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1.
Cell Mol Life Sci ; 81(1): 30, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38212456

RESUMO

BACKGROUND: Lipid droplets (LD), lipid-storing organelles containing neutral lipids like glycerolipids and cholesterol, are increasingly accepted as hallmarks of inflammation. The nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA with over 200 nucleotides, exerts an indispensable impact on regulating both LD agglomeration and autophagy in multiple neurological disorders. However, knowledge as to how NEAT1 modulates the formation of LD and associated signaling pathways is limited. METHODS: In this study, primary microglia were isolated from newborn mice and exposed to oxygen-glucose-deprivation/reoxygenation (OGD/R). To further explore NEAT1-dependent mechanisms, an antisense oligonucleotide (ASO) was adopted to silence NEAT1 under in vitro conditions. Studying NEAT1-dependent interactions with regard to autophagy and LD agglomeration under hypoxic conditions, the inhibitor and activator of autophagy 3-methyladenine (3-MA) and rapamycin (RAPA) were used, respectively. In a preclinical stroke model, mice received intraventricular injections of ASO NEAT1 or control vectors in order to yield NEAT1 knockdown. Analysis of readout parameters included qRT-PCR, immunofluorescence, western blot assays, and behavioral tests. RESULTS: Microglia exposed to OGD/R displayed a temporal pattern of NEAT1 expression, peaking at four hours of hypoxia followed by six hours of reoxygenation. After effectively silencing NEAT1, LD formation and autophagy-related proteins were significantly repressed in hypoxic microglia. Stimulating autophagy in ASO NEAT1 microglia under OGD/R conditions by means of RAPA reversed the downregulation of LD agglomeration and perilipin 2 (PLIN2) expression. On the contrary, application of 3-MA promoted repression of both LD agglomeration and expression of the LD-associated protein PLIN2. Under in vivo conditions, NEAT1 was significantly increased in mice at 24 h post-stroke. Knockdown of NEAT1 significantly alleviated LD agglomeration and inhibited autophagy, resulting in improved cerebral perfusion, reduced brain injury and increased neurological recovery. CONCLUSION: NEAT1 is a key player of LD agglomeration and autophagy stimulation, and NEAT1 knockdown provides a promising therapeutic value against stroke.


Assuntos
RNA Longo não Codificante , Acidente Vascular Cerebral , Animais , Camundongos , Apoptose/genética , Autofagia/genética , Gotículas Lipídicas/metabolismo , Microglia/metabolismo , Oxigênio/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo
2.
Cereb Cortex ; 33(3): 844-864, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-35296883

RESUMO

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.


Assuntos
Emoções , Esfingomielina Fosfodiesterase , Masculino , Camundongos , Animais , Feminino , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo , Consumo de Bebidas Alcoólicas , Ansiedade/metabolismo , Encéfalo/metabolismo , Etanol
3.
Mol Psychiatry ; 26(12): 7403-7416, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34584229

RESUMO

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.


Assuntos
Alcoolismo , Doenças Ósseas , Transtorno Depressivo Maior , Esfingomielina Fosfodiesterase , Alcoolismo/genética , Animais , Doenças Ósseas/genética , Comorbidade , Transtorno Depressivo Maior/genética , Humanos , Camundongos , Morbidade , Esfingomielina Fosfodiesterase/genética
4.
Addict Biol ; 25(3): e12758, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173432

