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1.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299015

RESUMO

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity.


Assuntos
Alcaloides/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzodioxóis/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pentanonas/farmacologia , Pirrolidinas/farmacologia , Ácido gama-Aminobutírico/metabolismo
2.
Biochemistry (Mosc) ; 86(6): 704-715, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225593

RESUMO

Early-life stress is a risk factor for the development of behavioral and cognitive disorders in humans and animals. Such stressful situations include social isolation in early postnatal ontogenesis. Behavioral and cognitive impairments associated with neuroplastic changes in brain structures. We have found that after ten weeks of social isolation, male Wistar rats show behavioral abnormalities and cognitive deficit, accompanied by an increase in the relative expression of gene encoding serine protease prolyl endopeptidase (PREP, EC 3.4.21.26) in the brain frontal cortex. The present study aimed to assess synaptophysin (SYP), brain-derived neurotrophic factor precursor (proBDNF), and PREP expression using Western blot in the brain structures - the hippocampus, frontal cortex, and striatum of the rats subjected to prolonged social isolation compared with group-housed animals. Twenty Wistar rats were used for this study (10 males and 10 females). Experimental animals (5 males and 5 females) were kept one per cage for nine months, starting from the age of one month. Ten-month-old socially isolated rats showed memory deficit in passive avoidance paradigm and Morris Water Maze and reactivity to novelty reduction. We used monoclonal antibodies for the Western blot analysis of the expression of SYP, proBDNF, and PREP in the rat brain structures. Social isolation caused a proBDNF expression reduction in the frontal cortex in females and a reduction in PREP expression in the striatum in males. These data suppose that neurotrophic factors and PREP are involved in the mechanisms of behavioral and cognitive impairments observed in the rats subjected to prolonged social isolation with an early life onset.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Encéfalo/metabolismo , Prolil Oligopeptidases/genética , Isolamento Social , Estresse Psicológico/metabolismo , Animais , Feminino , Lobo Frontal/metabolismo , Regulação da Expressão Gênica , Hipocampo/metabolismo , Masculino , Plasticidade Neuronal , Ratos , Ratos Wistar , Estresse Psicológico/enzimologia , Estresse Psicológico/genética , Sinaptofisina/genética
3.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299103

RESUMO

In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Citalopram/farmacologia , Depressão/tratamento farmacológico , Proteína 2 de Ligação a Metil-CpG/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Psicológico/complicações , Animais , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Caspase 3/genética , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Ratos , Ratos Wistar
4.
Science ; 372(6549)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34324427

RESUMO

The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that mouse MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with considerably modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.


Assuntos
Repetições de Dinucleotídeos , Proteína 2 de Ligação a Metil-CpG/metabolismo , Repetições de Microssatélites , Nucleossomos/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/química , 5-Metilcitosina/metabolismo , Animais , Células Cultivadas , Cromatina/química , Cromatina/metabolismo , Cromatina/ultraestrutura , Citosina/química , Citosina/metabolismo , Metilação de DNA , Células-Tronco Embrionárias/metabolismo , Fibroblastos , Lobo Frontal/metabolismo , Proteína 2 de Ligação a Metil-CpG/química , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Neurônios/metabolismo , Conformação de Ácido Nucleico , Oxirredução , Ligação Proteica , Domínios Proteicos , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Transcrição Genética
5.
Theranostics ; 11(14): 6644-6667, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093845

RESUMO

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. Methods: TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [18F]DPA-714 (TSPO, neuroinflammation), [18F]Florbetaben (Aß) and [18F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[18F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aß, NeuN, NeuroChrom) and Tau (S)-[18F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [18F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [18F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [18F]Florbetaben PET scanning detected Aß accumulation at 18 m, and (S)-[18F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aß plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aß plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aß plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By in vivo MRS, we showed a decrease in neuronal marker N-acetyl-aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and -31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG). Conclusions: This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in vivo in this model, validated by robust ex vivo approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by ex vivo techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Espectroscopia de Ressonância Magnética , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Doença de Alzheimer/patologia , Animais , Escala de Avaliação Comportamental , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Feminino , Radioisótopos de Flúor , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Gliose/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Imuno-Histoquímica , Inflamação/metabolismo , Locomoção/genética , Locomoção/fisiologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Transgênicos , Receptores Colinérgicos/metabolismo , Tálamo/metabolismo , Tálamo/patologia
6.
Am J Respir Cell Mol Biol ; 65(4): 403-412, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34014798

RESUMO

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.


