scholarly journals Microglia depletion prior to lipopolysaccharide and paraquat treatment differentially modulates behavioral and neuronal outcomes in wild type and G2019S LRRK2 knock-in mice.

2019 ◽  
Author(s):  
Zach Dwyer ◽  
Chris Rudyk ◽  
Divya Situt ◽  
Sheryl Beauchamp ◽  
Jawaria Abdali ◽  
...  
Keyword(s):  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Environmental Toxicants ◽  
Wild Type ◽  
Vulnerability Factors ◽  
G2019s Mutation ◽  
Inflammatory Processes ◽  
Environmental Toxin ◽  
Pre Treatment ◽  
Home Cage Activity

Abstract Background: Substantial data have implicated microglial-driven neuroinflammation in Parkinson’s disease (PD) and environmental toxicants have been long expected as triggers of such inflammatory processes. Of course, these environmental insults act in the context of genetic vulnerability factors and in this regard, leucine rich repeat kinase 2 (LRRK2), may play a prominent role.Methods: We used a double hit, lipopolysaccharide (LPS; endotoxin) followed by paraquat (pesticide toxicant) model of PD in mice with the most common LRRK2 mutation G2019S, knockin mice and wild type littermates. In order to assess the contribution of microglia, we depleted these cells (through 14 days of the CSF-1 antagonist, PLX-3397) prior to LPS and paraquat exposure.Results: We found that the G2019S mice displayed the greatest signs of behavioral pathology, but that the PLX-3397 induced microglial depletion at the time of LPS exposure diminished toxicity and weight loss and blunted the reduction in home-cage activity with subsequent paraquat exposure. However, neither the PLX-3397 pre-treatment nor the G2019S mutation affected the LPS + paraquat induced loss of substantia nigra pars compacta (SNc) dopamine neurons or elevation of circulating immune (IL-6) or stress (corticosterone) factors. Intriguingly, microglial morphological ratings were basally enhanced in G2019S mice and the PLX-3397 pre-treatment reversed this effect. Moreover, PLX-3397 pre-treatment selectively elevated soluble a-synuclein and SIRT3 levels, while reducing SNc caspase-1 and 3, along with CX3CR1. Hence, the re-populated “new” microglia following cessation of PLX-3397 clearly had an altered phenotype or were immature at the time of sacrifice (i.e. after 11 days).Conclusions: Collectively, these findings suggest that G2019S knock-in and PLX-3397 microglial depletion at the time of LPS exposure affects behavioral, but not neurodegenerative responses to subsequent environmental toxin exposure.

scholarly journals The tectonigral pathway regulates appetitive locomotion in predatory hunting in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Meizhu Huang ◽  
Dapeng Li ◽  
Xinyu Cheng ◽  
Qing Pei ◽  
Zhiyong Xie ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Superior Colliculus ◽  
Dopamine Release ◽  
Dorsal Striatum ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Neuronal Circuitry ◽  
Locomotion Speed ◽  
Brain Circuit ◽  
Goal Directed Behavior

AbstractAppetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior—predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice.

scholarly journals Animal Models of Autosomal Recessive Parkinsonism

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 812
Author(s):  
Guendalina Bastioli ◽  
Maria Regoni ◽  
Federico Cazzaniga ◽  
Chiara Maria Giulia De Luca ◽  
Edoardo Bistaffa ◽  
...  
Keyword(s):  
Animal Models ◽  
Sleep Disturbances ◽  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Cognitive Disorders ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Current Status ◽  
Unknown Etiology ◽  
Neuron Death

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. The neuropathological hallmark of the disease is the loss of dopamine neurons of the substantia nigra pars compacta. The clinical manifestations of PD are bradykinesia, rigidity, resting tremors and postural instability. PD patients often display non-motor symptoms such as depression, anxiety, weakness, sleep disturbances and cognitive disorders. Although, in 90% of cases, PD has a sporadic onset of unknown etiology, highly penetrant rare genetic mutations in many genes have been linked with typical familial PD. Understanding the mechanisms behind the DA neuron death in these Mendelian forms may help to illuminate the pathogenesis of DA neuron degeneration in the more common forms of PD. A key step in the identification of the molecular pathways underlying DA neuron death, and in the development of therapeutic strategies, is the creation and characterization of animal models that faithfully recapitulate the human disease. In this review, we outline the current status of PD modeling using mouse, rat and non-mammalian models, focusing on animal models for autosomal recessive PD.

