scholarly journals Positive symptom phenotypes appear progressively in “EDiPS”, a new animal model of the schizophrenia prodrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alice Petty ◽  
Xiaoying Cui ◽  
Asad Ali ◽  
Zilong Du ◽  
Sunil Srivastav ◽  
...  
Keyword(s):  
Animal Model ◽  
Molecular Mechanisms ◽  
Dorsal Striatum ◽  
Male Rats ◽  
Positive Symptom ◽  
Disease Course ◽  
Prodromal Stage ◽  
Genetic Construct ◽  
Behavioural Phenotypes ◽  
Da Release

AbstractAn increase in dopamine (DA) synthesis capacity in the dorsal striatum (DS) during the prodromal stage of schizophrenia becomes more pronounced as patients progress to the full disorder. Understanding this progression is critical to intervening in disease course. We developed an animal model—Enhanced Dopamine in Prodromal Schizophrenia (EDiPS)—which uses a genetic construct to increase DA synthesis capacity in the DS of male rats. We assessed pre-pulse inhibition (PPI) and amphetamine (AMPH)-induced locomotion (0.6 mg/kg) in EDiPS animals longitudinally after post-natal day 35 (when the EDiPS construct is administered). We also assessed their response to repeated acute restraint stress. In adult EDiPS animals, we measured baseline and evoked extracellular DA levels, and their stereotyped responses to 5 mg/kg AMPH. AMPH-induced hyperlocomotion was apparent in EDiPS animals 6-weeks after construct administration. There was an overall PPI deficit in EDiPS animals across all timepoints, however the stress response of EDiPS animals was unaltered. Adult EDiPS animals show normal baseline and potassium-evoked DA release in the DS. These findings suggest that key behavioural phenotypes in EDiPS animals show a progressive onset, similar to that demonstrated by patients as they transition to schizophrenia. The EDiPS model could therefore be used to investigate the molecular mechanisms underlying the prodrome of schizophrenia.

scholarly journals Dopamine D2/3 Receptor Availabilities and Evoked Dopamine Release in Striatum Differentially Predict Impulsivity and Novelty Preference in Roman High- and Low-Avoidance Rats

2020 ◽  
Author(s):  
Lidia Bellés ◽  
Andrea Dimiziani ◽  
Stergios Tsartsalis ◽  
Philippe Millet ◽  
François R Herrmann ◽  
...  
Keyword(s):  
Ventral Striatum ◽  
Single Photon ◽  
Ex Vivo ◽  
Photon Emission ◽  
Dorsal Striatum ◽  
Reaction Time Task ◽  
Emission Computed Tomography ◽  
Novelty Preference ◽  
Da Release

Abstract Background Impulsivity and novelty preference are both associated with an increased propensity to develop addiction-like behaviors, but their relationship and respective underlying dopamine (DA) underpinnings are not fully elucidated. Methods We evaluated a large cohort (n = 49) of Roman high- and low-avoidance rats using single photon emission computed tomography to concurrently measure in vivo striatal D2/3 receptor (D2/3R) availability and amphetamine (AMPH)-induced DA release in relation to impulsivity and novelty preference using a within-subject design. To further examine the DA-dependent processes related to these traits, midbrain D2/3-autoreceptor levels were measured using ex vivo autoradiography in the same animals. Results We replicated a robust inverse relationship between impulsivity, as measured with the 5-choice serial reaction time task, and D2/3R availability in ventral striatum and extended this relationship to D2/3R levels measured in dorsal striatum. Novelty preference was positively related to impulsivity and showed inverse associations with D2/3R availability in dorsal striatum and ventral striatum. A high magnitude of AMPH-induced DA release in striatum predicted both impulsivity and novelty preference, perhaps owing to the diminished midbrain D2/3-autoreceptor availability measured in high-impulsive/novelty-preferring Roman high-avoidance animals that may amplify AMPH effect on DA transmission. Mediation analyses revealed that while D2/3R availability and AMPH-induced DA release in striatum are both significant predictors of impulsivity, the effect of striatal D2/3R availability on novelty preference is fully mediated by evoked striatal DA release. Conclusions Impulsivity and novelty preference are related but mediated by overlapping, yet dissociable, DA-dependent mechanisms in striatum that may interact to promote the emergence of an addiction-prone phenotype.

