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OBJECTIVES: Sleep problems are common amongst children and adolescents with attention deficit hyperactivity disorder (ADHD). The purpose of this study was to investigate sleep problems in children and adolescents attending a specialist ADHD service. METHODS: This was a cross-sectional online survey combined with a retrospective chart review, conducted in the ADHD Assessment, Diagnosis, Management, initiation, Research and Education (ADMiRE) service, the first public specialist ADHD service for young people in Ireland. Participants were caregivers of children and adolescents with ADHD attending ADMiRE. Sleep was assessed using The Children's Sleep Habits Questionnaire (CSHQ) and ADHD symptoms were assessed using an abbreviated version of the Swanson, Nolan and Pelham Teacher and Parent Rating Scale (SNAP-IV). Details regarding patient demographics, co-morbidities and medication were collected from patient records. RESULTS: Eighty-four percent of young people scored above the clinical cut-off for a sleep disorder. The most frequently reported sleep problems were related to sleep onset and sleep duration, and 64% of respondents met the criteria for two or more sleep problems. ADHD severity was associated with greater sleep problems. Co-morbid physical, neurodevelopmental, and mental health disorders as well as stimulant use were not associated with greater sleep problems. CONCLUSION: Sleep problems are very common amongst children and adolescents with ADHD. This study has demonstrated an association between more sleep problems and ADHD severity. These findings highlight the need for both effective ADHD treatment to ensure optional sleep in young people as well as effective interventions for sleep problems to prevent worsening of ADHD symptoms.
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Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition that has been strongly associated with changes in sleep and circadian rhythms. Circadian rhythms are near 24-h cycles that are primarily generated by an endogenous circadian timekeeping system, encoded at the molecular level by a panel of clock genes. Stimulant and non-stimulant medication used in the management of ADHD has been shown to potentially impact on circadian processes and their behavioral outputs. In the current study, we have analyzed circadian rhythms in daily activity and sleep, and the circadian gene expression in a cohort of healthy controls (N = 22), ADHD participants not using ADHD-medication (N = 17), and participants with ADHD and current use of ADHD medication (N = 17). Rhythms of sleep/wake behavior were assessed via wrist-worn actigraphy, whilst rhythms of circadian gene expression were assessed ex-vivo in primary human-derived dermal fibroblast cultures. Behavioral data indicate that patients with ADHD using ADHD-medication have lower relative amplitudes of diurnal activity rhythms, lower sleep efficiency, more nocturnal activity but not more nocturnal wakenings than both controls and ADHD participants without medication. At the molecular level, there were alterations in the expression of PER2 and CRY1 between ADHD individuals with no medication compared to medicated ADHD patients or controls, whilst CLOCK expression was altered in patients with ADHD and current medication. Analysis of fibroblasts transfected with a BMAL1:luc reporter showed changes in the timing of the peak expression across the three groups. Taken together, these data support the contention that both ADHD and medication status impact on circadian processes.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Ritmo Circadiano , Sueño/fisiología , Actigrafía , Adulto , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Proteínas CLOCK/genética , Células Cultivadas , Relojes Circadianos/genética , Criptocromos/genética , Femenino , Fibroblastos/metabolismo , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Proteínas Circadianas Period/genéticaRESUMEN
To examine how the chemotactic agent stromal cell-derived factor-1alpha (SDF-1α) modulates the unique cellular milieu within rotator cuff muscle following tendon injury, we developed an injectable, heparin-based microparticle platform to locally present SDF-1α within the supraspinatus muscle following severe rotator cuff injury. SDF-1α loaded, degradable, N-desulfated heparin-based microparticles were fabricated, injected into a rat model of severe rotator cuff injury, and were retained for up to 7 days at the site. The resultant inflammatory cell and mesenchymal stem cell populations were analyzed compared to uninjured contralateral controls and, after 7 days, the fold-change in anti-inflammatory, M2-like macrophages (CD11b+CD68+CD163+, 4.3X fold-change) and mesenchymal stem cells (CD29+CD44+CD90+, 3.0X, respectively) was significantly greater in muscles treated with SDF-1α loaded microparticles than unloaded microparticles or injury alone. Our results indicate that SDF-1α loaded microparticles may be a novel approach to shift the cellular composition within the supraspinatus muscle and create a more pro-regenerative milieu, which may provide a platform to improve muscle repair following rotator cuff injury in the future.
