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1.
Nat Metab ; 5(11): 2002-2019, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37932430

RESUMO

Glucose is the primary source of energy for the brain; however, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production or if it is partially oxidized in astrocytes, as proposed by the astrocyte-neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose metabolism during cognitive processes is missing. Here, we uncover in Drosophila melanogaster a glia-to-neuron alanine transfer involving alanine aminotransferase that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in cholinergic neurons of the olfactory memory center to uphold their increased mitochondrial needs. Alanine, as a mediator of glia-neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.


Assuntos
Alanina , Drosophila , Animais , Drosophila/metabolismo , Alanina/metabolismo , Drosophila melanogaster , Neuroglia/metabolismo , Glicólise , Neurônios/metabolismo , Glucose/metabolismo , Mitocôndrias/metabolismo , Ácido Láctico/metabolismo
2.
Cell Rep ; 36(8): 109620, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433052

RESUMO

Brain function relies almost solely on glucose as an energy substrate. The main model of brain metabolism proposes that glucose is taken up and converted into lactate by astrocytes to fuel the energy-demanding neuronal activity underlying plasticity and memory. Whether direct neuronal glucose uptake is required for memory formation remains elusive. We uncover, in Drosophila, a mechanism of glucose shuttling to neurons from cortex glia, an exclusively perisomatic glial subtype, upon formation of olfactory long-term memory (LTM). In vivo imaging reveals that, downstream of cholinergic activation of cortex glia, autocrine insulin signaling increases glucose concentration in glia. Glucose is then transferred from glia to the neuronal somata in the olfactory memory center to fuel the pentose phosphate pathway and allow LTM formation. In contrast, our results indicate that the increase in neuronal glucose metabolism, although crucial for LTM formation, is not routed to glycolysis.


Assuntos
Memória de Longo Prazo/fisiologia , Neuroglia/metabolismo , Neurônios/metabolismo , Via de Pentose Fosfato/fisiologia , Animais , Astrócitos/metabolismo , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Glucose/metabolismo
3.
PLoS One ; 15(9): e0229475, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915783

RESUMO

The importance of glial cells in the modulation of neuronal processes is now generally accepted. In particular, enormous progress in our understanding of astrocytes and microglia physiology in the central nervous system (CNS) has been made in recent years, due to the development of genetic and molecular toolkits. However, the roles of satellite glial cells (SGCs) and macrophages-the peripheral counterparts of astrocytes and microglia-remain poorly studied despite their involvement in debilitating conditions, such as pain. Here, we characterized in dorsal root ganglia (DRGs), different genetically-modified mouse lines previously used for studying astrocytes and microglia, with the goal to implement them for investigating DRG SGC and macrophage functions. Although SGCs and astrocytes share some molecular properties, most tested transgenic lines were found to not be suitable for studying selectively a large number of SGCs within DRGs. Nevertheless, we identified and validated two mouse lines: (i) a CreERT2 recombinase-based mouse line allowing transgene expression almost exclusively in SGCs and in the vast majority of SGCs, and (ii) a GFP-expressing line allowing the selective visualization of macrophages. In conclusion, among the tools available for exploring astrocyte functions, a few can be used for studying selectively a great proportion of SGCs. Thus, efforts remain to be made to characterize other available mouse lines as well as to develop, rigorously characterize and validate new molecular tools to investigate the roles of DRG SGCs, but also macrophages, in health and disease.


Assuntos
Gânglios Espinais/fisiologia , Macrófagos/fisiologia , Modelos Animais , Células Satélites Perineuronais/fisiologia , Animais , Astrócitos , Técnicas Biossensoriais/métodos , Células Cultivadas , Gânglios Espinais/citologia , Imuno-Histoquímica , Microscopia Intravital/métodos , Camundongos , Camundongos Transgênicos , Sondas Moleculares/química , Sondas Moleculares/genética , Imagem Óptica , Fótons , Cultura Primária de Células
4.
J Neurosci ; 40(21): 4219-4229, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32303647