Assuntos
Anticorpos/farmacologia , Apoptose/efeitos dos fármacos , Delírio/metabolismo , Interleucina-6/antagonistas & inibidores , Neurônios/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Delírio/tratamento farmacológico , Delírio/patologia , Modelos Animais de Doenças , Feminino , Lobo Frontal/lesões , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Hipocampo/lesões , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Camundongos , Neurônios/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia
7.
Psychopharmacology (Berl) ; 238(8): 2349-2364, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34032876

RESUMO

RATIONALE: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a potent serotonin 5-HT2A/2C receptor agonist with hallucinogenic activity. There is no data on the 25I-NBOMe effect on brain neurotransmission and animal performance after chronic administration. OBJECTIVES: We examined the effect of a 7-day treatment with 25I-NBOMe (0.3 mg/kg/day) on neurotransmitters' release and rats' behavior in comparison to acute dose. METHODS: Changes in dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release were studied using microdialysis in freely moving rats. The hallucinogenic activity was measured in the wet dog shake (WDS) test. The animal locomotion was examined in the open field (OF) test, short-term memory in the novel object recognition (NOR) test. The anxiogenic/anxiolytic properties of the drug were tested using the light/dark box (LDB) test. RESULTS: Repeated administration of 25I-NBOMe decreased the response to a challenge dose of DA, 5-HT, and glutamatergic neurons in the frontal cortex as well as weakened the hallucinogenic activity in comparison to acute dose. In contrast, striatal and accumbal DA and 5-HT release and accumbal but not striatal glutamate release in response to the challenge dose of 25I-NBOMe was increased in comparison to acute treatment. The ACh release was increased in all brain regions. Behavioral tests showed a motor activity reduction and memory deficiency in comparison to a single dose and induction of anxiety after the drug's chronic and acute administration. CONCLUSIONS: Our findings suggest that multiple injections of 25I-NBOMe induce tolerance to hallucinogenic activity and produce alterations in neurotransmission. 25I-NBOMe effect on short-term memory, locomotor function, and anxiety seems to be the result of complex interactions between neurotransmitter pathways.


Assuntos
Química Encefálica/efeitos dos fármacos , Dimetoxifeniletilamina/análogos & derivados , Alucinógenos/farmacologia , Locomoção/efeitos dos fármacos , Animais , Química Encefálica/fisiologia , Dimetoxifeniletilamina/farmacologia , Dopamina/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Ácido Glutâmico/metabolismo , Locomoção/fisiologia , Masculino , Microdiálise/métodos , Ratos , Ratos Wistar , Serotonina/metabolismo
8.
Exp Mol Pathol ; 120: 104636, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33838119

RESUMO

Alzheimer's disease (AD) is an incurable neurodegenerative condition resulting in progressive cognitive decline. Pathological features include Aß plaques, neurofibrillary tangles, neuroinflammation and neuronal death. Purinergic receptors 7 and 4 (P2X7R and P2X4R) and calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) are implicated in neuronal death. We used immunohistochemistry to investigate the distribution of these proteins in neurones from frontal cortex of donors (n = 3/group; aged 79-83 years) who died with and without AD. Neurones were identified morphologically and immunoperoxidase staining was achieved using commercial antibodies. Immunoreactive neurones were counted for each protein by 2-3 raters blinded to the diagnoses. We observed no differences in percentages of P2X7R, P2X4R or CaMKK2 positive neurones (p = 0.2-0.99), but sections from individuals with AD had marginally fewer neurones (p = 0.10). Hence P2X7R, P2X4R or CaMKK2 appear to be expressed in neurones from older donors, but expression does not associate with AD.


Assuntos
Doença de Alzheimer/patologia , Biomarcadores/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Lobo Frontal/patologia , Células Piramidais/patologia , Receptores Purinérgicos P2X4/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Estudos de Casos e Controles , Feminino , Lobo Frontal/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Prognóstico , Células Piramidais/metabolismo
9.
J Stroke Cerebrovasc Dis ; 30(6): 105766, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33866227

