RESUMEN
Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder. Oxidative stress and inflammatory responses have a vital role in the pathophysiology of IBD as well as seizure. IBD is associated with extraintestinal manifestations. This study aimed to explore the relationship between colitis and susceptibility to seizures, with a focus on the roles of neuroinflammation and oxidative stress in acetic acid-induced colitis in mice. Forty male Naval Medical Research Institute mice were divided into four groups: control, colitis, pentylenetetrazole (PTZ), and colitis + PTZ. Colitis was induced by intrarectal administration of acetic acid, and seizures were induced by intravenous injection of PTZ 7 days postcolitis induction. Following the measurement of latency to seizure, the mice were killed, and their colons and prefrontal cortex (PFC) were dissected. Gene expression of inflammatory markers including interleukin-1ß, tumor necrosis factor-alpha, NOD-like receptor protein 3, and toll-like receptor 4, as well as total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels were measured in the colon and PFC. Histopathological evaluations were performed on the colon samples. Data were analyzed by t-test or one-way variance analysis. Colitis decreased latency to seizure, increased gene expression of inflammatory markers, and altered levels of MDA, nitrite, and TAC in both the colon and PFC. Simultaneous induction of colitis and seizure exacerbated the neuroimmune response and oxidative stress in the PFC and colon. Results concluded that neuroinflammation and oxidative stress in the PFC at least partially mediate the comorbid decrease in seizure latency in mice with colitis.
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Colitis , Estrés Oxidativo , Corteza Prefrontal , Convulsiones , Animales , Masculino , Ratones , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Convulsiones/metabolismo , Convulsiones/inducido químicamente , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Neuroinmunomodulación , Modelos Animales de EnfermedadRESUMEN
Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.
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Desmetilasa de ARN, Homólogo 5 de AlkB , Astrocitos , Trastorno Depresivo Mayor , Ratones Noqueados , Animales , Astrocitos/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Ratones , Humanos , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/patología , Masculino , Femenino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Neuronas/metabolismo , Estrés Psicológico/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Transportador 2 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Conducta Animal , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Depresión/metabolismo , Depresión/genética , Adulto , Transmisión Sináptica , Persona de Mediana EdadRESUMEN
Research into the health benefits of scents is on the rise. However, little is known about the effects of continuous inhalation, such as wearing scents on clothing, on brain structure. Therefore, in this study, an intervention study was conducted on a total of 50 healthy female people, 28 in the intervention group and 22 in the control group, asking them to wear a designated rose scent on their clothes for a month. The effect of continuous inhalation of essential oil on the gray matter of the brain was measured by calculating changes in brain images of participants taken before and after the intervention using Magnetic Resonance Imaging (MRI). The results showed that the intervention increased the gray matter volume (GMV) of the whole brain and posterior cingulate cortex (PCC) subregion. On the other hand, the GMV of the amygdala and orbitofrontal cortex (OFC) did not change. This study is the first to show that continuous scent inhalation changes brain structure.
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Sustancia Gris , Aceites Volátiles , Humanos , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Aceites Volátiles/farmacología , Corteza Cerebral , Encéfalo/diagnóstico por imagen , Corteza Prefrontal/patología , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVES: This study aimed to longitudinally observe the improvement mechanism of semantic fluency in subacute post-stroke aphasia (PSA) patients using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Twelve PSA patients, about one month after onset, were enrolled in this study and received speech-language therapy (SLT) for one month. Auditory comprehension and semantic fluency were evaluated using the Western Aphasia Battery (WAB) and the Animal Fluency Test. Before and after treatment, rs-fMRI data were collected, and the dice similarity coefficient was used to measure the spatial similarity between each patient's lesion and a reference lesion. The left posterior inferior temporal gyrus (pITG) was used as a seed to calculate the normalized functional connectivity in whole-brain voxel analysis using DPABI software for statistical analysis. RESULTS: The dice similarity coefficient between each patient's lesion and the reference lesion showed moderate to high intensity (0.57 ± 0.14) in the Montreal Neurological Institute space. After treatment, we found a significant increase in functional connectivity between the left pITG and the right prefrontal lobe convergence area (peak t = 8.219, Gaussian random field multiple comparison correction, voxel p < 0.001, cluster p < 0.05). The increase in functional connectivity was negatively correlated with the improvement in auditory comprehension (r =-0.707, p = 0.033) and positively correlated with the improvement in semantic fluency (r = 0.79, p = 0.02). CONCLUSION: The improvement of semantic fluency in subacute PSA patients may require the participation of the right convergence area of the prefrontal lobe.