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INTRODUCTION: The characteristic features of Papanicolaou (Pap) tests collected from female-to-male (FTM) transgender patients on androgen therapy have not been well defined in the literature. FTM transgender patients require cervical cancer screening with the same recommended frequency as cis-gender females. Dysplasia remains challenging to differentiate from atrophy. Without pertinent history, the atrophic findings in younger transgender patients can be misinterpreted as high-grade dysplasia. METHODS: A review of all cervical Pap tests of transgender patients receiving androgen therapy (2010-2017) was performed. Bethesda diagnosis, cytomorphological features, HPV testing and cervical biopsy results were reviewed. RESULTS: Eleven transgender patients receiving androgen therapy were identified with 23 cervical Pap tests, 11 HPV tests and five cervical biopsies performed. A review of the Pap tests demonstrated: 57% negative for intraepithelial lesion; 13% unsatisfactory; 13% atypical squamous cells of undetermined significance; 13% atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion; and 4% high-grade squamous intraepithelial lesion. The rates of abnormal tests were higher than our age-matched cis-gender atrophic cohort rates of unsatisfactory (0.5%), atypical squamous cells of undetermined significance (7%), atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (0%) and high-grade squamous intraepithelial lesion (0.5%). The cytological findings from liquid-based preparations included dispersed and clustered parabasal-type cells, scattered degenerated cells, smooth evenly dispersed chromatin, and occasional mild nuclear enlargement and irregularity. Dysplastic cells had larger nuclei, hyperchromatic clumped chromatin, and more irregular nuclear contours. CONCLUSIONS: The evaluation of dysplasia can be challenging on Pap tests from transgender patients on androgen therapy. The cohort evaluated had higher rates of unsatisfactory and abnormal Pap tests. Pathologists should be familiar with the distinctive cytomorphological changes in the Pap tests from patients on androgen therapy to evaluate them appropriately.
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Cuello del Útero/patología , Displasia Ectodérmica/patología , Andrógenos/uso terapéutico , Células Escamosas Atípicas del Cuello del Útero/patología , Femenino , Humanos , Prueba de Papanicolaou/métodos , Infecciones por Papillomavirus/patología , Estudios Retrospectivos , Lesiones Intraepiteliales Escamosas de Cuello Uterino/patología , Personas Transgénero , Neoplasias del Cuello Uterino/patología , Frotis Vaginal/métodos , Displasia del Cuello del Útero/patologíaRESUMEN
Circadian rhythms are recurring near-24 hour patterns driven by an endogenous circadian timekeeping system. The master pacemaker in this system is the hypothalamic suprachiasmatic nucleus (SCN). Recently interest has been drawn to how the SCN clock responds to immune system stimulation. A major signalling component in the immune system is nuclear factor (NF)-κB. In the present study we examined the role of NF-κB in SCN function. Whilst serum shocked fibroblasts showed rhythmic nuclear localisation of p65 and p65-dependent transcription, there were no circadian changes in the SCN in expression of the NF-κB components p65, c-Rel, p-IκB or p-IKK. Chronic treatment with the NF-κB inhibitor PDTC did not impact on circadian or diurnal rhythms. Phase-shifting light pulses did not impact on SCN expression of p65, and PDTC treatment did not attenuate the behavioural or molecular response to light pulses. Peripheral treatment with lipopolysaccharide resulted in increased NF-κB component expression in the SCN. In vitro experiments with SCN slice cultures showed that treatment with NF-κB inhibitors did not markedly alter rhythmic changes in PER2::LUC expression. Further, SCN slices from nf-κb::luc mice did not show any evidence for circadian rhythms in NF-κB-mediated transcription. Experiments utilising older mice (~16 months old) showed that SCN treatment in vitro with PDTC resulted in increased amplitude of rhythmic PER2::LUC expression, and LPS treatment resulted in altered PER2::LUC rhythm acrophase. Overall, we interpret our results as providing evidence for the involvement of NF-κB in the suprachiasmatic circadian clock following immune stimulation, but not under basal conditions.