RESUMO

BACKGROUND AND PURPOSE: In subarachnoid hemorrhage (SAH), impairments in motor and cognitive functions may occur and continue in later periods. MicroRNAs (miRNAs) are small non-coding RNAs that can directly or indirectly affect synaptic reconstruction. mir-132, mir-134, and mir-138 are the leading miRNAs that can be effective on some neurological functions through its effects on synaptic plasticity in the relevant brain areas. In our study, it was aimed to determine the levels of miRNAs in the hippocampus and frontal lobe of rats exposed to different environmental conditions after the experimental SAH. METHODS: SAH was created using the cisterna magna double blood-injection method. Brain tissues were collected at different times after the last blood injection. Rats were grouped according to the different environmental conditions in which they were kept. Expression levels of miRNAs were performed by qPCR and ultrastructural changes in samples were determined by transmission electron microscopy (TEM). RESULTS: After SAH, miR-132, miR-134, and miR-138 expressions in the frontal lobes of rats increased in impoverished environment on the 7th day and in the enriched environment on the 14th day. It was observed that the myelin and microtubule structures in the axons that were disrupted after SAH were more organized and stable in the enriched environment. CONCLUSIONS: After SAH, different environmental conditions may affect the miRNA levels associated with synaptic plasticity and microtubule organization in the frontal lobe, and this might have some effects especially on cognitive and motor functions related to this brain area.


Assuntos
Lobo Frontal/metabolismo , Hipocampo/metabolismo , MicroRNAs/metabolismo , Microtúbulos/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Hemorragia Subaracnóidea/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Lobo Frontal/ultraestrutura , Hipocampo/patologia , MicroRNAs/genética , Microtúbulos/genética , Microtúbulos/ultraestrutura , Neurônios/ultraestrutura , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/patologia
10.
Biomolecules ; 11(2)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669305

RESUMO

This study demonstrates how exposure to psychosocial crowding stress (CS) for 3, 7, and 14 days affects glutamate synapse functioning and signal transduction in the frontal cortex (FC) of rats. CS effects on synaptic activity were evaluated in FC slices of the primary motor cortex (M1) by measuring field potential (FP) amplitude, paired-pulse ratio (PPR), and long-term potentiation (LTP). Protein expression of GluA1, GluN2B mGluR1a/5, VGLUT1, and VGLUT2 was assessed in FC by western blot. The body's response to CS was evaluated by measuring body weight and the plasma level of plasma corticosterone (CORT), adrenocorticotropic hormone (ACTH), and interleukin 1 beta (IL1B). CS 3 14d increased FP and attenuated LTP in M1, while PPR was augmented in CS 14d. The expression of GluA1, GluN2B, and mGluR1a/5 was up-regulated in CS 3d and downregulated in CS 14d. VGLUTs expression tended to increase in CS 7d. The failure to blunt the effects of chronic CS on FP and LTP in M1 suggests the impairment of habituation mechanisms by psychosocial stressors. PPR augmented by chronic CS with increased VGLUTs level in the CS 7d indicates that prolonged CS exposure changed presynaptic signaling within the FC. The CS bidirectional profile of changes in glutamate receptors' expression seems to be a common mechanism evoked by stress in the FC.


Assuntos
Lobo Frontal/metabolismo , Receptores de Glutamato/biossíntese , Hormônio Adrenocorticotrópico/biossíntese , Animais , Peso Corporal , Corticosterona/biossíntese , Aglomeração , Eletrofisiologia , Ácido Glutâmico , Interleucina-1beta/biossíntese , Potenciação de Longa Duração , Masculino , Modelos Animais , Córtex Motor , Tamanho do Órgão , Ratos , Ratos Wistar , Receptores de AMPA/biossíntese , Receptores de Glutamato Metabotrópico/biossíntese , Receptores de N-Metil-D-Aspartato/biossíntese , Baço/patologia , Estresse Psicológico , Transmissão Sináptica/efeitos dos fármacos , Proteína Vesicular 1 de Transporte de Glutamato/biossíntese , Proteína Vesicular 2 de Transporte de Glutamato/biossíntese
11.
Neurochem Res ; 46(4): 964-979, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33586092