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Afasia , Accidente Cerebrovascular , Humanos , Semántica , Imagen por Resonancia Magnética , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patología , Afasia/diagnóstico por imagen , Afasia/etiología , Afasia/terapia , Encéfalo/patologíaRESUMEN
Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.
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Degeneración Lobar Frontotemporal , Factores Asociados con la Proteína de Unión a TATA , Humanos , Amiloide/química , Amiloide/metabolismo , Amiloide/ultraestructura , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Microscopía por Crioelectrón , Demencia Frontotemporal/etiología , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/complicaciones , Degeneración Lobar Frontotemporal/metabolismo , Degeneración Lobar Frontotemporal/patología , Corteza Motora/metabolismo , Corteza Motora/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Factores Asociados con la Proteína de Unión a TATA/química , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Factores Asociados con la Proteína de Unión a TATA/ultraestructura , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patologíaRESUMEN
The responsibility of persons with brain disorders who commit offenses may depend on how their disorders alter brain mechanisms for culpability. Criminal behavior can result from brain disorders that alter social cognition including a neuromoral system of intuitive moral emotions that are absolute (deontological) normative codes and that includes an emotion-mediated evaluation of intentionality. This neuromoral system has its hub in the ventromedial prefrontal cortex (VMPFC) with other frontal, anterior temporal-amygdalar, insular, and right temporoparietal connections. Among brain disorders, investigators report offenses in persons with brain tumors, epilepsy, and traumatic brain injury, but it is those with a form of dementia with VMPFC pathology, behavioral variant frontotemporal dementia (bvFTD), who are most prone to criminal behavior. This review presents four new patients with bvFTD who were interviewed after committing offenses. These patients knew the nature of their acts and the wrongness of the type of action but lacked substantial capacity to experience the criminality of their conduct at the intuitive, deontological, moral emotional level. Disease in VMPFC and its amygdalar connections may impair moral emotions in these patients. These findings recommend evaluation for the experience of moral emotions and VMPFC-amygdala dysfunction among persons with antisocial behavior, with or without brain disease.
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Demencia Frontotemporal , Humanos , Demencia Frontotemporal/psicología , Encéfalo , Emociones , Corteza Prefrontal/patología , Conducta Social , Pruebas NeuropsicológicasRESUMEN
Perinatal hypoxia-ischemia (HI) is a leading cause of morbidity and mortality among newborns. Infants with HI encephalopathy may experience lasting consequences, such as depression, in adulthood. In this study, we examined depressive-like behavior, neuronal population, and markers of monoaminergic and synaptic plasticity in the prefrontal cortex (PFC) of adolescent rats subjected to a prenatal HI model. Pregnant rats underwent a surgery in which uterine and ovarian blood flow was blocked for 45 min at E18 (HI procedure). Sham-operated subjects were also generated (SH procedure). Behavioral tests were conducted on male and female pups from P41 to P43, and animals were histologically processed or dissected for western blotting at P45. We found that the HI groups consumed less sucrose in the sucrose preference test and remained immobile for longer periods in the forced swim test. Additionally, we observed a significant reduction in neuronal density and PSD95 levels in the HI group, as well as a smaller number of synaptophysin-positive cells. Our results underscore the importance of this model in investigating the effects of HI-induced injuries, as it reproduces an increase in depressive-like behavior and suggests that the HI insult affects circuits involved in mood modulation.