RESUMO

There is still no widely effective pharmacotherapy for alcohol addiction available in the clinic. FK506-binding protein 51 (FKBP51) is a negative regulator of the glucocorticoid receptor signaling pathway that regulates the stress-induced glucocorticoid feedback circuit. Here we asked whether selective inhibitors of FKBP51, exemplified by SAFit2, may serve as a new pharmacological strategy to reduce alcohol consumption and conditioned alcohol effects in a mouse model. We report that a relatively short treatment with SAFit2 (20 mg/kg, ip) reduces ongoing 16 vol% alcohol consumption when administered during free access to alcohol in a two-bottle free-choice test. SAFit2 was also able to reduce alcohol consumption when given during an abstinence period immediately before relapse. In contrast, SAFit2 did not affect alcohol consumption when given during a relapse period after repeated withdrawal from alcohol. SAFit2 (10 and 20 mg/kg, ip) showed no effects when used in an intermittent drinking schedule. When 20 vol% alcohol was only available every other day, SAFit2 had no effect on drinking, no matter whether given during a drinking episode or the day before. SAFit2 (2 and 20 mg/kg, ip) did not affect the expression of an alcohol-induced conditioned place preference (CPP). However, SAFit2 was able to inhibit alcohol-induced reinstatement of an extinguished CPP in a dose-dependent way. Altogether, these data may suggest pharmacological inhibition of FKBP51 as a viable strategy to reduce alcohol seeking and consumption.


Assuntos
Consumo de Bebidas Alcoólicas , Comportamento Animal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Etanol/administração & dosagem , Proteínas de Ligação a Tacrolimo/antagonistas & inibidores , Alcoolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Autoadministração
5.
Addict Biol ; 25(6): e12847, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31828921

RESUMO

Depression and alcohol dependence are associated with increased plasma ceramide concentrations in humans. Pharmacological increase in C16 ceramide concentrations in the dorsal hippocampus (DH) induced a depressive-like phenotype in naïve mice. However, the effects of C16 ceramide on alcohol consumption and anxiety-like behavior as well as the behavioral effects of other ceramide species are yet unknown. Therefore, we investigated whether repeated infusion of ceramides with different fatty acid chain lengths (C8, C16, and C20) into the DH and the basolateral amygdala (BLA) alter alcohol consumption, emotional behavior, and tissue monoamine levels. Our results revealed that C16, but not C8 and C20, ceramide altered alcohol drinking and emotional behavior in a brain region-specific way without altering tissue noradrenaline, dopamine, and serotonin levels in the prefrontal cortex, ventral striatum, and dorsal mesencephalon. In more detail, C16 ceramide increased alcohol consumption when infused into the BLA, but not when infused into the DH. Furthermore, C16 ceramide induced a depressive-like phenotype when infused into the DH, but a predominantly anxiogenic-like phenotype (in a non-social, but not a social context) when infused into the BLA. In turn, alcohol drinking normalized C16 ceramide-induced depressive-like and anxiogenic-like phenotypes. This study demonstrates a complex ceramide species-specific and brain region-specific modulation of alcohol consumption and emotional behavior in mice and provides the framework for future studies investigating the involvement of distinct ceramide species in the regulation of emotional behavior.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Ansiedade/psicologia , Ceramidas/farmacologia , Depressão/psicologia , Córtex Pré-Frontal/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Ceramidas/administração & dosagem , Ceramidas/sangue , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Córtex Pré-Frontal/metabolismo , Serotonina/metabolismo , Comportamento Social , Especificidade da Espécie , Esfingosina/administração & dosagem , Esfingosina/sangue , Esfingosina/farmacologia
6.
Psychopharmacology (Berl) ; 236(7): 2059-2067, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30798401

RESUMO

RATIONALE: Social anxiety disorder (SAD) is highly comorbid with alcohol use disorders, but the complex relationship between social fear and alcohol drinking is poorly understood due to the lack of specific animal models. OBJECTIVES: We investigated whether social fear alters ethanol drinking under both stress-free and stress-inducing conditions and whether ethanol alleviates symptoms of social fear. METHODS: We used the social fear conditioning (SFC) paradigm, an animal model with face and predictive validity to SAD, to induce specific social fear in male CD1 mice, i.e., without comorbid depression or anxiety-like behavior. Plasma corticosterone (CORT) levels were measured in conditioned (SFC+) and unconditioned (SFC-) mice after exposure to non-social or social stimuli. Ethanol drinking was assessed in the two-bottle free-choice paradigm (1) for 16 days under stress-free conditions and (2) for 6 h after exposure to social stimuli. The effects of ethanol drinking and social fear on anxiety-like behavior and taste preference were tested in the elevated plus-maze and sucrose and quinine preference tests. RESULTS: We show that exposure to social but not non-social stimuli leads to higher plasma CORT levels in SFC+ compared with SFC- mice. We also show that social fear decreases voluntary ethanol consumption under stress-free conditions, but increases ethanol consumption after exposure to social stimuli. Ethanol drinking, on the other hand, reduces social fear without altering anxiety-like behavior, locomotor activity, and taste preference. CONCLUSIONS: These results have important clinical connotations as they suggest that voluntary ethanol drinking might specifically reverse symptoms of social fear in a SAD-relevant animal model.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Ansiedade/psicologia , Etanol/administração & dosagem , Medo/psicologia , Relações Interpessoais , Consumo de Bebidas Alcoólicas/sangue , Animais , Ansiedade/sangue , Corticosterona/sangue , Depressão/sangue , Depressão/psicologia , Medo/efeitos dos fármacos , Medo/fisiologia , Masculino , Camundongos
7.
Addict Biol ; 23(3): 904-920, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28776866