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Relojes Circadianos/fisiología , FN-kappa B/metabolismo , Neuroinmunomodulación/fisiología , Núcleo Supraquiasmático/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Animales , Bovinos , Técnicas de Cultivo de Célula , Fármacos del Sistema Nervioso Central/farmacología , Relojes Circadianos/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Medios de Cultivo , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , FN-kappa B/antagonistas & inhibidores , Células 3T3 NIH , Neuroinmunomodulación/efectos de los fármacos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Estimulación Luminosa/métodos , Suero , Núcleo Supraquiasmático/efectos de los fármacos , Técnicas de Cultivo de TejidosRESUMEN
OBJECTIVE: The 2001 Bethesda System for Reporting Cervical Cytology includes documenting 'endometrial cells in women ≥40 years of age' (E40) to help identify endometrial carcinoma (EC) on a Papanicolaou (Pap) test. The 2014 Bethesda System for Reporting Cervical Cytology raises the threshold to ≥45 years of age (E45). As many of these women are menstruating, routine biopsy after E40, or even E45, may lead to unnecessary procedures for benign endometrial cells. Establishing a different age threshold in combination with other clinical findings may help to guide management. METHODS: A retrospective chart review was performed on consecutive EC specimens and E40 Pap tests. Clinical, pathological data such as age, biopsy diagnosis, FIGO grade and the time of the last Pap test, Pap test diagnosis and resection diagnosis, depth of invasion, stage and metastases were recorded. RESULTS: Sixty-three EC cases had prior Pap smears, with the following diagnoses: negative for an intraepithelial lesion or malignancy (n = 27), atypical glandular cells, not otherwise specified (AGC, NOS) (n = 14), adenocarcinoma (n = 10) and E40 (n = 1; 51 years). Six hundred and forty-two E40 cases had 138 (21.5%) biopsies and/or hysterectomies. Out of the 138 cases, two (1.4%) had EC (both 51 years; postmenopausal), one had complex hyperplasia with atypia (52 years; abnormal uterine bleeding), and eight had hyperplasia without atypia. CONCLUSIONS: In asymptomatic women less than 50 years, E40 correlated with benign, non-hyperplastic endometrium. However, post-menopausal women with E40 had a risk of EC. Perhaps endometrial cells should only be reported in post-menopausal women or women greater than or equal to 50 years of age.
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Hiperplasia Endometrial/diagnóstico , Neoplasias Endometriales/diagnóstico , Prueba de Papanicolaou/métodos , Displasia del Cuello del Útero/diagnóstico , Anciano , Biopsia , Hiperplasia Endometrial/cirugía , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Retrospectivos , Frotis Vaginal , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/cirugíaRESUMEN
Attention deficit hyperactivity disorder (ADHD) in adults is a prevalent, yet under-appreciated, under-researched and poorly understood condition. Given this, it is imperative that information and awareness regarding this condition are made more widespread, both amongst the general public and amongst healthcare professionals. Further, given our poor understanding of the aetiology of the condition, meaningful translational research that migrates into and better informs clinical practice must be a priority. In this brief review we highlight areas regarding the clinical diagnosis and management of ADHD in adults (guidelines, rating scales, pharmacotherapy, psychotherapy) as well as areas of promising translational research (genetics, neuroimaging, sleep and circadian rhythms, animal models of ADHD). We address some of the challenges presented for both clinicians and healthcare providers and research scientists working to improve the lives of those adults with ADHD.
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Circadian rhythms are recurring cycles in physiology and behaviour that repeat with periods of near 24 h and are driven by an endogenous circadian timekeeping system with a master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Atomoxetine is a specific noradrenaline reuptake inhibitor that is used in the clinical management of attention-deficit/hyperactivity disorder (ADHD). In the current study we examined the effects of atomoxetine on circadian rhythms in mice. Atomoxetine (i.p.; 3 mg/kg) treatment of mice free-running in constant light (LL) at circadian time (CT) 6 induced large phase delays that were significantly different to saline controls. Treatment of animals with atomoxetine at CT13 or CT18 did not elicit any significant phase shifts. We also examined the effects of atomoxetine treatment of animals free-running in constant darkness (DD). Atomoxetine treatment at CT6 in these animals leads to more modest, but significant, phase advances, whereas treatment at CT18 did not elicit significant phase shifts. The effects of atomoxetine in LL were attenuated by pretreatment with the α-1 adrenoreceptor antagonist prazosin and were mimicked by another noradrenaline reuptake inhibitor, reboxetine. Further, atomoxetine treatment at CT6 induced a downregulation of c-Fos and CLOCK in the SCN, but did not alter the expression of PER2 and BMAL1. Atomoxetine during the night phase did not alter any of these factors. Atomoxetine treatment preceding a light pulse at CT15 enhanced the magnitude of the photic-phase shift, whereas it altered photic induction of the immediate early gene products c-Fos and ARC in the SCN. These data indicate that atomoxetine can reset the circadian clock and indicate that part of the therapeutic profile of atomoxetine may be through circadian rhythm modulation.
