RESUMEN
Sleep is a basic, physiological requirement for living things to survive and is a process that covers one third of our lives. Melatonin is a hormone that plays an important role in the regulation of sleep. Sleep deprivation affect brain structures and functions. Sleep deprivation causes a decrease in brain activity, with particularly negative effects on the hippocampus and prefrontal cortex. Despite the essential role of protein and lipids vibrations, polysaccharides, fatty acid side chains functional groups, and ratios between amides in brain structures and functions, the brain chemical profile exposed to gentle handling sleep deprivation model versus Melatonin exposure remains unexplored. Therefore, the present study, aims to investigate a molecular profile of these regions using FTIR spectroscopy measurement's analysis based on lipidomic approach with chemometrics and multivariate analysis to evaluate changes in lipid composition in the hippocampus, prefrontal regions of the brain. In this study, C57BL/6J mice were randomly assigned to either the control or sleep deprivation group, resulting in four experimental groups: Control (C) (n = 6), Control + Melatonin (C + M) (n = 6), Sleep Deprivation (S) (n = 6), and Sleep Deprivation + Melatonin (S + M) (n = 6). Interventions were administered each morning via intraperitoneal injections of melatonin (10 mg/kg) or vehicle solution (%1 ethanol + saline), while the S and S + M groups underwent 6 h of daily sleep deprivation from using the Gentle Handling method. All mice were individually housed in cages with ad libitum access to food and water within a 12-hour light-dark cycle. Results presented that the brain regions affected by insomnia. The structure of phospholipids, changed. Yet, not only changes in lipids but also in amides were noticed in hippocampus and prefrontal cortex tissues. Additionally, FTIR results showed that melatonin affected the lipids as well as the amides fraction in cortex and hippocampus collected from both control and sleep deprivation groups.
Asunto(s)
Hipocampo , Melatonina , Ratones Endogámicos C57BL , Corteza Prefrontal , Privación de Sueño , Animales , Privación de Sueño/fisiopatología , Privación de Sueño/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/química , Corteza Prefrontal/química , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Melatonina/farmacología , Melatonina/análisis , Masculino , Ratones , Lípidos/análisis , Lípidos/químicaRESUMEN
AIMS: Schizophrenia is a chronic relapsing psychiatric disorder that is characterized by many symptoms and has a high heritability. There were studies showing that the phospholipid abnormalities in subjects with schizophrenia (Front Biosci, S3, 2011, 153; Schizophr Bull, 48, 2022, 1125; Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933). Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in subjects with schizophrenia (Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933; Schizophr Res, 215, 2020, 493; J Psychiatr Res, 47, 2013, 636; Int J Mol Sci, 22, 2021). For exploring the signaling pathways contributing to the lipid changes in previous study (Sci Rep, 7, 2017, 6), we performed two types of transcriptome analyses in subjects with schizophrenia: an unbiased transcriptome analysis solely based on RNA-seq data and a correlation analysis between levels of gene expression and lipids. METHODS: RNA-Seq analysis was performed in the postmortem prefrontal cortex from 10 subjects with schizophrenia and 5 controls. Correlation analysis between the transcriptome and lipidome from 9 subjects, which are the same samples in the previous lipidomics study (Sci Rep, 7, 2017, 6). RESULTS: Extraction of differentially expressed genes (DEGs) and further sequence and functional group analysis revealed changes in gene expression levels in phosphoinositide 3-kinase (PI3K)-Akt signaling and the complement system. In addition, a correlation analysis clarified alterations in ether lipid metabolism pathway, which is not found as DEGs in transcriptome analysis alone. CONCLUSIONS: This study provided results of the integrated analysis of the schizophrenia-associated transcriptome and lipidome within the PFC and revealed that lipid-correlated alterations in the transcriptome are enriched in specific pathways including ether lipid metabolism pathway.