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Hipoxia-Isquemia Encefálica , Embarazo , Animales , Ratas , Femenino , Masculino , Hipoxia-Isquemia Encefálica/patología , Hipoxia , Isquemia , Corteza Prefrontal/patología , Plasticidad Neuronal/fisiología , Animales Recién NacidosRESUMEN
The ability to accurately predict pain is an adaptive feature in healthy individuals. However, in chronic pain, this mechanism may be selectively impaired and can lead to increased anxiety and excessive avoidance behavior. Recently, we reported the first data demonstrating brain activation in fibromyalgia (FM) patients during conditioned pain responses, in which FM patients revealed a tendency to form new pain-related associations rather than extinguishing irrelevant ones. The aim of the present study was to extend our previous analysis, to elucidate potential neural divergences between subjects with FM (n = 65) and healthy controls (HCs) (n = 33) during anticipatory information (ie, prior to painful stimulus onset). Using functional magnetic resonance imaging (fMRI), the current analyses include 1) a congruently cued paradigm of low and high pain predictive cues, followed by 2) an incongruently cued paradigm where low and high pain predictive cues were followed by an identical mid-intensity painful pressure. During incongruently cued high-pain associations, FM exhibited reduced left dorsolateral prefrontal cortex (dlPFC) activation compared to HCs, which was followed by an altered subsequent pain experience in FM, as patients continued to rate the following painful stimuli as high, even though the pressure had been lowered. During congruently cued low pain anticipation, FM exhibited decreased right dlPFC activation compared to HCs, as well as decreased brain connectivity between brain regions implicated in cognitive modulation of pain (dlPFC) and nociceptive processing (primary somatosensory cortex/postcentral gyrus [S1] and supplementary motor area [SMA]/midcingulate cortex [MCC]). These results may reflect an important feature of validating low pain expectations in HCs and help elucidate behavioral reports of impaired safety processing in FM patients. PERSPECTIVE: FM exhibited a stronger conditioned pain response for high-pain associations, which was associated with reduced dlPFC activation during the incongruent trial. During (congruent and incongruent) low pain associations, FM dlPFC brain activation remained indifferent. Imbalances in threat and safety pain perception may be an important target for psychotherapeutic interventions.
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Dolor Crónico , Fibromialgia , Humanos , Fibromialgia/complicaciones , Fibromialgia/diagnóstico por imagen , Corteza Prefontal Dorsolateral , Percepción del Dolor/fisiología , Encéfalo , Imagen por Resonancia Magnética/métodos , Corteza Prefrontal/patologíaRESUMEN
Background: Cigarette smoking (CS) and opioid use disorder (OUD) significantly alter brain structure. Although OUD and cigarette smoking are highly comorbid, most prior neuroimaging research in OUD did not control for smoking severity. Specifically, the combined effect of smoking and OUD on the brain gray matter volume (GMV) remains unknown.Objectives: We used structural magnetic resonance imaging (sMRI) to examine: (1) the GMV differences between OUD and non-OUD individuals with comparable smoking severity; and (2) the differential effect of smoking severity on the brain GMV between individuals with and without OUD.Methods: We performed a secondary analysis of existing sMRI datasets of 116 individuals who smoked cigarettes daily, among whom 60 had OUD (CS-OUD; 37 male, 23 female) and 56 did not (CS; 31 male, 25 female). Brain GMV was estimated by voxel-based morphometry analysis.Results: Compared to the CS group, the CS-OUD group had a higher GMV in the occipital cortex and lower GMV in the prefrontal and temporal cortex, striatum, and pre/postcentral gyrus (whole-brain corrected-p < .05). There was a significant interaction between group and smoking severity on GMV in the medial orbitofrontal cortex (whole-brain corrected-p < .05), such that heavier smoking was associated with lower medial orbitofrontal GMV in the CS-OUD but not CS participants (r=-0.32 vs. 0.12).Conclusions: Our findings suggest a combination of independent and interactive effects of cigarette smoking and OUD on the brain gray matter. Elucidating the neuroanatomical correlates of comorbid opioid and tobacco use may shed the light on the development of novel interventions for affected individuals.