scholarly journals 17-β-Estradiol Induces Heat Shock Proteins in Brain Arteries and Potentiates Ischemic Heat Shock Protein Induction in Glia and Neurons

2002 ◽  
Vol 22 (2) ◽  
pp. 183-195 ◽  
Author(s):  
Aigang Lu ◽  
Rui-qiong Ran ◽  
Joseph Clark ◽  
Melinda Reilly ◽  
Alex Nee ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Female Rats ◽  
Male Rats ◽  
Western Blots ◽  
Male And Female ◽  
Male And Female Rats

Estradiol reduces brain injury from many diseases, including stroke and trauma. To investigate the molecular mechanisms of this protection, the effects of 17-β-estradiol on heat shock protein (HSP) expression were studied in normal male and female rats and in male gerbils after global ischemia. 17-β-Estradiol was given intraperitoneally (46 or 460 ng/kg, or 4.6 μg/kg) and Western blots performed for HSPs. 17-β-Estradiol increased hemeoxygenase-1, HSP25/27, and HSP70 in the brain of male and female rats. Six hours after the administration of 17-β-estradiol, hemeoxygenase-1 increased 3.9-fold (460 ng/kg) and 5.4-fold (4.6 μg/kg), HSP25/27 increased 2.1-fold (4.6 μg/kg), and Hsp70 increased 2.3-fold (460 ng/kg). Immunocytochemistry showed that hemeoxygenase-1, HSP25/27,and HSP70 induction was localized to cerebral arteries in male rats, possibly in vascular smooth muscle cells. 17-β-Estradiol was injected intraperitoneally 20 minutes before transient occlusion of both carotids in adult gerbils. Six hours after global cerebral ischemia, 17-β-estradiol (460 ng/kg) increased levels of hemeoxygenase-1 protein 2.4-fold compared with ischemia alone, and HSP25/27 levels increased 1.8-fold compared with ischemia alone. Hemeoxygenase-1 was induced in striatal oligodendrocytes and hippocampal neurons, and HSP25/27 levels increased in striatal astrocytes and hippocampal neurons. Finally, Western blot analysis confirmed that estrogen induced heat shock factor-1, providing a possible mechanism by which estrogen induces HSPs in brain and other tissues. The induction of HSPs may be an important mechanism for estrogen protection against cerebral ischemia and other types of injury.

scholarly journals NNK-Induced Lung Tumors: A Review of Animal Model

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Hua-Chuan Zheng ◽  
Yasuo Takano
Keyword(s):  
Lung Cancer ◽  
Animal Model ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Genetic Mutation ◽  
Lung Tumors ◽  
Chemotherapeutic Agents ◽  
Signal Pathways ◽  
Lung Carcinogenesis

The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrupt the expression profiles of some proteins or enzymes in various cellular signal pathways. Transgenic animal with specific alteration of lung cancer-related molecules have also been introduced to clarify the molecular mechanisms of NNK in the pathogenesis and development of lung tumors. Based on these animal models, many antioxidant ingredients and antitumor chemotherapeutic agents have been proved to suppress the NNK-induced lung carcinogenesis. In the future, it is necessary to delineate the most potent biomarkers of NNK-induced lung tumorigenesis, and to develop efficient methods to fight against NNK-associated lung cancer using animal models.

scholarly journals Dopamine Release Neuroenergetics in Mouse Striatal Slices

2020 ◽  
Author(s):  
Msema Msackyi ◽  
Yuanxin Chen ◽  
Wangchen Tsering ◽  
Ninghan Wang ◽  
Jingyu Zhao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nucleus Accumbens ◽  
Oxidative Phosphorylation ◽  
Neurodegenerative Disorder ◽  
Dorsal Striatum ◽  
Striatal Slices ◽  
Axonal Projections ◽  
Specific Vulnerability ◽  
Da Release

