scholarly journals Substantia nigra degradation results in widespread changes in medial zona incerta afferent and efferent connectomics

2021 ◽  
Author(s):  
Linda H Kim ◽  
Taylor Chomiak ◽  
Michelle Tran ◽  
Stephanie Tam ◽  
Shane EA Eaton ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Marked Reduction ◽  
Complex Disease ◽  
Freezing Of Gait ◽  
Brain Regions ◽  
Afferent Input ◽  
Zona Incerta ◽  
Substantia Nigra Pars Compacta ◽  
Area Of Interest ◽  
Gait Dysfunction

Parkinson disease (PD) is a complex disease affecting many facets of movement, especially gait abnormalities such as shuffling and freezing of gait. The nigrostriatal pathways of the basal ganglia are traditionally targeted by existing therapies; however, other pathways may be more relevant to gait, such as the pedunculopontine nucleus and the zona incerta (ZI). The A13 nucleus may be such a target as it has emerged as an area of interest in dopamine motor function. Yet, this area remains understudied compared to other dopamine nuclei, especially in animal models of PD. In 6-OHDA mice, we found a reduction in locomotion in the open field and gait dysfunction during treadmill tests. Medial ZI dopamine cells, containing the A13 nucleus, were preserved following 6-OHDA, in contrast to a marked reduction in substantia nigra pars compacta (SNc) neurons. There was extensive remodelling of the A13 afferent and efferent connectome following nigrostriatal lesions. Afferent input patterns displayed a marked reduction in cross-correlation across brain regions in 6-OHDA mice, while efferent projections showed an increase. In a human PD patient with advanced gait dysfunction we found that the A13 nucleus was preserved, suggesting that remodelling could also occur in humans. This work points to the A13 region as a potential therapeutic target in PD.

scholarly journals nNOS-expressing neurons in the ventral tegmental area and substantia nigra pars compacta

2018 ◽  
Author(s):  
Eleanor J Paul ◽  
Eliza Kalk ◽  
Kyoko Tossell ◽  
Elaine E. Irvine ◽  
Dominic J. Withers ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Brain Regions ◽  
Substantia Nigra Pars Compacta ◽  
Neuron Activity ◽  
Potential Candidate ◽  
Gaba Neurons ◽  
Local Interneurons ◽  
Ventral Tegmental ◽  
Oxide Synthase

AbstractGABA neurons in the ventral tegmental area (VTA) and substantia nigra pars compact (SNc) play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range projections to several target regions including the nucleus accumbens. It is not clear if some of these GABA neurons are dedicated local interneurons or if they all collateralize and send projections externally as well as making local synaptic connections. Testing between these possibilities has been challenging in the absence of interneuron-specific molecular markers. We hypothesised that one potential candidate might be neuronal nitric oxide synthase (nNOS), a common interneuronal marker in other brain regions. To test this, we used a combination of immunolabelling (including antibodies for nNOS that we validated in tissue from nNOS-deficient mice) and cell-type-specific virus-based anterograde tracing in mice. We show that nNOS-expressing neurons in the parabrachial pigmented (PBP) part of the VTA and the SNc are GABAergic local interneurons, whereas nNOS-expressing neurons in the Rostral Linear Nucleus (RLi) are mostly glutamatergic and project to a number of regions, including the lateral hypothalamus, the ventral pallidum, and the median raphe nucleus. Taken together, these findings indicate that nNOS is expressed by neurochemically- and anatomically-distinct neuronal sub-groups in a sub-region-specific manner in the VTA and SNc.

scholarly journals Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

2020 ◽  
Author(s):  
Johannes Burtscher ◽  
Jean-Christophe Copin ◽  
Carmen Sandi ◽  
Hilal A. Lashuel
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Early Stage ◽  
Relevant Literature ◽  
Brain Regions ◽  
Substantia Nigra Pars Compacta ◽  
Ros Generation

AbstractIncreasing evidence suggests that crosstalk between α-synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinson’s disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinson’s disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology.Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala.We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinson’s disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as α-synuclein pathology in male mice.Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions.Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model.Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinson’s disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of α-synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.

scholarly journals Complex Network-Driven View of Genomic Mechanisms Underlying Parkinson’s Disease: Analyses in Dorsal Motor Vagal Nucleus, Locus Coeruleus, and Substantia Nigra

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Beatriz Raposo Corradini ◽  
Priscila Iamashita ◽  
Edilaine Tampellini ◽  
José Marcelo Farfel ◽  
Lea Tenenholz Grinberg ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Locus Coeruleus ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Substantia Nigra Pars Compacta ◽  
Gene Sets ◽  
Coexpression Networks ◽  
Ageing Brain

Parkinson’s disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient’s group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms.

scholarly journals Transcriptome responses to reduced dopamine in the Substantia Nigra Pars Compacta reveals a potential protective role for dopamine

2018 ◽  
Author(s):  
M. Koltun ◽  
K. Cichewicz ◽  
J.T. Gibbs ◽  
M. Darvas ◽  
J. Hirsh
Keyword(s):  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Brain Regions ◽  
Protective Role ◽  
Differentially Expressed ◽  
Substantia Nigra Pars Compacta ◽  
Selective Depletion ◽  
Transcriptional Changes ◽  
Dopaminergic Genes