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Fosfolípidos , Corteza Prefrontal , Esquizofrenia , Transcriptoma , Humanos , Pueblos del Este de Asia , Éteres/metabolismo , Metabolismo de los Lípidos/genética , Fosfatidilinositol 3-Quinasas/análisis , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfolípidos/análisis , Fosfolípidos/genética , Fosfolípidos/metabolismo , Corteza Prefrontal/química , Corteza Prefrontal/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , AutopsiaRESUMEN
Previous reports indicate that the right ventrolateral prefrontal cortex (VLPFC) is involved in emotional regulation. However, most such studies were performed under unphysiological conditions, like the administration of transcranial direct current or repetitive transcranial magnetic stimulation. We have shown that the right VLPFC is stimulated by an acute bout of daily activity, such as cleaning. Here, we investigated the relationship between the right VLPFC and mood changes using this system. Fourteen young adults vacuumed a floor as a cleaning task and kept a standing position as a control task on separate days. The oxyhemoglobin (oxy-Hb) and deoxy-hemoglobin (deoxy-Hb) signals of the prefrontal cortex were measured during the tasks. The mood scale scores of Profile of Mood States 2nd edition (POMS) and Two-Dimensional Mood Scale (TDMS) were measured before and after both tasks. The differences in subscale scores between pre- and post-tasks in both scales were calculated as ΔPOMS and ΔTDMS. The cleaning task significantly increased the oxy-Hb signal in the bilateral VLPFC and right frontopolar, but did not affect the deoxy-Hb signals. The control task significantly decreased the oxy-Hb signal in some brain regions. The Confusion-Bewilderment score in POMS changed after the cleaning task. Importantly, the oxy-Hb signal in the right VLPFC was negatively correlated with the ΔPOMS Confusion-Bewilderment score. The activity of the right VLPFC stimulated by the cleaning task might have a correlation with the Confusion-Bewilderment mood state.
Asunto(s)
Oxihemoglobinas , Espectroscopía Infrarroja Corta , Confusión , Hemodinámica/fisiología , Humanos , Corteza Prefrontal/química , Espectroscopía Infrarroja Corta/métodos , Adulto JovenRESUMEN
The capacity to suppress learned responses is essential for animals to adapt in dynamic environments. Extinction is a process by which animals learn to suppress conditioned responding when an expected outcome is omitted. The infralimbic (IL) cortex to nucleus accumbens shell (NAcS) neural circuit is implicated in suppressing conditioned responding after extinction, especially in the context of operant cocaine-seeking behavior. However, the role of the IL-to-NAcS neural circuit in the extinction of responding to appetitive Pavlovian cues is unknown, and the psychological mechanisms involved in response suppression following extinction are unclear. We trained male Long Evans rats to associate a 10 s auditory conditioned stimulus (CS; 14 trials per session) with a sucrose unconditioned stimulus (US; 0.2 ml per CS) in a specific context, and then following extinction in a different context, precipitated a renewal of CS responding by presenting the CS alone in the original Pavlovian conditioning context. Unilateral, optogenetic stimulation of the IL-to-NAcS circuit selectively during CS trials suppressed renewal. In a separate experiment, IL-to-NAcS stimulation suppressed CS responding regardless of prior extinction and impaired extinction retrieval. Finally, IL-to-NAcS stimulation during the CS did not suppress the acquisition of Pavlovian conditioning but was required for the subsequent expression of CS responding. These results are consistent with multiple studies showing that the IL-to-NAcS neural circuit is involved in the suppression of operant cocaine-seeking, extending these findings to appetitive Pavlovian cues. The suppression of appetitive Pavlovian responding following IL-to-NAcS circuit stimulation, however, does not appear to be an extinction-dependent process.SIGNIFICANCE STATEMENT Extinction is a form of inhibitory learning through which animals learn to suppress conditioned responding in the face of nonreinforcement. We investigated the role of the IL cortex inputs to the NAcS in the extinction of responding to appetitive Pavlovian cues and the psychological mechanisms involved in response suppression following extinction. Using in vivo optogenetics, we found that stimulating the IL-to-NAcS neural circuit suppressed context-induced renewal of conditioned responding after extinction. In a separate experiment, stimulating the IL-to-NAcS circuit suppressed conditioned responding in an extinction-independent manner. These findings can be used by future research aimed at understanding how corticostriatal circuits contribute to behavioral flexibility and mental disorders that involve the suppression of learned behaviors.