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease. Dopamine (DA) neurons in the substantia nigra par compacta with axonal projections to the dorsal striatum (dSTR) degenerate in PD while in contrast, DA neurons in the ventral tegmental area with axonal projections to the ventral striatum including the nucleus accumbens (NAcc) shell, are largely spared. To understand the pathogenesis of PD, it is important to study the neuroenergetics of DA neurons. This study aims to uncover the relative contribution of glycolysis and oxidative phosphorylation (OxPhos) to evoked DA release in the striatum. We measured evoked DA release in mouse striatal brain slices by fast-scan cyclic voltammetry every 2 minutes. Blocking OxPhos caused a greater reduction in evoked DA release in the dSTR compared to the NAcc shell, and blocking glycolysis caused a greater reduction in evoked DA release in the NAcc shell than in the dSTR. Furthermore, when glycolysis was bypassed in favor of direct OxPhos, evoked DA release in the NAcc shell was decreased by ∼50% over 40 minutes whereas evoked DA release in the dSTR was largely unaffected. These results demonstrated that the dSTR relies primarily on OxPhos for energy production to maintain evoked DA release whereas the NAcc shell relies more on glycolysis. Using two-photon imaging, we consistently found that the oxidation level of the DA terminals was higher in the dSTR than in the NAcc shell. Together, these findings partially explain the specific vulnerability of DA terminals in the dSTR to degeneration in PD.Significant statementThe neuroenergetics of dopaminergic neuron is important to understand Parkinson’s disease (PD), a neurodegenerative disorder associated with mitochondrial dysfunctions. However, the relative contributions of glycolysis and oxidative phosphorylation (OxPhos) to presynaptic energy demands in DA terminals are unclear. We addressed this question by measuring DA release in the dorsal striatum and nucleus accumbens (NAcc) shell of mouse brain using FSCV under reagents blocking different energy systems. We found that the NAcc shell relies on both glycolysis and OxPhos to maintain DA release while the dSTR relies heavily on OxPhos. We demonstrate the different neuroenergetics of DA terminals in these two brain areas, providing new fundamentally important insight into the specific vulnerability of DA terminals in the dSTR to degeneration in PD.

scholarly journals MECHANISMS OF NEPHROSCLEROSIS DEVELOPMENT IN CHILDREN WITH VESICOURETERAL REFLUX

2018 ◽  
Vol 17 (3) ◽  
pp. 186-193
Author(s):  
Olga L. Morozova ◽  
Peter F. Litvitskiy ◽  
Dmitri A. Morozov ◽  
Larisa D. Maltseva
Keyword(s):  
Vesicoureteral Reflux ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Reflux Nephropathy ◽  
Disease Development ◽  
Disease Course ◽  
Multiple Choice Tests ◽  
Lecture Material ◽  
Choice Tests ◽  
Higher Medical Education

The lecture discusses the issue of reflux nephropathy for specialists of the system of higher medical education: the article provides the definition, characterizes the epidemiology, risk factors for disease development in children with vesicoureteral reflux, causes and molecular mechanisms of renal fibrosis formation and progression in reflux nephropathy, and markers for diagnosing and predicting the disease course. In order to control the retention of the lecture material, the text includes case problems and multiple-choice tests.

scholarly journals Neurexins Regulate GABA Co-release by Dopamine Neurons

2021 ◽  
Author(s):  
Charles Ducrot ◽  
Gregory de Carvalho ◽  
Benoit Delignat-Lavaud ◽  
Constantin Delmas ◽  
Nicolas Giguere ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dopamine Neurons ◽  
Electrophysiological Recording ◽  
Conditional Deletion ◽  
Synaptic Cell Adhesion Molecules ◽  
Midbrain Dopamine ◽  
Neuron Terminals ◽  
Reduced Rate ◽  
Activity Dependent ◽  
Da Release

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) revealed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings reveal that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions.