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Inhibidores de Captación Adrenérgica/farmacología , Atención/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Propilaminas/farmacología , Análisis de Varianza , Animales , Clorhidrato de Atomoxetina , Conducta Animal/efectos de los fármacos , Proteínas CLOCK/metabolismo , Oscuridad , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Morfolinas/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Reboxetina , Núcleo Supraquiasmático/efectos de los fármacos , Núcleo Supraquiasmático/metabolismoRESUMEN
Attention-deficit hyperactivity disorder (ADHD) in adults is associated with impaired sleep, and it has been postulated that this impairment may contribute to the psychopathology of this common condition. One key driver of sleep/wake cycles is the circadian system, which at the molecular level consists of a series of transcriptional feedback loops of clock genes, which in turn produce endocrine, physiological and behavioural outputs with a near 24 h periodicity. We set out to examine circadian rhythms at the behavioural, endocrine and molecular levels in ADHD. Adults with ADHD as well as age- and sex-matched controls were recruited. Circadian rhythms were measured by means of actigraphy for the determination of gross motor patterns, by self-sampling of oral mucosa for assessment of rhythmic expression of the clock genes BMAL1 and PER2, and by estimation of salivary cortisol and melatonin levels. Actigraphic analysis revealed significant diurnal and nocturnal hyperactivity in the ADHD group, as well as a significant shorter period of best fit for the locomotor circadian rhythm in ADHD. BMAL1 and PER2 showed circadian rhythmicity in controls with this being lost in the ADHD group. Cortisol rhythms were significantly phase delayed in the ADHD group. These findings indicate that adult ADHD is accompanied by significant changes in the circadian system, which in turn may lead to decreased sleep duration and quality in the condition. Further, modulation of circadian rhythms may represent a novel therapeutic avenue in the management of ADHD.
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Factores de Transcripción ARNTL/genética , Trastorno por Déficit de Atención con Hiperactividad , Ritmo Circadiano/fisiología , Sistema Endocrino/fisiopatología , Proteínas Circadianas Period/genética , Actigrafía , Adulto , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Estudios de Casos y Controles , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Hidrocortisona/metabolismo , Masculino , Melatonina/metabolismo , Persona de Mediana Edad , Psicometría , Estudios Retrospectivos , Saliva/metabolismo , Autoinforme , Estadísticas no Paramétricas , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
Circadian rhythms are daily oscillations in physiology and behaviour that recur with a period of 24h, and that are entrained by the daily photoperiod. The cycle of sunrise and sunset provided a reliable time cue for many thousands of years, until the advent of artificial lighting disrupted the entrainment of human circadian rhythms to the solar photoperiod. Circadian desynchrony (CD) occurs when endogenous rhythms become misaligned with daily photoperiodic cycles, and this condition is facilitated by artificial lighting. This review examines the hypothesis that chronic CD that has accompanied the availability of electric lighting in the developed world induces a metabolic and behavioural phenotype that is predisposed to the development of obesity. The evidence to support this hypothesis is based on epidemiological data showing coincidence between the appearance of obesity and the availability of artificial light, both geographically, and historically. This association links CD to obesity in humans, and is corroborated by experimental studies that demonstrate that CD can induce obesity and metabolic dysfunction in humans and in rodents. This association between CD and obesity has far reaching implications for human health, lifestyle and work practices. Attention to the rhythmicity of daily sleep, exercise, work and feeding schedules could be beneficial in targeting or reversing the modern human predisposition to obesity.
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Trastornos Cronobiológicos/complicaciones , Iluminación/efectos adversos , Enfermedades Metabólicas/complicaciones , Modelos Biológicos , Obesidad/epidemiología , Obesidad/etiología , Fotoperiodo , Animales , Trastornos Cronobiológicos/etiología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Iluminación/historia , Iluminación/estadística & datos numéricos , Enfermedades Metabólicas/etiología , Ratones , RatasRESUMEN
Disturbed circadian rhythms with sleep problems and disrupted diurnal activity are often seen in patients suffering from Alzheimer disease (AD). Both endogenous CLOCK genes and external Zeitgeber are responsible for the maintenance of circadian rhythmicity in humans. Therefore, modifications of the internal CLOCK system and its interactions with exogenous factors might constitute the neurobiological basis for clinically observed disruptions in rhythmicity, which often have grave consequences for the quality of life of patients and their caregivers. Presently, more and more data are emerging demonstrating how alterations of the CLOCK gene system might contribute to the pathophysiology of AD and other forms of dementia. At the same time, the impact of neuropsychiatric medication on CLOCK gene expression is under investigation.
