed to be absent in the dorsal striatum. Recently the ability to release glutamate from a subpopulation of the VTA dopaminergic neurons has been shown to control the prefrontal cortex (PFC) excitation through the exclusive innervation of GABAergic fast spiking interneurons. Here, using an optogenetic approach, we expand this view by presenting that the VTA dopaminergic neurons do not only innervate interneurons but also pyramidal PFC neurons. This finding opens the range of possibilities for the VTA dopaminergic neurons to modulate the activity of PFC.
Dopaminergic neurons play important roles in brain function and studying dopaminergic system has been a major field of neuroscience research. Genetically modified mice have greatly advanced research of dopaminergic neurons. However, it has been shown that dopaminergic neurons contain several subtypes expressing distinct genetic markers, and it is challenging to study genetically different subtypes of dopaminergic neurons using current mouse lines. Here, we report a newly developed Dat-ires-flp line, in which flippase gene is knocked in after the stop codon of Slc6a3 (dopamine transporter, DAT) gene. We validated this line to show that flp is specifically expressed in dopaminergic neurons, and by breeding with Cre-expressing line (i.e. Vglut2-cre) we can study a specific subpopulation of dopaminergic neurons. We expect this line will be widely used to study different subtypes of dopaminergic neurons in diverse contexts.
Dietary lipids, particularly omega-3 polyunsaturated fatty acids, are speculated to impact behaviors linked to the dopaminergic system, such as movement and control of circadian rhythms. However, the ability to draw a direct link between dopaminergic omega-3 fatty acid metabolism and behavioral outcomes has been limited to the use of diet-based approaches, which are confounded by systemic effects. Here, neuronal lipid metabolism was targeted in a diet-independent manner by manipulation of long-chain acyl-CoA synthetase 6 (ACSL6) expression. ACSL6 performs the initial reaction for cellular fatty acid metabolism and prefers the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). The loss of Acsl6 in mice (Acsl6-/- ) depletes neuronal membranes of DHA content and results in phenotypes linked to dopaminergic control, such as hyperlocomotion, impaired short-term spatial memory, and imbalances in dopamine neurochemistry. To investigate the role of dopaminergic ACSL6 on these outcomes, a dopaminergic neuron-specific ACSL6 knockout mouse was generated (Acsl6DA-/- ). Acsl6DA-/- mice demonstrated hyperlocomotion and imbalances in striatal dopamine neurochemistry. Circadian rhythms of both the Acsl6-/- and the Acsl6DA-/- mice were similar to control mice under basal conditions. However, upon light entrainment, a mimetic of jet lag, both the complete knockout of ACSL6 and the dopaminergic-neuron-specific loss of ACSL6 resulted in a longer recovery to entrainment compared to control mice. In conclusion, these data demonstrate that ACSL6 in dopaminergic neurons alters dopamine metabolism and regulation of light entrainment suggesting that DHA metabolism mediated by ACSL6 plays a role in dopamine neuron biology.
Hypothalamic neuroendocrine dopaminergic neurons exhibit a diurnal rhythm. Higher level input to these neurons has not been described. In the present study, we identified fibers known to originate in the suprachiasmatic nucleus (SCN), which were associated with neuroendocrine dopaminergic neurons. Hypothalamic sections were obtained from either ovariectomized (OVX) female rats or OVX female rats implanted with estrogen and progesterone (E+P). Confocal microscopic images were acquired from the periventricular nucleus, as well as the rostral, dorsomedial, ventrolateral, and caudal regions of the arcuate nucleus. Using antibodies directed against vasoactive intestinal peptide (VIP) and tyrosine hydroxylase (TH) the rate-limiting enzyme in dopamine synthesis, fine VIP fibers in close apposition to TH-immunoreactive (IR) soma and proximal dendrites were revealed. Of the antibodies for the two VIP receptor subtypes (VIP1R and VIP2R), only VIP2R was found on TH-IR neurons. E+P significantly increased the incidence and density of neuroendocrine dopaminergic neurons expressing VIP2R, when compared to OVX animals. E+P did not affect the percent of neuroendocrine dopaminergic neurons associated with VIP fibers. No VIP fibers or VIP2R were found on dopaminergic neurons in the zona incerta. Brain sections triple labeled for Synapsin (a protein localized in synaptic vesicles) VIP, and TH demonstrated that Synapsin was colocalized with VIP fibers that were associated with TH-IR neurons in the arcuate nucleus. Double-label immuno-electron microscopy of hypothalamic sections labeled with antibodies for VIP and TH revealed VIP boutons associated with TH-IR soma and proximal dendrites. These results suggest VIPergic neurons may directly regulate neuroendocrine dopaminergic neuron activity, and ovarian steroids may play a modulatory role.