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Conducta Apetitiva/fisiología , Condicionamiento Clásico/fisiología , Cuerpo Estriado/fisiología , Red Nerviosa/fisiología , Corteza Prefrontal/fisiología , Animales , Cuerpo Estriado/química , Extinción Psicológica/fisiología , Masculino , Red Nerviosa/química , Optogenética/métodos , Corteza Prefrontal/química , Ratas , Ratas Long-EvansRESUMEN
BACKGROUND: Chloride intracellular channel 4 (CLIC4) is a multifunctional metamorphic protein for which a growing body of evidence supports a major role in the brain's molecular and behavioral responses to ethanol (EtOH). Although key to understanding the functional biology underlying this role, little is known about the cellular and subcellular expression patterns of CLIC4 in brain and how they are affected by EtOH. METHODS: We used qRT-PCR to assess Clic4 mRNA expression in the medial prefrontal cortex (mPFC) of C57BL/6J mice in the absence and presence of acute EtOH exposure. Two complementary immunohistochemical techniques were employed to assess the subcellular localization of the CLIC4 protein and its pattern of expression across brain cell types in the mPFC in the absence and presence of acute EtOH. RESULTS: Through immunohistochemical and stereological techniques, we show that CLIC4 protein is robustly expressed by oligodendrocytes (most abundant), microglia, and astrocytes, with minimal expression in neurons. Following acute EtOH exposure, we observed a rapid increase in Clic4 mRNA expression in female but not male mice and an overall increase in the number of oligodendrocytes and astrocytes expressing the CLIC4 protein. CONCLUSIONS: These findings suggest that Clic4 functions as an early response gene for acute EtOH in brain, which likely underlies its ability to modulate EtOH behavior. Our results also suggest that the role of CLIC4 in the brain's response to EtOH is mediated through oligodendrocytes.
Asunto(s)
Canales de Cloruro/genética , Etanol/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Mitocondriales/genética , Corteza Prefrontal/metabolismo , Transcriptoma/efectos de los fármacos , Animales , Astrocitos/metabolismo , Astrocitos/ultraestructura , Conducta Animal/efectos de los fármacos , Canales de Cloruro/análisis , Canales de Cloruro/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Mitocondriales/análisis , Proteínas Mitocondriales/fisiología , Oligodendroglía/metabolismo , Corteza Prefrontal/química , Corteza Prefrontal/efectos de los fármacos , ARN Mensajero/análisis , Caracteres SexualesRESUMEN
Prepulse inhibition (PPI) is disrupted in many neuropsychiatric diseases. Molecules such as 5-HT2C receptor agonists alleviate PPI deficits in rodents; however, the precise mechanisms and critical regions of the brain responsible for the reversal effect of these agonists remain inconclusive. The present study aimed to investigate the areas of the brain critical for the reversal effect of 5-HT2C receptor agonists on PPI deficits in mice. The results showed that systemic administration of the 5-HT2C receptor agonist MK212 did not affect normal PPI behavior, but reversed the PPI deficits induced by the N-methyl d-aspartate receptor antagonist MK801 in mice. In addition, the 5-HT2C receptor antagonist SB242084 had no effect on PPI behavior despite MK801 treatment. Moreover, local infusion of MK212 into the medial prefrontal cortex and ventral hippocampus, excluding the nucleus accumbens or ventral tegmental area, rescued the PPI deficits induced by MK801. These data suggest that the medial prefrontal cortex and ventral hippocampus are critical brain areas responsible for the reversal of 5-HT2C agonists on PPI deficits. The results will contribute to our current knowledge on the molecular and neural mechanisms underlying the antipsychotic effects of 5-HT2C receptor agonists, especially the neural circuits modulated by 5-HT2C receptor activity.
Asunto(s)
Hipocampo , Corteza Prefrontal , Inhibición Prepulso/efectos de los fármacos , Pirazinas/farmacología , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Aminopiridinas/farmacología , Animales , Encéfalo/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Hipocampo/química , Hipocampo/fisiología , Indoles/farmacología , Ratones , Corteza Prefrontal/química , Corteza Prefrontal/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development.SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders.
Asunto(s)
Interacción Gen-Ambiente , Hipocampo/crecimiento & desarrollo , Trastornos Mentales/genética , Trastornos Mentales/fisiopatología , Red Nerviosa/crecimiento & desarrollo , Corteza Prefrontal/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Hipocampo/química , Masculino , Trastornos Mentales/psicología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/química , Corteza Prefrontal/química , Factores de RiesgoRESUMEN
Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome-interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring's prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring's prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.