RESUMO

Alcohol use disorders are major psychiatric disorders. Correlational studies in humans suggested organizational hormonal effects during embryonic development as a risk factor for adult alcohol dependence. Permanent changes can be induced by the activity of sex hormones, like testosterone. Here, we demonstrate a relationship between prenatal androgen receptor (AR)-activation and adult alcohol as well as water drinking in mice in a sex-dependent fashion. Prenatal AR inhibition using the antagonist flutamide decreased adult male alcohol consumption. In contrast, prenatal AR activation by dihydrotestosterone (DHT) led to an increase in adult alcohol consumption in females. These effects were different in adult water drinking, flutamide increased water consumption in females and DHT increased water consumption in males. Prenatal flutamide reduced locomotion and anxiety in adult males but was ineffective in females. We found that prenatal AR activation controls adult levels of monoaminergic modulatory transmitters in the brain and blood hormone levels in a sex-specific way. RNA-Seq analysis confirmed a prenatal AR mediated control of adult expression of alcohol drinking-related genes like Bdnf and Per2. These findings demonstrate that prenatal androgen activity is a risk factor for the establishment of alcohol consumption in adults by its organizational effects.


Assuntos
Consumo de Bebidas Alcoólicas , Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/farmacologia , Di-Hidrotestosterona/farmacologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Flutamida/farmacologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores Androgênicos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Comportamento de Ingestão de Líquido/fisiologia , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Proteínas Circadianas Period/efeitos dos fármacos , Proteínas Circadianas Period/genética , Gravidez , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Fatores Sexuais , Água
8.
PLoS One ; 12(11): e0188752, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29176856

RESUMO

Prenatal sex hormones exert organizational effects. It has been suggested that prenatal sex hormones affect adult morphological parameters, such as the finger length. Especially the second-to-fourth finger length (2D:4D) ratio has been implicated to be modified when exposed to higher androgen levels in utero. Here we show in a mouse model that experimental manipulation of the prenatal androgen level, by blocking the androgen receptor with flutamide or activating the androgen receptor with dihydrotestosterone (DHT), leads to changes in the length of the fingers of all paws in males and females. In addition to that, also total paw length and the 2D:4D ratio was affected. In males treated with DHT, the 2D:4D ratio was increased, while flutamide-treatment in females led to a reduced 2D:4D ratio. We also measured other parameters, such as head size, body length and tail length and demonstrate that body morphology is affected by prenatal androgen exposure with more prominent effects in females. Another factor that is thought to be influenced by early androgens is handedness. We tested mice for handedness, but did not find a significant effect of the prenatal treatment. These findings demonstrate that prenatal androgen activity is involved in the development of body morphology and might be a useful marker for prenatal androgen exposure.