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Biological rhythms that oscillate with periods close to 24 h (circadian cycles) are pervasive features of mammalian physiology, facilitating entrainment to the 24 h cycle generated by the rotation of the Earth. In the absence of environmental time cues, circadian rhythms default to their endogenous period called tau, or the free-running period. This sustained circadian rhythmicity in constant conditions has been reported across the animal kingdom, a ubiquity that could imply that innate rhythmicity confers an adaptive advantage. In this study, we found that the deviation of tau from 24 h was inversely related to the lifespan in laboratory mouse strains, and in other rodent and primate species. These findings support the hypothesis that misalignment of endogenous rhythms and 24 h environmental cycles may be associated with a physiological cost that has an effect on longevity.
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Ritmo Circadiano , Esperanza de Vida , Mamíferos/fisiología , Animales , FilogeniaRESUMEN
The study of neural arousal mechanisms has been greatly aided by the discovery of the orexin peptides (orexin A and orexin B), the subsequent identification of the neurons that synthesize these peptides, their projections in the brain, and the distribution of orexin receptors in the central nervous system. Orexin neuron activation is partly controlled by circadian signals generated in the brain's main circadian pacemaker, the suprachiasmatic nuclei (SCN). The SCN clock is in turn reset by arousal-promoting stimuli and, intriguingly, orexin fibers and receptor expression are detected in the SCN region. It is unclear, however, if orexin can alter SCN neuronal activity. Here using a coronal brain slice preparation, we found that orexin A and orexin B (0.1-1 microM) elicited significant changes in the extracellularly recorded firing rate and firing pattern in approximately 80% of rat SCN cells tested; the most common response was suppression of firing rate. Co-application of orexin A with a cocktail of ionotropic GABA and glutamate receptor antagonists did not alter the actions of this peptide on firing rate, but did change some its effects on firing pattern. We conclude that orexins can alter SCN neurophysiology and may influence the transmission of information through the SCN to other CNS regions.
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Péptidos y Proteínas de Señalización Intracelular/farmacología , Neuronas/efectos de los fármacos , Neuropéptidos/farmacología , Núcleo Supraquiasmático/efectos de los fármacos , Animales , Nivel de Alerta , Relación Dosis-Respuesta a Droga , Electrofisiología , Agonistas de Aminoácidos Excitadores/farmacología , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/fisiología , Técnicas In Vitro , Masculino , Microelectrodos , N-Metilaspartato/farmacología , Orexinas , Ratas , Ratas Wistar , Núcleo Supraquiasmático/citologíaRESUMEN
Attention deficit/hyperactivity disorder (ADHD) is a complex, highly heritable psychiatric condition. Neuropsychological and pharmacological studies suggest a dysregulation of central noradrenergic neurotransmission in addition to dopaminergic and serotonergic mechanisms. Only a few studies have focused on the association of noradrenergic susceptibility genes with ADHD. In this study, we investigated the association of several ADHD symptom scores (German short form of the Wender Utah Rating Scale, WURS-k; ADHD self report, ADHD-SB, and the German validated version of the WRAADDS, WRI) with haplotypes of the catechol-O-methyltransferase (COMT) and the norepinephrine transporter (SLC6A2) genes. Subjects were genotyped for three SLC6A2 (rs5569, rs998424, rs2242447) and two COMT single nucleotide polymorphisms (rs4680, rs4818). In addition, psychosocial adversity in childhood was assessed in order to evaluate putative gene-environment interactions. We did not find main effects of the COMT and SLC6A2 NET1 gene haplotypes on any ADHD symptom severity score. Childhood psychosocial adversity was strongly associated with number of ADHD symptoms. No gene-environment interaction was found. A specific combination of two COMT and SLC6A2 gene haplotypes, containing the low functioning COMT variant was nominally associated with low ADHD scores in all scales. Results do not support the hypothesis that common variants in the SLC6A2 and COMT genes in particular are associated with ADHD, but might give some evidence for interactive effects between these gene variants on ADHD severity.