Asunto(s)
Trastorno del Espectro Autista/genética , Compuestos de Bencidrilo/efectos adversos , Perfilación de la Expresión Génica/métodos , Fenoles/efectos adversos , Corteza Prefrontal/química , Efectos Tardíos de la Exposición Prenatal/genética , Factores de Transcripción/genética , Animales , Trastorno del Espectro Autista/inducido químicamente , Modelos Animales de Enfermedad , Receptor alfa de Estrógeno/genética , Femenino , Regulación de la Expresión Génica , Simulación del Acoplamiento Molecular , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Receptores Androgénicos/genética , Análisis de Secuencia de ARN , Caracteres SexualesRESUMEN
Prenatal adversity or stress can have long-term consequences on developmental trajectories and health outcomes. Although the biological mechanisms underlying these effects are poorly understood, epigenetic modifications, such as DNA methylation, have the potential to link early-life environments to alterations in physiological systems, with long-term functional implications. We investigated the consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. As these insults can have sex-specific effects on biological outcomes, we analyzed epigenome-wide DNA methylation patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females. We found sex-dependent and sex-concordant influences of these insults on epigenetic patterns. These alterations occurred in genes and pathways related to brain development and immune function, suggesting that PAE and food-related stress may reprogram neurobiological/physiological systems partly through central epigenetic changes, and may do so in a sex-dependent manner. Such epigenetic changes may reflect the sex-specific effects of prenatal insults on long-term functional and health outcomes and have important implications for understanding possible mechanisms underlying fetal alcohol spectrum disorder and other neurodevelopmental disorders.
Asunto(s)
Alcoholes/efectos adversos , Metilación de ADN/efectos de los fármacos , Corteza Prefrontal/química , Efectos Tardíos de la Exposición Prenatal/genética , Análisis de Secuencia de ADN/métodos , Animales , Modelos Animales de Enfermedad , Epigénesis Genética/efectos de los fármacos , Función Ejecutiva/efectos de los fármacos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Masculino , Corteza Prefrontal/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Caracteres SexualesRESUMEN
Steroid hormones such as glucocorticoids and their metabolites are closely related to mental diseases and neuroendocrine diseases. Quantitative analysis of these substances will help in understanding their roles in related research fields. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to detect the concentration of corticosterone (CORT) and its metabolites, progesterone (PROG) and testosterone in rat plasma and prefrontal cortex (PFC), and was applied to investigate the changes in hormones in rats with depression induced by chronic unpredictable mild stress (CUMS). The method was shown to be linear in the quantitation range for all analytes. Intra- and inter-day accuracy and precision were between 80% and 120%. Furthermore, we found that the level of CORT in plasma and PFC increased, whereas that of 11-dehydrocorticosterone (11-DHCORT) as well as the ratio of 11-DHCORT and CORT declined in rats with CUMS-induced depression. The trends of these changes in central PFC and peripheral plasma were consistent. In conclusion, this study successfully established an UPLC-MS/MS method for simultaneous measurement of CORT and its metabolites, PROG and testosterone in rat plasma and PFC, and applied it to rats with depression. The method could be further applied to the research of depression and diseases related to these steroid hormones.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Corticosterona , Depresión , Corteza Prefrontal/química , Estrés Psicológico , Animales , Corticosterona/análisis , Corticosterona/metabolismo , Depresión/sangre , Depresión/metabolismo , Modelos Animales de Enfermedad , Límite de Detección , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Estrés Psicológico/sangre , Estrés Psicológico/metabolismo , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: Parkinson's disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless, and despite the emerging role of epigenetics in age-related brain disorders, the question of whether aberrant histone acetylation is involved in PD remains unresolved. METHODS: We studied fresh-frozen brain tissue from two independent cohorts of individuals with idiopathic PD (n = 28) and neurologically healthy controls (n = 21). We performed comprehensive immunoblotting to identify histone sites with altered acetylation levels in PD, followed by chromatin immunoprecipitation sequencing (ChIP-seq). RNA sequencing data from the same individuals was used to assess the impact of altered histone acetylation on gene expression. RESULTS: Immunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. ChIP-seq analysis further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data from the same individuals revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Strikingly, this decoupling was most pronounced among nuclear-encoded mitochondrial genes, corroborating the notion that impaired crosstalk between the nucleus and mitochondria is involved in the pathogenesis of PD. Our findings independently replicated in the two cohorts. CONCLUSIONS: Our findings strongly suggest that aberrant histone acetylation and altered transcriptional regulation are involved in the pathophysiology of PD. We demonstrate that PD-associated genes are particularly prone to epigenetic dysregulation and identify novel epigenetic signatures associated with the disease.