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 Substantia nigra neuromelanin magnetic resonance imaging in patients with different subtypes of Parkinson disease

2021 ◽  
Author(s):  
Lu Wang ◽  
Yayun Yan ◽  
Liyao Zhang ◽  
Yan Liu ◽  
Ruirui Luo ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Substantia Nigra ◽  
Parkinson Disease ◽  
Clinical Symptoms ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Resonance Imaging ◽  
Mean Values

AbstractNeuromelanin (NM) is a dark pigment that mainly exists in neurons of the substantia nigra pars compacta (SNc). In Parkinson disease (PD) patients, NM concentration decreases gradually with degeneration and necrosis of dopamine neurons, suggesting potential use as a PD biomarker. We aimed to evaluate associations between NM concentration in in vivo SN and PD progression and different motor subtypes using NM magnetic resonance imaging (NM-MRI). Fifty-four patients with idiopathic PD were enrolled. Patients were divided into groups by subtypes with different clinical symptoms: tremor dominant (TD) group and postural instability and gait difficulty (PIGD) group. Fifteen healthy age-matched volunteers were enrolled as controls. All subjects underwent clinical assessment and NM-MRI examination. PD patients showed significantly decreased contrast-to-noise ratio (CNR) values in medial and lateral SN (P < 0.05) compared to controls. CNR values in lateral SN region decreased linearly with PD progression (P = 0.001). PIGD patients showed significant decreases in CNR mean values in lateral SN compared to TD patients (P = 0.004). Diagnostic accuracy of using lateral substantia nigra (SN) in TD and PIGD groups was 79% (sensitivity 76.5%, specificity 78.6%). NM concentration in PD patients decreases gradually during disease progression and differs significantly between PD subtypes. NM may be a reliable biomarker for PD severity and subtype identification.

Two native types of phytochrome A, phyAʹ and phyAʺ, differ by the state of phosphorylation at the N-terminus as revealed by fluorescence investigations of the Ser/Ala mutant of rice phyA expressed in transgenic Arabidopsis

2018 ◽  
Vol 45 (2) ◽  
pp. 150 ◽  
Author(s):  
Vitaly A. Sineshchekov ◽  
Larissa A. Koppel ◽  
Cordelia Bolle
Keyword(s):  
Transgenic Arabidopsis ◽  
Emission Spectra ◽  
Total Content ◽  
The State ◽  
Serine Phosphorylation ◽  
Phytochrome A ◽  
Wild Type ◽  
Etiolated Seedlings ◽  
Pre Treatment

Phytochrome A (phyA) mediates different photoresponses what may be connected with the existence of its two types, phyAʹ and phyAʹʹ, differing by spectroscopic, photochemical and functional properties. We investigated a role of phyA phosphorylation in their formation turning to transgenic Arabidopsis thaliana (L. Heynh.) phyA or phyAphyB mutants overexpressing rice wild-type phyA (phyA WT) or mutant phyA (phyA SA) with the first 10 serines substituted by alanines. This prevents phyA phosphorylation at these sites and modifies photoresponses. Etiolated seedlings were employed and phyA parameters were evaluated with the use of low temperature fluorescence spectroscopy and photochemistry. Germination of seeds was induced by white light (WL) pre-treatment for 15 min or 3 h. Emission spectra of rice phyA WT and phyA SA were similar and their total content was comparable. However, the phyAʹ/phyAʹʹ proportion in phyA WT was high and varied with the duration of the WL pre-treatment, whereas in phyA SA it was substantially shifted towards phyAʹʹ and did not depend on the pre-illumination. This suggests that phyA SA comprises primarily or exclusively the phyAʹʹ pool and supports the notion that the two phyA types differ by the state of serine phosphorylation. phyAʹʹ was also found to be much more effective in the germination induction than phyAʹ.