RESUMO

In Drosophila, the mushroom bodies (MB) constitute the central brain structure for olfactory associative memory. As in mammals, the cAMP/PKA pathway plays a key role in memory formation. In the MB, Rutabaga (Rut) adenylate cyclase acts as a coincidence detector during associative conditioning to integrate calcium influx resulting from acetylcholine stimulation and G-protein activation resulting from dopaminergic stimulation. Amnesiac encodes a secreted neuropeptide required in the MB for two phases of aversive olfactory memory. Previous sequence analysis has revealed strong homology with the mammalian pituitary adenylate cyclase-activating peptide (PACAP). Here, we examined whether amnesiac is involved in cAMP/PKA dynamics in response to dopamine and acetylcholine co-stimulation in living flies. Experiments were conducted with both sexes, or with either sex. Our data show that amnesiac is necessary for the PKA activation process that results from coincidence detection in the MB. Since PACAP peptide is cleaved by the human membrane neprilysin hNEP, we searched for an interaction between Amnesiac and Neprilysin 1 (Nep1), a fly neprilysin involved in memory. We show that when Nep1 expression is acutely knocked down in adult MB, memory deficits displayed by amn hypomorphic mutants are rescued. Consistently, Nep1 inhibition also restores normal PKA activation in amn mutant flies. Taken together, the results suggest that Nep1 targets Amnesiac degradation to terminate its signaling function. Our work thus highlights a key role for Amnesiac in establishing within the MB the PKA dynamics that sustain middle-term memory (MTM) formation, a function modulated by Nep1.SIGNIFICANCE STATEMENT The Drosophila amnesiac gene encodes a secreted neuropeptide whose expression is required for specific memory phases in the mushroom bodies (MB), the olfactory memory center. Here, we show that Amnesiac is required for PKA activation resulting from coincidence detection, a mechanism by which the MB integrate two spatially distinct stimuli to encode associative memory. Furthermore, our results uncover a functional relationship between Amnesiac and Neprilysin 1 (Nep1), a membrane peptidase involved in memory and expressed in the MB. These results suggest that Nep1 modulates Amnesiac levels. We propose that on conditioning, Amnesiac release from the MB allows, via an autocrine process, the sustaining of PKA activation-mediating memory, which subsequently is inactivated by Nep1 degradation.


Assuntos
Aprendizagem da Esquiva/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Drosophila/genética , Memória/fisiologia , Corpos Pedunculados/metabolismo , Neprilisina/metabolismo , Neuropeptídeos/genética , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Neuropeptídeos/metabolismo , Olfato/fisiologia
5.
Psychiatry Res ; 176(1): 17-21, 2010 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-20064665

RESUMO

Inhibition of return (IOR) is a phenomenon thought to reflect a mechanism to protect the organism from redirecting attention to previously scanned insignificant locations. A number of studies reported altered IOR in schizophrenia patients with a reduction of its amplitude. However, incomplete sampling of stimulus onset asynchronies (SOAs) makes data on IOR time course incomplete. We examined 14 stabilized young patients with recent onset schizophrenia and 16 healthy controls matched for gender, age, and years of education. Schizophrenia patients (13 males, 1 female) had a mean age of 26.3+/-5.8 years and a mean number of years of study of 9.6+/-3.6. Their illness had a mean duration of 147 weeks. Patients displayed moderate overall slow reaction times (387 ms) in comparison with controls (322 ms). Onset of IOR was found to be delayed in schizophrenia patients appearing between 700 and 800 ms following the cue onset while it appeared at 300 ms in controls. In patients, IOR was constant up to 1100 ms; however, its amplitude was weak with an average of 6 ms. Validity effects (overall and at each SOA value) were uncorrelated to age, years of study, duration of illness, or total or subscale scores on the Positive and Negative Syndrome Scale.


Assuntos
Atenção/fisiologia , Inibição Psicológica , Tempo de Reação/fisiologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Adulto , Análise de Variância , Estudos de Casos e Controles , Sinais (Psicologia) , Feminino , Humanos , Masculino , Estimulação Luminosa/métodos , Reprodutibilidade dos Testes , Fatores de Tempo , Campos Visuais/fisiologia , Adulto Jovem
6.
BMC Psychiatry ; 9: 66, 2009 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-19814827

RESUMO

BACKGROUND: Despite a huge well-documented literature on cognitive deficits in schizophrenia, little is known about the own perception of patients regarding their cognitive functioning. The purpose of our study was to create a scale to collect subjective cognitive complaints of patients suffering from schizophrenia with Tunisian Arabic dialect as mother tongue and to proceed to a validation study of this scale. METHODS: The authors constructed the Self-Assessment Scale of Cognitive Complaints in Schizophrenia (SASCCS) based on a questionnaire covering five cognitive domains which are the most frequently reported in the literature to be impaired in schizophrenia. The scale consisted of 21 likert-type questions dealing with memory, attention, executive functions, language and praxia. In a second time, the authors proceeded to the study of psychometric qualities of the scale among 105 patients suffering from schizophrenia spectrum disorders (based on DSM- IV criteria). Patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), the Global Assessment Functioning Scale (GAF scale) and the Calgary Depression Scale (CDS). RESULTS: The scale's reliability was proven to be good through Cronbach alpha coefficient equal to 0.85 and showing its good internal consistency. The intra-class correlation coefficient at 11 weeks was equal to 0.77 suggesting a good stability over time. Principal component analysis with Oblimin rotation was performed and yielded to six factors accounting for 58.28% of the total variance of the scale. CONCLUSION: Given the good psychometric properties that have been revealed in this study, the SASCCS seems to be reliable to measure schizophrenic patients' perception of their own cognitive impairment. This kind of evaluation can't substitute for objective measures of cognitive performances in schizophrenia. The purpose of such an evaluation is to permit to the patient to express his own well-being and satisfaction of quality of life.


Assuntos
Transtornos Cognitivos/diagnóstico , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Inquéritos e Questionários , Adulto , Transtornos Cognitivos/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Nível de Saúde , Humanos , Idioma , Masculino , Testes Neuropsicológicos , Psicometria , Qualidade de Vida , Reprodutibilidade dos Testes , Tunísia
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