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Sustancia Gris , Trastornos Relacionados con Opioides , Humanos , Masculino , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Fumar , Encéfalo , Corteza Prefrontal/patología , Imagen por Resonancia Magnética/métodos , NicotianaRESUMEN
BACKGROUND: The hyperdirect pathway - a circuit involved in executing inhibitory control (IC) - is dysregulated among individuals with nicotine dependence. The right inferior frontal gyrus (rIFG), a cortical input to the hyperdirect circuit, has been shown to be functionally and structurally altered among nicotine-dependent people who smoke. The rIFG is composed of 3 cytoarchitecturally distinct subregions: The pars opercularis, pars triangularis, and pars orbitalis. The present study assessed the relationship between rIFG subregion morphometry and inhibitory control among individuals with nicotine dependence. METHODS: Behavioral and magnetic resonance brain imaging (MRI) data from 127 nicotine-dependent adults who smoke (MFTND = 5.4, ± 1.9; MCPD = 18.3, ± 7.0; Myears = 25.04, ± 11.97) (Mage = 42.9, ± 11.1) were assessed. Brain morphometry was assessed from T1-weighted MRIs using Freesurfer. IC was assessed with a response-inhibition Go/Go/No-Go (GGNG) task and a smoking relapse analog task (SRT). RESULTS AND CONCLUSIONS: Vertex-wise analyses revealed that GGNG task scores were positively associated with cortical thickness and volume in the right pars triangularis (cluster-wise p = 0.006, 90% CI = 0.003 - 0.009; cluster-wise p = 0.040, 90% CI = 0.032 - 0.048), and the ability to inhibit ad lib smoking during the SRT was positively associated with cortical thickness in the right pars orbitalis (cluster-wise p = 0.011, 90% CI = 0.007 - 0.015). Our results indicate that cortical thickness of distinct rIFG subregions may serve as biomarkers for unique forms of IC deficits.
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Nicotina , Tabaquismo , Adulto , Humanos , Corteza Prefrontal/patología , Encéfalo/fisiología , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND: Previous magnetic resonance imaging studies in regular cannabis users report altered grey matter volume (GMV) in brain regions, including the prefrontal cortex (PFC), putamen and hippocampus. However, most studies have tended to recruit recreational users with high levels of cannabis use, and have not controlled for the possible confounding effects of tobacco use. We attempt to address these limitations in the present study. METHODS: We acquired volumetric images in sex, age and IQ-matched groups of (1) regular Cannabis users who also smoke Tobacco cigarettes ('CT'; n = 33), (2) non-cannabis-using Tobacco cigarette smokers ('T'; n = 19) and (3) non-cannabis/tobacco-using Controls ('C'; n = 35). GMV in bilateral PFC, putamen and hippocampal regions was compared across groups. We also examined the associations between GMV differences and levels of cannabis and tobacco use, measures of intellectual function, and of depression, anxiety and stress. RESULTS: Relative to controls, both CT and T groups showed lower GMV in the left inferior frontal gyrus, and greater GMV in the putamen. In addition, lower GMV in the right frontal pole in the CT group (but not the T group) was associated with lifetime cannabis use, but not with cigarette use. CONCLUSIONS: Regular cannabis users who also smoked tobacco cigarettes showed altered GMV patterns relative to controls. However, a similar pattern of GMV differences was also seen between regular tobacco users that did not use cannabis. Further research is needed to disentangle the effects of cannabis and tobacco use on brain structure.