RESUMO

Alzheimer's disease (AD) is a growing health concern worldwide. MicroRNAs (miRNAs) have been extensively studied in many diseases, including AD. To identify differentially expressed miRNAs (DEmiRNAs) and genes specific to AD, we used bioinformatic analyses to investigate candidate miRNA-mRNA pairs involved in the pathogenesis of AD. We focused on differentially expressed genes (DEGs) that are targets of DEmiRNAs. The GEO2R tool and the HISAT2-DESeq2 software were used to identify DEmiRNAs and DEGs. Bioinformatic tools available online, such as TAM and the Database for Annotation, Visualization and Integrated Discovery (DAVID), were used to perform functional annotation and enrichment analysis. Targets of miRNAs were predicted using the miRTarBase. The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape, which are available online, were utilized to construct protein-protein interaction (PPI) networks and identify hub genes. Furthermore, transcription factors (TFs) encoded by the DEGs were predicted using the TransmiR database and TF-miRNA-mRNA networks were constructed. Finally, the expression profile of a hub gene in peripheral blood mononuclear cells was compared between healthy individuals and AD patients. We identified 26 correlated miRNA-mRNA pairs. In the parietal lobe, miRNA-mRNA pairs involved in protein folding were enriched, and in the frontal lobe, miRNA-mRNA pairs involved in synaptic transmission, abnormal protein degradation, and apoptosis were enriched. In addition, HSP90AB1 in peripheral blood mononuclear cells was found to be significantly downregulated in AD patients, and this was consistent with its expression profile in the parietal lobe of AD patients. Our results provide brain region-specific changes in miRNA-mRNA associations in AD patients, further our understanding of potential underlying molecular mechanisms of AD, and reveal promising diagnostic and therapeutic targets for AD.


Assuntos
Doença de Alzheimer/metabolismo , Lobo Frontal/metabolismo , MicroRNAs/metabolismo , Lobo Parietal/metabolismo , RNA Mensageiro/metabolismo , Doença de Alzheimer/genética , Biologia Computacional , Bases de Dados Genéticas , Regulação para Baixo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , MicroRNAs/genética , Mapas de Interação de Proteínas , RNA Mensageiro/genética , Regulação para Cima
12.
Nat Methods ; 18(3): 283-292, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33589836

RESUMO

Genome-wide profiling of histone modifications can reveal not only the location and activity state of regulatory elements, but also the regulatory mechanisms involved in cell-type-specific gene expression during development and disease pathology. Conventional assays to profile histone modifications in bulk tissues lack single-cell resolution. Here we describe an ultra-high-throughput method, Paired-Tag, for joint profiling of histone modifications and transcriptome in single cells to produce cell-type-resolved maps of chromatin state and transcriptome in complex tissues. We used this method to profile five histone modifications jointly with transcriptome in the adult mouse frontal cortex and hippocampus. Integrative analysis of the resulting maps identified distinct groups of genes subject to divergent epigenetic regulatory mechanisms. Our single-cell multiomics approach enables comprehensive analysis of chromatin state and gene regulation in complex tissues and characterization of gene regulatory programs in the constituent cell types.


Assuntos
Lobo Frontal/metabolismo , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Código das Histonas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Animais , Linhagem Celular Tumoral , Cromatina/metabolismo , Epigênese Genética/genética , Lobo Frontal/citologia , Perfilação da Expressão Gênica , Células HeLa , Hipocampo/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Processamento de Proteína Pós-Traducional , Análise de Célula Única , Transcriptoma/genética
13.
Transl Psychiatry ; 11(1): 139, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627625

RESUMO

Accumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer's disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, ß-amyloid (Aß) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brain's transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P = 0.005) but not the other four personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P < 0.05) with four neuronal modules, which are more related to PHFtau than Aß across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P = 0.008). To conclude, neuroticism has a broad impact on the transcriptome of human brains, and its effect on cognitive decline and AD may be mediated through gene transcription programs related to TAU pathology.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Lobo Frontal/metabolismo , Humanos , Neuroticismo , Transcriptoma , Proteínas tau/metabolismo
14.
Neuroimage ; 230: 117795, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33503483