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Catecol O-Metiltransferasa/genética , Predisposición Genética a la Enfermedad , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Análisis de Varianza , Distribución de Chi-Cuadrado , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The circadian pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) receives photic information directly via the retinohypothalamic tract (RHT) and indirectly from retinally innervated cells in the thalamic intergeniculate leaflet (IGL) that project to the SCN. Using standard immunohistochemical methods, we examined the presence and distribution of substance P (SP) and the neurokinin-1 receptor (NK-1) in the SCN and IGL of rat and determined whether the patterns of immunostaining generalized to the SCN and IGL of Syrian hamster, Siberian hamster, and mouse. Terminals immunoreactive for SP were sparse within the SCN of Siberian and Syrian hamsters and mouse but were intense in the ventral, retinally innervated portion of the rat SCN. Immunostaining for the NK-1 receptor was mainly absent from the SCN of hamster and mouse. In contrast, a plexus of NK-1-ir cells and processes that was in close proximity to SP-ir terminals was found in the ventral SCN of the rat. Substance P-ir terminals were observed in the IGL of all four species, as were NK-1-ir cells and fibres. Double-labelled IGL sections of hamster or rat revealed SP-ir terminals in close apposition to NK-1-immunostained cells and/or fibres. These data indicate that SP could be a neurotransmitter of the RHT in rat, but not in hamster or in mouse, and they highlight potential species differences in the role of SP within the SCN circadian pacemaker. Such species differences do not appear to exist at the level of the IGL, where SP-ir and NK-1-ir were similar in all species studied.
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Cricetinae/metabolismo , Cuerpos Geniculados/metabolismo , Ratones Endogámicos C57BL/metabolismo , Ratas Wistar/metabolismo , Receptores de Neuroquinina-1/metabolismo , Sustancia P/metabolismo , Núcleo Supraquiasmático/metabolismo , Animales , Axones/metabolismo , Cricetinae/anatomía & histología , Cuerpos Geniculados/citología , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL/anatomía & histología , Ratas , Ratas Wistar/anatomía & histología , Núcleo Supraquiasmático/citologíaRESUMEN
The neuropeptide neurotensin and two classes of its receptors, the neurotensin receptor-1 and 2, are present in the suprachiasmatic nucleus of the mammalian hypothalamus. The suprachiasmatic nucleus houses the mammalian central circadian pacemaker, but the effects of neurotensin on cellular activity in this circadian pacemaker are unknown. In this study, we examined the effects of neurotensin on the spontaneous discharge rate of rat SCN cells in an in vitro slice preparation. Neurotensin (1-10 microM) increased cell firing rate in approximately 50% of cells tested, while approximately 10% of suprachiasmatic cells tested showed a decrease in firing rate in response to neurotensin. These effects of neurotensin were not altered by the GABA receptor antagonist bicuculline (20 microM) or the glutamate receptor antagonists, D-aminophosphopentanoic acid (50 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM). The neurotensin receptor selective antagonists SR48692 and SR142948a (10 microM) failed to antagonise neurotensin responses in the majority of cells examined. Compounds that function as agonists selective for the neurotensin-receptor subtypes 1 and 2, JMV-510 and JMV-431 respectively, elicited neurotensin-like responses in approximately 90% of cells tested. Six out of seven cells tested responded to both JMV-510 and JMV-431. Neuropeptide Y (100nM) treatment of suprachiasmatic nucleus slices was found to elicit profound suppression of neuronal firing rate. Co-application of neurotensin with neuropeptide Y significantly (P<0.05) reduced the duration of the response, as compared to that elicited with neuropeptide Y alone. Together, these results demonstrate for the first time the actions of neurotensin in the suprachiasmatic nucleus and raise the possibility that this neuropeptide may play a role in modulating circadian pacemaker function.