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Cannabis , Sustancia Gris , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Nicotiana , Cannabis/efectos adversos , Putamen/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patología , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Long-term survivors of pediatric acute lymphoblastic leukemia are at elevated risk for neurocognitive deficits and corresponding brain dysfunction. This study examined sex-based differences in functional neuroimaging outcomes in acute lymphoblastic leukemia survivors treated with chemotherapy alone. METHODS: Functional magnetic resonance imaging (fMRI) and neurocognitive testing were obtained in 123 survivors (46% male; median [min-max] age = 14.2 years [8.3-26.5 years]; time since diagnosis = 7.7 years [5.1-12.5 years]) treated on the St. Jude Total XV treatment protocol. Participants performed the n-back working memory task in a 3 T scanner. Functional neuroimaging data were processed (realigned, slice time corrected, normalized, smoothed) and analyzed using statistical parametric mapping with contrasts for 1-back and 2-back conditions, which reflect varying degrees of working memory and task load. Group-level fMRI contrasts were stratified by sex and adjusted for age and methotrexate exposure. Statistical tests were 2-sided (P < .05 statistical significance threshold). RESULTS: Relative to males, female survivors exhibited less activation (ie, reduced blood oxygen dependent-level signals) in the right parietal operculum, supramarginal gyrus and inferior occipital gyrus, and bilateral superior frontal medial gyrus during increased working memory load (family-wise error-corrected P = .004 to .008, adjusting for age and methotrexate dose). Female survivors were slower to correctly respond to the 2-back condition than males (P < .05), though there were no differences in overall accuracy. Performance accuracy was negatively correlated with fMRI activity in female survivors (Pearson's r = -0.39 to -0.29, P = .001 to .02), but not in males. CONCLUSIONS: These results suggest the working memory network is more impaired in female survivors than male survivors, which may contribute to ongoing functional deficits.
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Memoria a Corto Plazo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Niño , Femenino , Humanos , Masculino , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Corteza Prefrontal/patología , SobrevivientesRESUMEN
Stressful life events (SLEs) in adulthood are a risk factor for various disorders such as depression, cancer or infections. Part of this risk is mediated through pathways altering brain physiology and structure. There is a lack of longitudinal studies examining associations between SLEs and brain structural changes. High-resolution structural magnetic resonance imaging data of 212 healthy subjects were acquired at baseline and after 2 years. Voxel-based morphometry was used to identify associations between SLEs using the Life Events Questionnaire and grey matter volume (GMV) changes during the 2-year period in an ROI approach. Furthermore, we assessed adverse childhood experiences as a possible moderator of SLEs-GMV change associations. SLEs were negatively associated with GMV changes in the left medial prefrontal cortex. This association was stronger when subjects had experienced adverse childhood experiences. The medial prefrontal cortex has previously been associated with stress-related disorders. The present findings represent a potential neural basis of the diathesis-stress model of various disorders.
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Encéfalo , Sustancia Gris , Adulto , Encéfalo/patología , Corteza Cerebral , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patologíaRESUMEN
Over the past two decades, circuit-based neurosurgical procedures have gained increasing acceptance as a safe and efficacious approach to the treatment of the intractable obsessive-compulsive disorder (OCD). Lesions and deep brain stimulation (DBS) of the longitudinal corticofugal white matter tracts connecting the prefrontal cortex with the striatum, thalamus, subthalamic nucleus (STN), and brainstem implicate orbitofrontal, medial prefrontal, frontopolar, and ventrolateral cortical networks in the symptoms underlying OCD. The highly parallel distributed nature of these networks may explain the relative lack of adverse effects observed following surgery. Additional pre-post studies of cognitive tasks in more surgical patients are needed to confirm the role of these networks in OCD and to define therapeutic responses to surgical intervention.