Asunto(s)
Química Encefálica , Código de Histonas , Histonas/metabolismo , Enfermedad de Parkinson/genética , Procesamiento Proteico-Postraduccional , Transcripción Genética , Acetilación , Antiparkinsonianos/farmacología , Secuencia de Bases , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Regulación de la Expresión Génica/efectos de los fármacos , Genoma Humano , Humanos , Neuronas/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Corteza Prefrontal/química , Sirtuina 1/análisis , Sirtuina 2/análisis , Sirtuina 3/análisisRESUMEN
Working memory, the ability to maintain and transform information, is critical for cognition. Spatial working memory is particularly well studied. The premier model for spatial memory is the continuous attractor network, which posits that cells maintain constant activity over memory periods. Alternative models propose complex dynamics that result in a variety of cell activity time courses. We recorded from neurons in the frontal eye fields and dorsolateral prefrontal cortex of 2 macaques during long (5-15 s) memory periods. We found that memory cells turn on early after stimulus presentation, sustain activity for distinct and fixed lengths of time, then turn off and stay off for the remainder of the memory period. These dynamics are more complex than the dynamics of a canonical bump attractor network model (either decaying or nondecaying) but more constrained than the dynamics of fully heterogeneous memory models. We speculate that memory may be supported by multiple attractor networks working in parallel, with each network having its own characteristic mean turn-off time such that mnemonic resources are gradually freed up over time.
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Red Nerviosa/fisiología , Neuronas/fisiología , Memoria Espacial/fisiología , Animales , Corteza Prefontal Dorsolateral , Fenómenos Electrofisiológicos , Lóbulo Frontal/citología , Lóbulo Frontal/fisiología , Macaca fascicularis , Memoria a Corto Plazo/fisiología , Red Nerviosa/citología , Estimulación Luminosa , Corteza Prefrontal/química , Corteza Prefrontal/fisiología , Desempeño Psicomotor/fisiología , Movimientos Sacádicos , Campos Visuales/fisiologíaRESUMEN
Chronic Kidney Disease (CKD) and neurodegenerative diseases are aging-related diseases. CKD with declined renal function is associated with an elevation of circulating indoxyl sulfate, a metabolite synthesized by gut microbes. We explored the roles of gut microbial metabolites in linking with Central Nervous System (CNS) diseases by administrating indoxyl sulfate intraperitoneally to male C57BL/6 mice with unilateral nephrectomy. Upon exposure, the accumulation of indoxyl sulfate was noted in the blood, prefrontal cortical tissues, and cerebrospinal fluid. Mice showed behavioral signs of mood disorders and neurodegeneration such as anxiety, depression, and cognitive impairment. Those behavioral changes were accompanied by disturbed neuronal survival, neural stem cell activity, expression of Brain-Derived Neurotrophic Factor, serotonin, corticosterone, and Repressor Element-1 Silencing Transcription Factor, and post-receptor intracellular signaling, as well as upregulated oxidative stress and neuroinflammation. Uremic toxin adsorbent AST-120 improved the above mentioned changes. Intriguingly, intracerebroventricular indoxyl sulfate administration only caused limited alterations in the normal mice and the alterations were reversed by aryl hydrocarbon receptor antagonism. The findings suggest pathogenic roles of indoxyl sulfate in the development of CNS diseases, and highlight gut microbiota as alternative targets for intervention with the aim of slowing down the progression of CKD and decreasing CNS complications.