RESUMO

Neuroimaging research frequently demonstrates load-dependent activation in prefrontal and parietal cortex during working memory tasks such as the N-back. Most of this work has been conducted in fMRI, but functional near-infrared spectroscopy (fNIRS) is gaining traction as a less invasive and more flexible alternative to measuring cortical hemodynamics. Few fNIRS studies, however, have examined how working memory load-dependent changes in brain hemodynamics relate to performance. The current study employs a newly developed and robust statistical analysis of task-based fNIRS data in a large sample, and demonstrates the utility of data-driven, multivariate analyses to link brain activation and behavior in this modality. Seventy participants completed a standard N-back task with three N-back levels (N = 1, 2, 3) while fNIRS data were collected from frontal and parietal cortex. Overall, participants showed reliably greater fronto-parietal activation for the 2-back versus the 1-back task, suggesting fronto-parietal fNIRS measurements are sensitive to differences in cognitive load. The results for 3-back were much less consistent, potentially due to poor behavioral performance in the 3-back task. To address this, a multivariate analysis (behavioral partial least squares, PLS) was conducted to examine the interaction between fNIRS activation and performance at each N-back level. Results of the PLS analysis demonstrated differences in the relationship between accuracy and change in the deoxyhemoglobin fNIRS signal as a function of N-back level in eight mid-frontal channels. Specifically, greater reductions in deoxyhemoglobin (i.e., more activation) were positively related to performance on the 3-back task, unrelated to accuracy in the 2-back task, and negatively associated with accuracy in the 1-back task. This pattern of results suggests that the metabolic demands correlated with neural activity required for high levels of accuracy vary as a consequence of task difficulty/cognitive load, whereby more automaticity during the 1-back task (less mid-frontal activity) predicted superior performance on this relatively easy task, and successful engagement of this mid-frontal region was required for high accuracy on a more difficult and cognitively demanding 3-back task. In summary, we show that fNIRS activity can track working memory load and can uncover significant associations between brain activity and performance, thus opening the door for this modality to be used in more wide-spread applications.


Assuntos
Cognição/fisiologia , Análise de Dados , Lobo Frontal/metabolismo , Memória de Curto Prazo/fisiologia , Desempenho Psicomotor/fisiologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Adolescente , Adulto , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Estimulação Luminosa/métodos , Espectroscopia de Luz Próxima ao Infravermelho/normas , Adulto Jovem
15.
Nat Neurosci ; 24(2): 276-287, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432193

RESUMO

Alzheimer's disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus-brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively-from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.


Assuntos
Doença de Alzheimer/metabolismo , Córtex Entorrinal/metabolismo , Lobo Frontal/metabolismo , Neurônios/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Córtex Entorrinal/patologia , Feminino , Lobo Frontal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Neurônios/patologia , Proteínas tau/metabolismo
16.
Psychopharmacology (Berl) ; 238(4): 1111-1120, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33511450

RESUMO

RATIONALE: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. OBJECTIVES: We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits. METHODS: Specific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. RESULTS: While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. CONCLUSIONS: While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.


Assuntos
Comportamento Animal/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Substituição de Aminoácidos , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Genótipo , Hipercinese/genética , Hipercinese/psicologia , Indóis/farmacologia , Masculino , Camundongos , Mutação/genética , Inibição Pré-Pulso/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Filtro Sensorial/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia
17.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33431672

RESUMO

The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's disease (PD) where functional up-regulation of postsynaptic D2 receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the oculomotor system as a model to study reorganization of dopaminergic networks. This model is ideal because this system reorganizes due to frontal-to-parietal shifts in blood oxygen level-dependent (BOLD) activity. We tested the prediction that functional activation plasticity is associated with postsynaptic dopaminergic modifications by combining positron emission tomography/functional magnetic resonance imaging to investigate striatal postsynaptic reorganization of dopamine D2 receptors (using 11C-raclopride) and neural activation in PD. We used covariance (connectivity) statistics at molecular and functional levels to probe striato-cortical reorganization in PD in on/off medication states to show that functional and molecular forms of reorganization are related. D2 binding across regions defined by prosaccades showed increased molecular connectivity between both caudate/putamen and hyperactive parietal eye fields in PD in contrast with frontal eye fields in controls, in line with the shift model. Concerning antisaccades, parietal-striatal connectivity dominated in again in PD, unlike frontal regions. Concerning molecular-BOLD covariance, a striking sign reversal was observed: PD patients showed negative frontal-putamen functional-molecular associations, consistent with the reorganization shift, in contrast with the positive correlations observed in controls. Follow-up analysis in off-medication PD patients confirmed the negative BOLD-molecular correlation. These results provide a link among BOLD responses, striato-cortical synaptic reorganization, and neural plasticity in PD.


Assuntos
Núcleo Caudado/metabolismo , Lobo Frontal/metabolismo , Plasticidade Neuronal , Lobo Parietal/metabolismo , Doença de Parkinson/metabolismo , Putamen/metabolismo , Receptores de Dopamina D2/metabolismo , Idoso , Mapeamento Encefálico , Estudos de Casos e Controles , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/patologia , Dopamina/metabolismo , Antagonistas de Dopamina/uso terapêutico , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Oxigênio/sangue , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/patologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Putamen/efeitos dos fármacos , Putamen/patologia , Racloprida/uso terapêutico , Movimentos Sacádicos/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia
18.
J Neurochem ; 157(4): 963-981, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33025572