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Estimulación Encefálica Profunda , Trastorno Obsesivo Compulsivo , Núcleo Subtalámico , Estimulación Encefálica Profunda/métodos , Humanos , Procedimientos Neuroquirúrgicos/efectos adversos , Procedimientos Neuroquirúrgicos/métodos , Trastorno Obsesivo Compulsivo/psicología , Trastorno Obsesivo Compulsivo/cirugía , Corteza Prefrontal/patología , Corteza Prefrontal/cirugíaRESUMEN
Human and animal studies have conclusively shown that prenatal nicotine exposure alters fetal brain development and causes persistent impairment in the cognitive function of offspring. However, the mechanisms underlying the effect of prenatal nicotine exposure on cognitive function in offspring are still unclear. The objective of this review is to discuss the published studies on the mechanisms underlying the effects of prenatal nicotine exposure on cognitive impairment and discuss the potential mechanisms of action. The findings of the reviewed studies show that the main mechanisms involved are alteration in the composition of nicotinic acetylcholine receptor subunits, increase in surface expression of the glutamate receptor subunit GluR2, a reduction in neurogenesis, alteration of Akt and ERK1/2 activity, and mitochondrial dysfunction in the hippocampus and cortex. These pathways could shed light on future molecular markers and therapeutic targets for the prevention and treatment of cognitive dysfunction induced by prenatal nicotine exposure.
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Disfunción Cognitiva/etiología , Nicotina/efectos adversos , Efectos Tardíos de la Exposición Prenatal/etiología , Animales , Cognición/efectos de los fármacos , Disfunción Cognitiva/fisiopatología , Femenino , Desarrollo Fetal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Nicotina/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Receptores Nicotínicos/metabolismoRESUMEN
Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.
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Encéfalo/efectos de los fármacos , Hierro/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Cerebelo/patología , Ceruloplasmina/farmacología , Cobre/metabolismo , Deferiprona/farmacología , Modelos Animales de Enfermedad , Ferritinas/efectos de los fármacos , Ferritinas/metabolismo , Quelantes del Hierro/farmacología , Ratones , Ratones Transgénicos , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patología , Atrofia de Múltiples Sistemas/fisiopatología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Putamen/efectos de los fármacos , Putamen/metabolismo , Putamen/patología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , alfa-Sinucleína/genéticaRESUMEN
The mechanisms involved in the maintenance of cigarette smoking and nicotine reward remain unclear. Immune response might play an important role in this context. Nicotine may induce both central and systemic inflammatory responses as well as changes in the regulation of brain-derived neurotrophic factor (BDNF). The conditioned place preference (CPP) is a method used for the evaluation of nicotine-induced reward, reproducing nicotine-seeking behavior in humans. So far, there are no studies investigating the relationship between neuroinflammation and nicotine-induced CPP. This study aimed to evaluate the levels of inflammatory mediators and neurotrophic factors in key areas of the central nervous system (CNS) of mice subject to nicotine-induced CPP. CPP was induced with an intraperitoneal administration of 0.5â¯mg/kg of nicotine in male Swiss mice, using an unbiased protocol. Control group received vehicle by the same route. The levels of cytokines, chemokines, and neurotrophic factors were measured using Enzyme-Linked Immunosorbent Assay (ELISA) in the brain after CPP test. As expected, nicotine induced place preference behavior. In parallel, we observed increased peripheral levels of IL-6 and IL-10 alongside increased hippocampal levels of NGF but decreased GDNF in mice treated with nicotine compared to controls. In the striatum, nicotine promoted decrease of IL-1ß, IL-10 and GDNF levels, while the levels of all the mediators were similar between groups in the pre-frontal cortex. Our results provide evidence on the role of cytokines and neurotrophic factors in nicotine-induced CPP in mice.