The Beneficial Effect of Nanostructured Oligochitosan against Gamma Irradiation and/or Carbon Tetrachloride-Induced Hepatic Injury in Rats

2021 ◽  
pp. 2243-2257
Author(s):  
Enas A. Mohamed ◽  
Ahmed M. Elbarbary ◽  
Nashat M. M. Abd alaty ◽  
Nashwa K. Ibrahim ◽  
Mahmoud M. Said ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Gamma Irradiation ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Molecular Data ◽  
Male Rats ◽  
Transmission Electron ◽  
Ccl4 Intoxication ◽  
Hepatotoxic Effect ◽  
Bax Gene

The current study was undertaken to investigate the hepatoprotective potential of nanostructured oligochitosan (NOC) against the synergistic toxic effects of -irradiation exposure and carbon tetrachloride (CCl4) intoxication in male rats. Adult male rats were allocated into eight groups; control, NOC-administered, -irradiated, CCl4-intoxicated, NOC-pretreated -irradiated, NOC-pretreated CCl4-intoxicated, -irradiated and CCl4-intoxicated, NOC-pretreated CCl4-intoxicated and -irradiated. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results demonstrated that the oligochitosan prepared by exposure to gamma irradiation was in the range of nanoparticles. A synergistic hepatotoxic effect was demonstrated following the exposure of rats to -irradiation and CCl4 intoxication, along with the induction of oxidative stress, inflammation and apoptosis. NOC was able to protect the hepatocytes from the combined toxic insults through suppressing lipid and protein oxidations, maintaining hepatic functions, downregulating the expression of some inflammatory genes, including nuclear factor kappa B (NF-B) and interleukin 1 beta (IL-1β), as well as enhancing the expression of the antiapoptotic Bcl2 gene and suppressing the proapoptotic Bax gene expression. Histological findings of liver tissues verified the biochemical and molecular data. The study clarified some of the molecular mechanisms by which NOC protects the liver against the synergistic toxic effect of -irradiation and CCl4.

scholarly journals Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1966 ◽  
Author(s):  
Helena Xicoy ◽  
Jos F. Brouwers ◽  
Bé Wieringa ◽  
Gerard J. M. Martens
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Molecular Mechanisms ◽  
Lipid Analysis ◽  
Dorsal Striatum ◽  
Receptor Subtype ◽  
Lipid Profiling ◽  
New Genes ◽  
Genes Encoding

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons from the substantia nigra (SN) that project to the dorsal striatum (caudate-putamen). To better understand the molecular mechanisms underlying PD, we performed combined lipid profiling and RNA sequencing of SN and putamen samples from PD patients and age-matched controls. SN lipid analysis pointed to a neuroinflammatory component and included elevated levels of the endosomal lipid Bis (Monoacylglycero)Phosphate 42:8, while two of the three depleted putamen lipids were saturated sphingomyelin species. Remarkably, we observed gender-related differences in the SN and putamen lipid profiles. Transcriptome analysis revealed that the top-enriched pathways among the 354 differentially expressed genes (DEGs) in the SN were “protein folding” and “neurotransmitter transport”, and among the 261 DEGs from putamen “synapse organization”. Furthermore, we identified pathways, e.g., “glutamate signaling”, and genes, encoding, e.g., an angiotensin receptor subtype or a proprotein convertase, that have not been previously linked to PD. The identification of 33 genes that were common among the SN and putamen DEGs, which included the α-synuclein paralog β-synuclein, may contribute to the understanding of general PD mechanisms. Thus, our proof-of-concept data highlights new genes, pathways and lipids that have not been explored before in the context of PD.

scholarly journals Forebrain NgR1 Overexpression Impairs DA Release Suggesting Synergy of Local and Global Synaptic Plasticity Mechanisms