Assuntos
Extremidades/anatomia & histologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores Androgênicos/metabolismo , Animais , Tamanho Corporal , Di-Hidrotestosterona/farmacologia , Feminino , Flutamida/farmacologia , Lateralidade Funcional/efeitos dos fármacos , Hormônios Esteroides Gonadais/metabolismo , Masculino , Camundongos , Gravidez
9.
Acta Neuropathol ; 133(3): 463-483, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28000031

RESUMO

Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking-but not forced alcohol exposure-reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Etanol/uso terapêutico , Homeostase/genética , Esfingolipídeos/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Animais , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Depressão/genética , Etanol/sangue , Preferências Alimentares/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reflexo de Endireitamento/efeitos dos fármacos , Reflexo de Endireitamento/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Esfingomielina Fosfodiesterase/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
10.
Neuropsychopharmacology ; 41(8): 2024-33, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26717882

RESUMO

Activin, a member of the transforming growth factor-ß family, exerts multiple functions in the nervous system. Originally identified as a neurotrophic and -protective agent, increasing evidence implicates activin also in the regulation of glutamatergic and GABAergic neurotransmission in brain regions associated with cognitive and affective functions. To explore how activin impacts on ethanol potentiation of GABA synapses and related behavioral paradigms, we used an established transgenic model of disrupted activin receptor signaling, in which mice express a dominant-negative activin receptor IB mutant (dnActRIB) under the control of the CaMKIIα promoter. Comparison of GABAA receptor currents in hippocampal neurons from dnActRIB mice and wild-type mice showed that all concentrations of ethanol tested (30-150 mM) produced much stronger potentiation of phasic inhibition in the mutant preparation. In dentate granule cells of dnActRIB mice, tonic GABA inhibition was more pronounced than in wild-type neurons, but remained insensitive to low ethanol (30 mM) in both preparations. The heightened ethanol sensitivity of phasic inhibition in mutant hippocampi resulted from both pre- and postsynaptic mechanisms, the latter probably involving PKCɛ. At the behavioral level, ethanol produced significantly stronger sedation in dnActRIB mice than in wild-type mice, but did not affect consumption of ethanol or escalation after withdrawal. We link the abnormal narcotic response of dnActRIB mice to ethanol to the excessive potentiation of inhibitory neurotransmission. Our study suggests that activin counteracts oversedation from ethanol by curtailing its augmenting effect at GABA synapses.


Assuntos
Ativinas/fisiologia , Etanol/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Receptores de Ativinas/genética , Receptores de Ativinas/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Camundongos , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Proteína Quinase C-épsilon/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Recompensa
11.
Neuropharmacology ; 62(4): 1619-26, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22079159

RESUMO

Fear extinction is defined as the attenuation of a conditioned-fear memory by re-exposing animals to the conditioned stimulus without the aversive stimulus. This process is known to be effectively enhanced via administration of D-cycloserine (DCS), a partial NMDA-receptor agonist. However, other glutamatergic mechanisms, such as interference with metabotropic glutamate receptor (mGluR) subtypes 5 and 7 in the extinction of aversive memories are insufficiently understood. Using the allosteric mGluR5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), and DCS for comparison, we aimed to study how pharmacological blockade of mGluR5 and activation of mGluR7 influenced within- and between-session conditioned-fear extinction training and extinction retention in rats. We show that when injected before extinction training, mGluR7 activation with AMN082 enhanced freezing and thereby attenuated within-session fear extinction, whereas both DCS and the mGluR5 receptor antagonist MPEP had no effect on this process. However, these differential drug effects were not long lasting, as no difference in extinction retention were observed 24 h later. Therefore, we assessed whether the compounds affect 24 h consolidation of extinction training following incomplete extinction training (between-session extinction). Similar to DCS, AMN082- but not MPEP-treated rats showed facilitated extinction retention, as exhibited by decreased freezing. Finally, using fluoxetine, we provide evidence that the effect of AMN082 on between-session extinction retention is most likely not via increasing 5-HT transmission. These findings demonstrate that mGluR7 activation differentially modulates conditioned-fear extinction, in dependence on the protocol employed, and suggests drugs with AMN082-like mechanisms as potential add-on drugs following exposure-based psychotherapy for fear-related human disorders.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Compostos Benzidrílicos/farmacologia , Condicionamento Clássico/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Fluoxetina/farmacologia , Masculino , Piridinas/farmacologia , Ratos , Ratos Wistar , Receptor de Glutamato Metabotrópico 5 , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
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