Asunto(s)
Condicionamiento Psicológico/efectos de los fármacos , Enfermedades Neuroinflamatorias/psicología , Nicotina/administración & dosificación , Recompensa , Tabaquismo/psicología , Animales , Factor Neurotrófico Derivado del Encéfalo/análisis , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/inmunología , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Hipocampo/inmunología , Hipocampo/patología , Humanos , Inyecciones Intraperitoneales , Interleucina-10/análisis , Interleucina-10/metabolismo , Interleucina-1beta/análisis , Interleucina-1beta/metabolismo , Masculino , Ratones , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/patología , Nicotina/efectos adversos , Corteza Prefrontal/inmunología , Corteza Prefrontal/patología , Tabaquismo/inmunología , Tabaquismo/patologíaRESUMEN
OBJECTIVE: Antipsychotics, in particular olanzapine, are first-line medications for schizophrenia. The prefrontal cortex (PFC) is an important region for antipsychotics' therapeutic effects. The PFC inflammatory and immune pathways are associated with schizophrenia pathogenesis. However, the effect of antipsychotics on the inflammatory and immune pathways in the PFC remains unclear. We aimed to examined the time-dependent effect of olanzapine on inflammatory and immune markers in the PFC of rats. Since the inflammatory and immune pathways are related to endoplasmic reticulum (ER) stress, we further investigated whether or not olanzapine-induced inflammation and immune responses were related to ER stress. METHODS: Expression of pro-inflammatory markers including IkappaB kinase ß (IKKß), nuclear factor kappa B (NFκB), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and IL-1ß, and immune-related proteins including inducible nitric oxide synthase (iNOS), toll-like receptor 2 (TLR2) and cluster of differentiation 14 (CD14) were examined by Western blotting. RESULTS: Olanzapine treatments for 1, 8 and 36 days significantly activated the inflammatory IKKß/NFκB signaling, and increased the expression of TNF-α, IL-6, IL-1ß and immune-related proteins such as iNOS, TLR4 and CD14. Olanzapine treatment for 1 day, 8 and 36 days also induced ER stress in the PFC. Co-treatment with an ER stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced inflammation and the immune response in the PFC. CONCLUSION: These results suggested olanzapine exposure could be a factor that induces central inflammation and immunological abnormities in schizophrenia subjects. Olanzapine induces PFC inflammation and immune response, possibly via activating ER stress signaling.
Asunto(s)
Estrés del Retículo Endoplásmico/genética , Inflamación/metabolismo , Olanzapina/farmacología , Corteza Prefrontal/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Quinasa I-kappa B/genética , Inmunidad/efectos de los fármacos , Inmunidad/genética , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/patología , Interleucina-1beta/genética , Interleucina-6/genética , Óxido Nítrico Sintasa de Tipo II/genética , Estrés Oxidativo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Ratas , Esquizofrenia/complicaciones , Esquizofrenia/genética , Esquizofrenia/patología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 2/genéticaRESUMEN
OBJECTIVE: Patients with brain tumors frequently present neurocognitive deficits. Aiming at better understanding the impact of tumor localization on neurocognitive processes, we evaluated neurocognitive function prior to glioma surgery within one of four specific regions in the left speech-dominant hemisphere. METHODS: Between 04/2011 and 12/2019, 43 patients undergoing neurocognitive evaluation prior to awake surgery for gliomas (WHO grade I: 2; II: 6; III: 23; IV: 11) in the inferior frontal gyrus (IFG; n = 20), the anterior temporal lobe (ATL; n = 6), the posterior superior temporal region/supramarginal gyrus (pST/SMG; n = 7) or the posterior middle temporal gyrus (pMTG; n = 10) of the language dominant left hemisphere were prospectively included in the study. Cognitive performances were analyzed regarding an influence of patient characteristics and tumor localization. RESULTS: Severe impairment in at least one neurocognitive domain was found in 36 (83.7%) patients. Anxiety and depression were observed most frequently, followed by verbal memory impairments. Verbal memory was more strongly affected in patients with ATL or pST/SMG tumors compared to IFG tumors (p = 0.004 and p = 0.013, resp.). Overall, patients suffering from tumors in the ATL were most frequently and severely impaired. CONCLUSION: Patients suffering from gliomas involving different regions within the language dominant hemisphere frequently present impairments in neurocognitive domains also other than language. Considering individual functions at risk may help in better advising patients prior to treatment and in tailoring the individual therapeutic strategy to preserve patients' quality of life.
Asunto(s)
Neoplasias Encefálicas/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Glioma/patología , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/complicaciones , Femenino , Lateralidad Funcional , Glioma/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Corteza Prefrontal/patología , Lóbulo Temporal/patología , Área de Wernicke/patología , Adulto JovenRESUMEN
BACKGROUND: Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. METHODS: The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. RESULTS: Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. CONCLUSION: This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.