AbstractParkinson’s Disease (PD), is a neurodegenerative disorder affecting both cognitive and motor functions. It is characterized by decreased brain dopamine (DA) and a selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), whereas dopaminergic neurons in the ventral tegmental area (VTA) show reduced vulnerability. The majority of animal models of PD are genetic lesion or neurotoxin exposure models that lead to death of dopaminergic neurons. Here we use a DAT:TH KO mouse model that by inactivation of the tyrosine hydroxylase (Th) gene in dopamine transporter-expressing neurons, causes selective depletion of striatal dopamine without affecting DA neuron survival. We analyzed transcriptome responses to decreased DA in both pre- and post-synaptic dopaminergic brain regions of DAT:TH KO animals. We detected only few differentially expressed genes in the post-synaptic regions as a function of DA deficiency. This suggests that the broad striatal transcriptional changes in neurodegeneration-based PD models are not direct effects of DA depletion, but are rather a result of DA neuronal death. However, we find a number of dopaminergic genes differentially expressed in SNc, and to a lesser extent in VTA, as a function of DA deficiency, providing evidence for a DA-dependent feedback loop. Of particular interest, expression ofNr4a2, a crucial transcription factor maintaining DA neuron identity, is significantly decreased in SNc, but not VTA, of DAT:TH KO mice, implying a potential protective role for DA in the SNc.

scholarly journals In vivo long-lasting alterations of central serotonin transporter activity and associated dopamine synthesis after acute repeated administration of methamphetamine

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Wen-Sheng Huang ◽  
Guann-Juh Chen ◽  
Tung-Han Tsai ◽  
Chen-Yi Cheng ◽  
Chyng-Yann Shiue ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Serotonin Transporter ◽  
Pet Imaging ◽  
Repeated Administration ◽  
Brain Regions ◽  
Male Rats ◽  
Substantia Nigra Pars Compacta ◽  
Dopamine Synthesis ◽  
Dependent Manner

Abstract Background Methamphetamine (METH)-associated alterations in the striatal dopamine (DA) system or dopamine transport (DAT) have been identified in clinical and preclinical studies with positron emission tomography (PET) imaging but have not been well correlated with in vivo serotonin transporter (SERT) availability due to the lack of appropriate imaging agents to assess SERTs. N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio) benzylamine (4-[18F]-ADAM) has been developed by our group and validated for its high affinity and selectivity for SERTs, allowing the in vivo examination of SERT density, location, and binding function. The aims of this study were to investigate the potential of SERT imaging using 4-[18F]-ADAM PET to estimate the long-lasting effects of METH-induced serotonergic neurotoxicity, and further determine whether a correlative relationship exists between SERT availability/activity and tyrosine hydroxylase (TH) activity in various brain regions due to the long-lasting consequences of METH treatment. Results Male rats received four administrations of METH (5 or 10 mg/kg, s.c.) or saline (1 ml/kg, s.c.) at 1-h intervals. At 30 days post-administration, in vivo SERT availability and activity were measured by 4-[18F]ADAM PET imaging. In contrast to the controls, the uptake of 4-[18F]ADAM in METH-treated mice was significantly reduced in a dose-dependent manner in the midbrain, followed by the hypothalamus, thalamus, striatum, hippocampus, and frontal cortex. The regional effects of METH on TH activity were assessed by quantitative immunohistochemistry and presented as integrated optical density (IOD). A significant decrease in TH immunostaining and IOD ratios was seen in the caudate, putamen, nucleus accumbens, substantia nigra pars compacta, and substantia nigra pars reticulata in the METH-treated rats compared to controls. Conclusion The present results suggested that the long-lasting response to METH decreased the uptake of 4-[18F]-ADAM and varied regionally along with TH immunoreactivity. In addition, 4-[18F]ADAM PET could be used to detect serotonergic neuron loss and to evaluate the severity of serotonergic neurotoxicity of METH.

scholarly journals Neuroinflammation and protein pathology in Parkinson’s disease dementia

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Antonina Kouli ◽  
Marta Camacho ◽  
Kieren Allinson ◽  
Caroline H. Williams-Gray
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
T Lymphocytes ◽  
Substantia Nigra ◽  
Amyloid Β ◽  
Brain Regions ◽  
Parkinson’S Disease Dementia ◽  
Activated Microglia ◽  
Cell Counts ◽  
The Brain

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

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 Incerto-thalamic modulation of fear via GABA and dopamine

2021 ◽  
Author(s):  
Archana Venkataraman ◽  
Sarah C. Hunter ◽  
Maria Dhinojwala ◽  
Diana Ghebrezadik ◽  
JiDong Guo ◽  
...  
Keyword(s):  
Brain Regions ◽  
Zona Incerta ◽  
Dependent Manner ◽  
Post Traumatic Stress ◽  
Functional Roles ◽  
Functional Connections ◽  
Optogenetic Stimulation ◽  
Fear Generalization ◽  
Stimulation Of

AbstractFear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.

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