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Conducta Animal/efectos de los fármacos , Indicán/farmacología , Nefrectomía , Afecto/efectos de los fármacos , Animales , Ansiedad/inducido químicamente , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Carbono/farmacología , Supervivencia Celular/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Corticosterona/metabolismo , Depresión/inducido químicamente , Indicán/análisis , Inyecciones Intraperitoneales , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Ratones Endogámicos C57BL , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Estrés Oxidativo , Óxidos/farmacología , Corteza Prefrontal/química , Corteza Prefrontal/metabolismo , ARN Mensajero/metabolismo , Insuficiencia Renal Crónica , Proteínas Represoras/metabolismo , Serotonina/metabolismoRESUMEN
An alteration in the balance of excitation-inhibition has been proposed as a common characteristic of the cerebral cortex in autism, which may be due to an alteration in the number and/or function of the excitatory and/or inhibitory cells that form the cortical circuitry. We previously found a decreased number of the parvalbumin (PV)+ interneuron known as Chandelier (Ch) cell in the prefrontal cortex in autism. This decrease could result from a decreased number of Ch cells, but also from decreased PV protein expression by Ch cells. To further determine if Ch cell number is altered in autism, we quantified the number of Ch cells following a different approach and different patient cohort than in our previous studies. We quantified the number of Ch cell cartridges-rather than Ch cell somata-that expressed GAT1-rather than PV. Specifically, we quantified GAT1+ cartridges in prefrontal areas BA9, BA46, and BA47 of 11 cases with autism and 11 control cases. We found that the density of GAT1+ cartridges was decreased in autism in all areas and layers. Whether this alteration is cause or effect remains unclear but could result from alterations that take place during cortical prenatal and/or postnatal development.
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Trastorno Autístico/patología , Interneuronas/patología , Red Nerviosa/patología , Corteza Prefrontal/patología , Adolescente , Recuento de Células/métodos , Niño , Femenino , Humanos , Interneuronas/química , Interneuronas/citología , Masculino , Red Nerviosa/química , Red Nerviosa/citología , Corteza Prefrontal/química , Corteza Prefrontal/citología , Adulto JovenRESUMEN
Food restriction (FR) evokes running, which may promote adaptive foraging in times of food scarcity, but can become lethal if energy expenditure exceeds caloric availability. Here, we demonstrate that chemogenetic activation of either the general medial prefrontal cortex (mPFC) pyramidal cell population, or the subpopulation projecting to dorsal striatum (DS) drives running specifically during hours preceding limited food availability, and not during ad libitum food availability. Conversely, suppression of mPFC pyramidal cells generally, or targeting mPFC-to-DS cells, reduced wheel running specifically during FR and not during ad libitum food access. Post mortem c-Fos analysis and electron microscopy of mPFC layer 5 revealed distinguishing characteristics of mPFC-to-DS cells, when compared to neighboring non-DS-projecting pyramidal cells: 1) greater recruitment of GABAergic activity and 2) less axo-somatic GABAergic innervation. Together, these attributes position the mPFC-to-DS subset of pyramidal cells to dominate mPFC excitatory outflow, particularly during FR, revealing a specific and causal role for mPFC-to-DS control of the decision to run during food scarcity. Individual differences in GABAergic activity correlate with running response to further support this interpretation. FR enhancement of PFC-to-DS activity may influence neural circuits both in studies using FR to motivate animal behavior and in human conditions hallmarked by FR.
Asunto(s)
Restricción Calórica/tendencias , Toma de Decisiones/fisiología , Metabolismo Energético/fisiología , Red Nerviosa/metabolismo , Corteza Prefrontal/metabolismo , Carrera/fisiología , Animales , Toma de Decisiones/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Red Nerviosa/química , Red Nerviosa/efectos de los fármacos , Piperazinas/administración & dosificación , Piperazinas/metabolismo , Corteza Prefrontal/química , Corteza Prefrontal/efectos de los fármacos , Células Piramidales/química , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Carrera/psicologíaRESUMEN