RESUMO

Traumatic events during early life have been linked with later life psychopathology. To understand this risk factor, researchers have studied the effects of prenatal and postnatal early life stress on neurochemical changes. Here we review the rodent literature on sex differences and sex-specific impact of early life stress on frontal cortex neurochemistry. This region is implicated in regulating motivation and emotion, which are often disrupted in psychological disorders. The prefrontal cortex (PFC) in particular is one of the last brain regions to develop, and there are sex differences in the rate of this development. To draw direct comparisons between sexes, our review of the literature was restricted to studies where the effects of prenatal or postnatal stress had been described in male and female littermates. This literature included research describing glutamate, γ-amino butyric acid (GABA), corticosteroids, monoamines, and cannabinoids. We found that sex-dependent effects of stress are mediated by the age at which stress is experienced, age at test, and type of stress endured. More research is required, particularly into the effects of adolescent stress on male and female littermates. We hope that a greater understanding of sex-specific susceptibilities in response to stress across development will help to uncover risk factors for psychological disorders in vulnerable populations.


Assuntos
Experiências Adversas da Infância , Lobo Frontal , Caracteres Sexuais , Estresse Psicológico , Animais , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Humanos , Masculino , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia
19.
Comput Methods Biomech Biomed Engin ; 24(2): 115-121, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32915075

RESUMO

BACKGROUND: Understanding the mechanisms associated with locomotor networks may be of benefit for rehabilitation of burn victims with neurological locomotor deficits. A wearable functional near-infrared spectroscopy (fNIRS) device has been developed for studying cortical hemodynamics. OBJECTIVES: To investigate cortical brain activity during usual walking, we examined patterns of cortical activation using fNIRS device (NIRSIT®; OBELAB Inc., Seoul, Korea), in patients with neurological injury caused by lower extremity burns. METHODS: This cross-sectional study assessed 15 patients with lower extremity burns, 10 patients with upper extremity burns, and 11 healthy controls. We measured walking-related cortical activity using an fNIRS device at baseline and during usual walking. RESULTS: There was no significant difference between the burns groups in terms of age (43.50 ± 14.08 and 44.67 ± 6.92 years, P = 1.00), pain score of NRS (Numeric rating scale) (5.83 ± 1.19 and 6.67 ± 1.21, P = 0.18) or the mean time since injury (228.50 ± 83.43 and 199.33 ± 68.84 days, P = 0.78). Measures showed increased cortical activation in the prefrontal cortex in patients with lower extremity burns than in patients with healthy controls(P = 0.015). The measured HbO2 datas of the regions during usual walking in patients with lower extremity burn were insignificantly higher compared with the datas in patient with upper extremity burn (P = 0.302). CONCLUSIONS: The patients with neurological injury due to lower extremity burns significantly rely more on cognitive resources even when performing a usual walking task.


Assuntos
Queimaduras/metabolismo , Lobo Frontal/metabolismo , Extremidade Inferior/patologia , Oxiemoglobinas/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho/instrumentação , Caminhada/fisiologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Projetos Piloto
20.
Neurosci Lett ; 741: 135470, 2021 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-33157174

RESUMO

Morphine is one of the most abused drugs in the world, which has resulted in serious social problems. The frontal association cortex (FrA) has been shown to play a key role in memory formation and drug addiction. N-Methyl-d-aspartate receptors (NMDARs) are abundant in the prefrontal cortex (PFc) and much evidence indicates that GluN2B-containing NMDARs are involved in morphine-induced conditioned place preference (CPP). However, the function of GluN2B in the FrA during morphine-induced CPP has yet to be fully investigated. In the present work, a CPP animal model was employed to measure the expression of phosphorylated (p-) GluN2B (Serine; Ser 1303) in the FrA and NAc in different phases of morphine-induced CPP. We found that p-GluN2B (Ser 1303) was increased in the FrA during the development and reinstatement phases but unchanged in the extinction phase. The use of ifenprodil, a GluN2B-specific antagonist, to block the activity of GluN2B in the two phases attenuated morphine-induced CPP and reinstatement. Furthermore, ifenprodil also blocked morphine-induced upregulation of p-GluN2B (Ser 1303) in the FrA in both phases. These results indicate that GluN2B-containing NMDARs in the FrA may be involved in the regulation of morphine-induced CPP and reinstatement.


Assuntos
Comportamento de Procura de Droga/fisiologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Morfina/administração & dosagem , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Condicionamento Clássico/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Fosforilação
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