Rationale: Contactin-associated protein-like 4 (CNTNAP4) belongs to the neurexin superfamily and has critical functions in neurological development and synaptic function. Loss of CNTNAP4 in interneurons has been linked to autism, schizophrenia, and epilepsy. CNTNAP4 is also highly enriched in dopaminergic (DA) neurons in the substantia nigra (SN), however, few studies have investigated the role of CNTNAP4 in DA neurons, and whether CNTNAP4 deficiency in DA neurons contributes to Parkinson's disease (PD) remains unclear. Methods: Effects of CNTNAP4 knockdown or overexpression on the DA MN9D cell line were assessed via Western blotting, immunocytochemistry, and RNA sequencing. An in vivo animal model, including CNTNAP4 knockout mice and stereotaxic injections of adeno-associated viral short-hairpin RNA with the tyrosine-hydroxylase promotor to silence CNTNAP4 in the SN, as well as the resulting physiological/behavioral effects, were evaluated via behavioral tests, Western blotting, immunohistochemistry, and transmission electron microscopy. Enzyme-linked immunosorbent assays (ELISAs) were performed to examine the cerebrospinal fluid (CSF) and plasma CNTNAP4 concentrations in PD patients. Results: We demonstrated that CNTNAP4 knockdown induced mitophagy and increased α-synuclein expression in MN9D cells. CNTNAP4 knockdown in the SN induced PD-like increases in SN-specific α-synuclein expression, DA neuronal degeneration, and motor dysfunction in mice. In addition, CNTNAP4 knockdown in SN-DA neurons increased autophagosomes and reduced synaptic vesicles in the SN. Furthermore, CNTNAP4 knockout mice showed movement deficits, nigral DA degeneration, and increased autophagy, which were consistent with the SN-specific knockdown model. We also found that CSF and plasma CNTNAP4 expression was increased in PD patients; in particular, plasma CNTNAP4 was increased in male PD patients compared with controls or female PD patients. Conclusion: Our findings suggest that CNTNAP4 deficiency may initiate phenotypes relevant to PD, of which we elucidated some of the underlying mechanisms.
Adipose derived stem cells (ASCs) secrete numerous neurotrophic factors and cytokines in conditioned medium (CM), which protect neurons by its antioxidative and trophic effects. This research assesses the neuroprotective effect of ASCCM on neurotrophins genes expressions and tyrosine hydroxylase positive (TH+) cell density in male Wistar rats lesioned by 6-hydroxydopamine (6-OHDA).
Monoamines, including dopamine (DA), have been linked to aggression in various species. However, the precise role or roles served by the amine in aggression have been difficult to define because dopaminergic systems influence many behaviors, and all can be altered by changing the function of dopaminergic neurons. In the fruit fly, with the powerful genetic tools available, small subsets of brain cells can be reliably manipulated, offering enormous advantages for exploration of how and where amine neurons fit into the circuits involved with aggression. By combining the GAL4/upstream activating sequence (UAS) binary system with the Flippase (FLP) recombination technique, we were able to restrict the numbers of targeted DA neurons down to a single-cell level. To explore the function of these individual dopaminergic neurons, we inactivated them with the tetanus toxin light chain, a genetically encoded inhibitor of neurotransmitter release, or activated them with dTrpA1, a temperature-sensitive cation channel. We found two sets of dopaminergic neurons that modulate aggression, one from the T1 cluster and another from the PPM3 cluster. Both activation and inactivation of these neurons resulted in an increase in aggression. We demonstrate that the presynaptic terminals of the identified T1 and PPM3 dopaminergic neurons project to different parts of the central complex, overlapping with the receptor fields of DD2R and DopR DA receptor subtypes, respectively. These data suggest that the two types of dopaminergic neurons may influence aggression through interactions in the central complex region of the brain involving two different DA receptor subtypes.
Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport. Moreover, in-cell experiments confirmed that loss of parkin affects mitochondria mobility and showed that this defect depends on MT system as it is rescued by paclitaxel, a well-known MT-targeted agent. Furthermore, both in PC12 neuronal cells and in patients' induced pluripotent stem cell-derived midbrain neurons, we observed that parkin deficiencies cause the fragmentation of stable MTs. Therefore, we suggest that parkin acts as a regulator of MT system during neuronal aging, and we endorse the hypothesis that MT dysfunction may be crucial in the pathogenesis of Parkinson's disease.
Motivational states are important determinants of behavior. In Drosophila melanogaster, courtship behavior is robust and crucial for species continuation. However, the motivation of courtship behavior remains unexplored. We first find the phenomenon that courtship behavior is modulated by motivational state. A male fly courts another male fly when it first courts a decapitated female fly, however, male-male courtship behavior rarely occurs under normal conditions. Therefore, in this phenomenon, the male fly's courtship motivational state is induced by its exposure to female flies. Blocking dopaminergic neurons synaptic transmission by expressing Tetanus toxin light chain (TNTe) decreases motivational state induced male-male courtship behavior without affecting male-female courtship behavior. Vision cues are another key component in sexually driven Drosophila male-male courtship behavior. Here, we identify a base theory that the inner motivational state could eventually decide Drosophila behavior.