Alzheimer's disease (AD) is a progressive and incurable brain disorder that has been associated with structural changes in brain phospholipids (PLs), including diacyl species and ether-linked PLs known as plasmalogens. Most studies have characterized total changes in brain PL pools (e.g., choline plasmalogens), particularly in prefrontal cortex, but detailed and quantitative information on the molecular PL species impacted by the disease is limited. In this study, we used a comprehensive mass-spectrometry method to quantify diacyl and plasmalogen species, alkyl synthetic precursors of plasmalogens, and lysophospholipid degradation products of diacyl and plasmalogen PLs, in postmortem samples of prefrontal cortex from 21 AD patients and 20 age-matched controls. Total PLs were also quantified with gas-chromatography analysis of bound fatty acids following thin layer chromatography isolation. There was a significant 27% reduction in the concentration (nmol/g wet weight) of choline plasmalogen containing stearic acid (alkenyl group) and docosahexaenoic acid in AD compared to controls. Stearic acid concentration in total PLs was reduced by 26%. Our findings suggest specific changes in PLs containing stearic acid and docosahexaenoic acid in AD prefrontal cortex, highlighting structural and turnover PL pathways that could be targeted.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Ácidos Docosahexaenoicos/análisis , Lipidómica , Plasmalógenos/análisis , Cambios Post Mortem , Corteza Prefrontal/química , Ácidos Esteáricos/análisis , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión , Ácidos Grasos/análisis , Femenino , Humanos , Lisofosfolípidos/metabolismo , Masculino , Modelos Moleculares , Fosfolípidos/análisis , Espectrometría de Masas en TándemRESUMEN
Speech is a complex and ambiguous acoustic signal that varies significantly within and across speakers. Despite the processing challenge that such variability poses, humans adapt to systematic variations in pronunciation rapidly. The goal of this study is to uncover the neurobiological bases of the attunement process that enables such fluent comprehension. Twenty-four native English participants listened to words spoken by a "canonical" American speaker and two non-canonical speakers, and performed a word-picture matching task, while magnetoencephalography was recorded. Non-canonical speech was created by including systematic phonological substitutions within the word (e.g. [s] â [sh]). Activity in the auditory cortex (superior temporal gyrus) was greater in response to substituted phonemes, and, critically, this was not attenuated by exposure. By contrast, prefrontal regions showed an interaction between the presence of a substitution and the amount of exposure: activity decreased for canonical speech over time, whereas responses to non-canonical speech remained consistently elevated. Grainger causality analyses further revealed that prefrontal responses serve to modulate activity in auditory regions, suggesting the recruitment of top-down processing to decode non-canonical pronunciations. In sum, our results suggest that the behavioural deficit in processing mispronounced phonemes may be due to a disruption to the typical exchange of information between the prefrontal and auditory cortices as observed for canonical speech.
Asunto(s)
Corteza Prefrontal/fisiología , Habla , Estimulación Acústica , Adaptación Fisiológica , Adulto , Corteza Auditiva/química , Corteza Auditiva/fisiología , Femenino , Humanos , Magnetoencefalografía , Masculino , Corteza Prefrontal/química , Adulto JovenRESUMEN
Objectives: Maternal-pup nurturing behavior has previously been shown to impact offspring neurodevelopment independent of diet. Here we investigated the effects of perinatal maternal n-3 fatty acid deficiency on maternal-pup nurturing behavior and potential associations with pro-inflammatory signaling.Methods: Eight-week-old virgin female Long-Evans hooded rats were randomized to a control diet containing alpha-linolenic acid (ALA, 18:3n-3) (CON, n = 10) or an ALA-free diet (Deficient, DEF, n = 11) 30 d prior to mating. On postnatal day 2 (P2) litters were culled to eight per dam. On P3, P6, and P9 dams and their litters were video recorded and maternal nurturing behaviors, including licking/grooming of pups and arched-back nursing, were scored by a blinded rater. Following weaning on P21, dam postmortem central (prefrontal cortex, PFC) and peripheral (red blood cell, RBC) fatty acid composition and central (PFC IL-1ß, IL-2, IL-6, TNFα, cPLA2, COX-2 mRNA) and peripheral (plasma IL-1ß, IL-2, IL-6, TNFα, CRP) pro-inflammatory biostatus assessed.Results: DEF dams exhibited significantly lower RBC (p ≤ 0.0001) and PFC (p ≤ 0.0001) docosahexaenoic acid (DHA) levels compared with CON dams. Irrespective of diet dams exhibited significantly lower RBC, but not PFC, DHA levels compared with non-parous rats. DEF dams exhibited less licking/grooming (p = 0.008), arched-back nursing (p ≤ 0.0001) and blanket nursing (p = 0.003), and exhibited more passive nursing (p = 0.003) but not time off pups (p = 0.1), compared with CON dams. PFC and plasma inflammatory measures did not differ significantly between groups.Discussion: Perinatal dietary n-3 fatty acid deficiency reduces maternal nurturing behavior and this effect is not associated with enduring elevations in pro-inflammatory signaling.