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 Effect of various extracts of Tabernaemontana divaricata on haloperidol induced catalepsy in rats

2014 ◽  
Vol 3 (3) ◽  
pp. 240-242 ◽  
Author(s):  
Chanchal N. Raj ◽  
A. Balasubramaniam ◽  
Sayyed Nadeem
Keyword(s):  
Animal Model ◽  
Substantia Nigra ◽  
Neurodegenerative Diseases ◽  
Pharmaceutical Journal ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Selective Loss ◽  
Tabernaemontana Divaricata ◽  
Medicinal Use ◽  
Different Doses

Parkinson’s disease (PD) is one of the neurodegenerative diseases with selective loss of dopamine neurons of the substantia nigra pars compacta. In the present study, anti-cataleptic activity of Tabernaemontana divaricata leaves extracts viz. aqueous and ethanolic at different doses (50, 100 and 150 mg/kg i.p.) were studied using haloperidol (1 mg/kg, i.p.) induced catalepsy in rats which is a useful animal model for screening drugs for Parkinson’s disease. Both the extracts were found to reduce catalepsy significantly (P<0.001) as compared to the haloperidol treated rats showing greater effect at 150 mg/kg i.p. dose. Thus the present study reveals the anti-cataleptic activity of Tabernaemontana divaricata evaluating the traditional folklore medicinal use of the plant.DOI: http://dx.doi.org/10.3329/icpj.v3i3.17891 International Current Pharmaceutical Journal, February 2014, 3(3): 240-242

Low-Threshold L-type Calcium Channels in Rat Dopamine Neurons

2004 ◽  
Vol 91 (3) ◽  
pp. 1450-1454 ◽  
Author(s):  
P. Durante ◽  
C. G. Cardenas ◽  
J. A. Whittaker ◽  
S. T. Kitai ◽  
R. S. Scroggs
Keyword(s):  
Ganglion Cells ◽  
Oscillatory Potentials ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Whole Cell ◽  
Voltage Range ◽  
Channel Current ◽  
Whole Cell Patch Clamp ◽  
P Type ◽  
Dorsal Root Ganglion Cells

Ca2+ channel subtypes expressed by dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) were studied using whole cell patch-clamp recordings and blockers selective for different channel types (L, N, and P/Q). Nimodipine (Nim, 2 μM), ω-conotoxin GVIA (Ctx, 1 μM), or ω-agatoxin IVA (Atx, 50 nM) blocked 27, 36, and 37% of peak whole cell Ca2+ channel current, respectively, indicating the presence of L-, N-, and P-type channels. Nim blocked approximately twice as much Ca2+ channel current near activation threshold compared with Ctx or Atx, suggesting that small depolarizations preferentially opened L-type versus N- or P-type Ca2+ channels. N- and L-channels in DA neurons opened over a significantly more negative voltage range than those in rat dorsal root ganglion cells, recorded from using identical conditions. These data provide an explanation as to why Ca2+-dependent spontaneous oscillatory potentials and rhythmic firing in DA neurons are blocked by L-channel but not N-channel antagonists and suggest that pharmacologically similar Ca2+ channels may exhibit different thresholds for activation in different types of neurons.

scholarly journals Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo

2020 ◽  
Author(s):  
Melissa Conti Mazza ◽  
Victoria Nguyen ◽  
Alexandra Beilina ◽  
Jinhui Ding ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Association Studies ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Genome Wide Association Studies ◽  
Double Knockout ◽  
Knockout Mouse Model

AbstractCoding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

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