2020 ◽  
Vol 12 ◽  
Author(s):  
Emma Arvidsson ◽  
Sarolta Gabulya ◽  
Alvin Tore Brodin ◽  
Tobias Erik Karlsson ◽  
Lars Olson
Keyword(s):  
Synaptic Plasticity ◽  
Potassium Chloride ◽  
Neural Activity ◽  
Dorsal Striatum ◽  
Inverse Correlation ◽  
Long Term Memory ◽  
The Status ◽  
Global Systems ◽  
Da Release

Structural synaptic reorganizations needed to permanently embed novel memories in the brain involve complex plasticity-enhancing and plasticity-inhibiting systems. Increased neural activity is linked to rapid downregulation of Nogo receptor 1 (NgR1), needed to allow local structural synaptic plasticity. This local regulation of plasticity is thought to be moderated by global systems, such as the ascending cholinergic and monoaminergic systems, adding significance to locally increased neural activity. Here we address the reverse possibility that the global systems may also be influenced by the status of local plasticity. Using NgR1-overexpressing mice, with impaired plasticity and long-term memory, we measured the ability to release dopamine (DA), implicated in regulating plasticity and memory. In vivo chronoamperometric recording with high temporal and spatial resolution revealed severe impairment of potassium chloride (KCl)-induced increase of extracellular DA in the dorsal striatum of mice overexpressing NgR1 in forebrain neurons. A similar, but lesser, impairment of DA release was seen following amphetamine delivery. In contrast, potassium chloride-evoked DA release in NgR1 knockout (KO) mice led to increased levels of extracellular DA. That NgR1 can impair DA signaling, thereby further dampening synaptic plasticity, suggests a new role for NgR1 signaling, acting in synergy with DA signaling to control synaptic plasticity.Significance Statement:The inverse correlation between local NgR1 levels and magnitude of KCl-inducible amounts of DA release in the striatum reinforces the rule of NgR1 as a regulator of structural synaptic plasticity and suggests synergy between local and global plasticity regulating systems.

scholarly journals Altered levels of dopamine transporter in the frontal pole and dorsal striatum in schizophrenia

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Hirotaka Sekiguchi ◽  
Geoff Pavey ◽  
Brian Dean
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Transporter ◽  
Molecular Mechanisms ◽  
Radioligand Binding ◽  
Dorsal Striatum ◽  
Synaptic Cleft ◽  
Human Brain Tissue ◽  
Frontal Pole ◽  
Postmortem Human Brain ◽  
Mazindol Binding

AbstractThe dopamine hypothesis proposes that there is a hypodopaminergic state in the prefrontal cortex and a hyperdopaminergic state in the striatum of patients with schizophrenia. Evidence suggests the hyperdopaminergic state in the striatum is due to synaptic dopamine elevation, particularly in the dorsal striatum. However, the molecular mechanisms causing disrupted dopaminergic function in schizophrenia remains unclear. We postulated that the dopamine transporter (DAT), which regulates intra-synaptic dopamine concentrations by transporting dopamine from the synaptic cleft into the pre-synaptic neuron, could be involved in dopaminergic dysfunction in schizophrenia. Therefore, we measured levels of DAT in the cortex and striatum from patients with schizophrenia and controls using postmortem human brain tissue. Levels of desmethylimipramine-insensitive mazindol-sensitive [3H]mazindol binding to DAT were measured using in situ radioligand binding and autoradiography in gray matter from Brodmann’s area (BA) 10, BA 17, the dorsal striatum, and nucleus accumbens from 15 patients with schizophrenia and 15 controls. Levels of desmethylimipramine-insensitive mazindol-sensitive [3H]mazindol binding were significantly higher in BA 10 from patients with schizophrenia (p = 0.004) and significantly lower in the dorsal striatum (dorsal putamen p = 0.005; dorsal caudate p = 0.007) from those with the disorder. There were no differences in levels of desmethylimipramine-insensitive [3H]mazindol binding in BA 17 or nucleus accumbens. These data raise the possibility that high levels of DAT in BA 10 could be contributing to lower synaptic cortical dopamine, whereas lower levels of DAT could be contributing to a hyperdopaminergic state in the dorsal striatum.

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