Asunto(s)
Conducta Animal/fisiología , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/deficiencia , Inflamación/metabolismo , Conducta Materna/fisiología , Animales , Biomarcadores/análisis , Biomarcadores/sangre , Dieta , Ácidos Docosahexaenoicos/análisis , Ácidos Docosahexaenoicos/sangre , Eritrocitos/química , Femenino , Aseo Animal/fisiología , Inflamación/sangre , Corteza Prefrontal/química , Embarazo , Ratas , Ratas Long-Evans , Transducción de SeñalRESUMEN
AIMS: Chronic stress plays an important role in promoting the progression and migration of cancers. However, little is known of any direct impact on tumor progression related to the regulation of emotion-related circuitry. The aim of this study was to explore the neural-circuit mechanisms underlying stress-induced progression of cancers and the impact of emotion-related regulation of circuitry on tumor growth. METHODS: Optogenetic manipulation was applied to unpredictable chronic mild stress (UCMS)-treated mice bearing breast tumor cell. The stress-related hormones, tumor-related cytokines, the tyrosine hydroxylase (TH)-positive neurons and their fibers, dopamine receptor-positive cells, and anxiety level were measured using ELISA, immunohistochemical staining, fluorescence in situ hybridization, and behavioral test, respectively. RESULTS: By investigating breast cancer mouse models with a chronic mild stress model, optogenetic stimulation, and behavioral analysis, we show that chronic stress induced anxiety-like behavior in mice and increased serum concentration of norepinephrine and corticosterone, hormones closely related to stress and anxiety. Optogenetic activation of VTA TH terminals in the mPFC rescued anxiety-like behavior induced by chronic stress. Chronic stress resulted in marked progression of breast tumors, and repetitive optogenetic activation of VTA TH terminals in the mPFC significantly attenuated stress-induced progression of breast cancers and reduced serum concentration of norepinephrine and corticosterone. Furthermore, there was a positive correlation between serum norepinephrine or corticosterone concentration and tumor size. CONCLUSIONS: These findings indicate a positive role of an emotion regulation circuit on the progression of breast cancer and reveal a link between stress, emotion regulation, and the progression of breast cancers. Our findings provide new insights pertinent to therapeutic interventions in the treatment of breast cancers.
Asunto(s)
Neoplasias de la Mama/metabolismo , Progresión de la Enfermedad , Neuronas Dopaminérgicas/metabolismo , Corteza Prefrontal/metabolismo , Estrés Psicológico/metabolismo , Área Tegmental Ventral/metabolismo , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/psicología , Enfermedad Crónica , Neuronas Dopaminérgicas/química , Femenino , Humanos , Células MCF-7 , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Optogenética/métodos , Corteza Prefrontal/química , Estrés Psicológico/patología , Estrés Psicológico/psicología , Área Tegmental Ventral/química , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The anterior cingulate cortex (ACC) is important for decision-making as it integrates motor plans with affective and contextual limbic information. Disruptions in these networks have been observed in depression, bipolar disorder, and post-traumatic stress disorder. Yet, overlap of limbic and motor connections within subdivisions of the ACC is not well understood. Hence, we administered a combination of retrograde and anterograde tracers into structures important for contextual memories (entorhinal cortex), affective processing (amygdala), and motor planning (dorsal premotor cortex) to assess overlap of labeled projection neurons from (outputs) and axon terminals to (inputs) the ACC of adult rhesus monkeys (Macaca mulatta). Our data show that entorhinal and dorsal premotor cortical (dPMC) connections are segregated across ventral (A25, A24a) and dorsal (A24b,c) subregions of the ACC, while amygdalar connections are more evenly distributed across subregions. Among all areas, the rostral ACC (A32) had the lowest relative density of connections with all three regions. In the ventral ACC, entorhinal and amygdalar connections strongly overlap across all layers, especially in A25. In the dorsal ACC, outputs to dPMC and the amygdala strongly overlap in deep layers. However, dPMC input to the dorsal ACC was densest in deep layers, while amygdalar inputs predominantly localized in upper layers. These connection patterns are consistent with diverse roles of the dorsal ACC in motor evaluation and the ventral ACC in affective and contextual memory. Further, distinct laminar circuits suggest unique interactions within specific ACC compartments that are likely important for the temporal integration of motor and limbic information during flexible goal-directed behavior.