Anterograde tract-tracing and immunohistochemical methods were used to study projections from the pedunculopontine tegmental nucleus (PPN) to midbrain dopaminergic neurons in the squirrel monkey (Saimiri sciureus). The PPN harbored numerous cholinergic and glutamatergic neurons, as well as neurons that displayed both cholinergic and glutamatergic markers. Injections of anterograde tracer into the PPN led to intense fiber labeling in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). This pedunculonigral projection was partly bilateral. At the electron microscopic level, about 40-60% of the anterogradely labeled terminal boutons were glutamate-positive and formed asymmetric synapses with the dopaminergic neurons of the SNc-VTA complex. These data provide direct evidence for a pedunculonigral glutamatergic projection. This projection may play a crucial role in the control of the firing pattern of SNc-VTA dopaminergic neurons and could be involved in glutamate-mediated excitotoxicity that is believed to lead to SNc cell death in Parkinson's disease.
A unique sensitivity to specific biochemical processes is responsible for selective vulnerability of midbrain dopamine neurons in several diseases. Prior studies have shown these neurons are susceptible to energy failure and mitochondrial dysfunction, oxidative stress, and impaired disposal of misfolded proteins. These neurons also are especially vulnerable to the loss of purine recycling. In the brains of humans or mice with inherited defects of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), the most prominent defect is loss of basal ganglia dopamine. To investigate the nature of the relationship between HPRT deficiency and dopamine, the mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking HPRT. The mutant sublines grew more slowly than the parent line, but without morphological signs of impaired viability. As a group, the mutant sublines had significantly lower dopamine than the parent line. The loss of dopamine in the mutants did not reflect impaired energy status, as judged by ATP levels or vulnerability to inhibitors of energy production. Indeed, the mutant lines as a group appeared energetically more robust than the parent line. The loss of dopamine also was not accompanied by enhanced susceptibility to oxidative stress or proteasome inhibitors. Instead, the loss of dopamine reflected only one aspect of a broad change in the molecular phenotype of the cells affecting mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase. These changes were selective for the dopamine phenotype, since multiple control mRNAs were normal. These studies suggest purine recycling is an intrinsic metabolic process of particular importance to the molecular phenotype of dopaminergic neurons independent of previously established mechanisms involving energy failure, oxidative stress, or proteasome dysfunction.
Neurons co-expressing kisspeptin, neurokinin B (NKB), and dynorphin in the hypothalamic arcuate nucleus, named KNDy neurons, are directly affected by sex hormones, and are well known for regulating the secretion of gonadotropin-releasing hormone. However, recent studies have shown that KNDy neurons also project and terminate to tuberoinfundibular dopaminergic (TIDA) neurons, suggesting a role in prolactin secretion. Moreover, there is a possibility that other neurosecretory dopaminergic neurons regulating prolactin secretion, such as periventricular hypophyseal dopaminergic (PHDA) neurons, may also be innervated by KNDy neurons. In the present study, by means of double immunohistochemistry and retrograde neural tracer, we examined whether KNDy neurons project directly to PHDA neurons that project to blood vessels, as well as to TIDA neurons. The results revealed that KNDy neurons are widely projecting to neurosecretory dopaminergic neurons of the PHDA and TIDA neurons in rats and mice. Secondary, presence of a major receptor for NKB, neurokinin-3 receptor (NK3R), in PHDA and TIDA neurons was examined and it appeared that most TIDA and PHDA neurons possess NK3R. These findings indicate that, in rodents, KNDy neurons widely project to neurosecretory dopaminergic neurons distributed in the hypothalamus, and may affect them via the NKB-NK3R signaling pathway.
Kisspeptin neurons in the arcuate nucleus (ARC) regulate prolactin secretion, and are in physical contact with tuberoinfundibular dopaminergic (TIDA) neurons, which inhibit prolactin secretion. Prolactin levels in the blood are increased with advancing age in rats; therefore, we investigated the interactions with TIDA neurons and kisspeptin neurons in aged female rats (24 months of age), relative to those of young adult female rats (9-10 weeks of age). Plasma prolactin levels in the aged rats were significantly higher than those of young adult rats. Tyrosine hydroxylase (TH)-immunoreactive (ir) cell bodies and kisspeptin-ir nerve fibers were found in the dorsomedial ARC of both groups. The number of TH-ir cell bodies in the dorsomedial ARC did not differ significantly between groups. Additionally, no significant differences in the number of TH-ir cells in contact with kisspeptin-ir fibers was observed between groups. However, the number of kisspeptin-ir or Kiss1 mRNA-expressing cells in the ARC was significantly reduced in the aged rats compared with that of the young rats. These results suggest that the contacts between TIDA neurons and kisspeptin neurons are maintained after reproductive senescence, while production of kisspeptin in the ARC decreases significantly during aging.
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