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Neuronas/efectos de los fármacos , Neuronas/fisiología , Neurotensina/análogos & derivados , Neurotensina/farmacología , Fragmentos de Péptidos/farmacología , Núcleo Supraquiasmático/efectos de los fármacos , Núcleo Supraquiasmático/fisiología , Animales , Interacciones Farmacológicas , Electrofisiología , Técnicas In Vitro , Masculino , Neurotransmisores/fisiología , Isoformas de Proteínas/agonistas , Ratas , Ratas Wistar , Receptores de Neurotensina/agonistas , Núcleo Supraquiasmático/citologíaRESUMEN
The main mammalian circadian pacemaker is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Gastrin-releasing peptide (GRP) and its receptor (BB(2)) are synthesized by rodent SCN neurons, but the role of GRP in circadian rhythm processes is unknown. In this study, we examined the phase-resetting actions of GRP on the electrical activity rhythms of hamster and rat SCN neurons in vitro. In both rat and hamster SCN slices, GRP treatment during the day did not alter the time of peak SCN firing. In contrast, GRP application early in the subjective night phase-delayed, whereas similar treatment later in the subjective night phase-advanced the firing rate rhythm in rat and hamster SCN slices. These phase shifts were completely blocked by the selective BB(2) receptor antagonist, [d-Phe(6), Des-Met(14)]-bombesin 6-14 ethylamide. We also investigated the temporal changes in the expression of genes for the BB(1) and BB(2) receptors in the rat SCN using a quantitative competitive RT-PCR protocol. The expression of the genes for both receptors was easily detected, but their expression did not vary over the diurnal cycle. These data show that GRP phase-dependently phase resets the rodent SCN circadian pacemaker in vitro apparently via the BB(2) receptor. Because this pattern of phase shifting resembles that of light on rodent behavioral rhythms, these results support the contention that GRP participates in the photic entrainment of the rodent SCN circadian pacemaker.
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Bombesina/análogos & derivados , Ritmo Circadiano/fisiología , Péptido Liberador de Gastrina/metabolismo , Neuronas/metabolismo , Núcleo Supraquiasmático/metabolismo , Análisis de Varianza , Animales , Relojes Biológicos/efectos de los fármacos , Bombesina/farmacología , Ritmo Circadiano/efectos de los fármacos , Cricetinae , Oscuridad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Péptido Liberador de Gastrina/administración & dosificación , Técnicas In Vitro , Masculino , Mesocricetus , Neuronas/citología , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Fotoperiodo , ARN Mensajero/análisis , Ratas , Ratas Wistar , Receptores de Bombesina/antagonistas & inhibidores , Receptores de Bombesina/biosíntesis , Receptores de Bombesina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Núcleo Supraquiasmático/citología , Núcleo Supraquiasmático/efectos de los fármacosRESUMEN
It is now clear that IL-1 beta has profound and complex actions in the CNS. At pathophysiological concentrations it has an inhibitory effect on LTP in many regions of the hippocampus. There is also evidence emerging for a physiological role for IL-1 beta in the brain. Table 1 summarizes the effects of IL-1 beta and some other pro-inflammatory cytokines in the CNS.
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Interleucina-1/fisiología , Transmisión Sináptica/fisiología , Animales , Hipocampo/fisiología , Humanos , Potenciación a Largo Plazo/fisiología , Receptores de Interleucina-1/metabolismoRESUMEN
Levels of the pro-inflammatory cytokine interleukin-1beta are known to be elevated in patients with chronic disorders such as Alzheimer's disease. We have investigated the effects of interleukin-1beta on long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials in the rat dentate gyrus in vitro utilizing field extracellular recordings obtained from the middle third of the molecular layer of the dentate gyrus. Presynaptic stimulation was applied to the commissural/association pathway at a frequency of 0.05 Hz and at a distance of 50 microm from the granule cell body layer. As previously reported, interleukin-1beta (1 ng/ml) caused an inhibition of long-term potentiation (108+/-2% of baseline 1 h following application of tetanic stimulation compared with 145+/-5% in vehicle control slices). This action of interleukin-1beta on long-term potentiation, as well as an inhibition of N-methyl-D aspartate receptor-mediated field potentials, was attenuated by pre-treatment of slices with the p38 mitogen-associated protein kinase inhibitor SB203580 (1 microM). SB203580 alone had no significant affect on long-term potentiation, but did cause an increase in baseline synaptic transmission [107+/-2% of baseline, 1 h after SB203580 (1 microM) treatment]. The p42/44 mitogen-activated protein kinase cascade inhibitor PD98059 (50 microM) did not inhibit the interleukin-1beta-induced inhibition of N-methyl-D-aspartate receptor-mediated field potentials. The cyclooxygenase inhibitor indomethacin (50 microM) was found to attenuate the interleukin-1beta-induced effects on both long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials. The lipid second messenger analogue C2 ceramide (20 microM) was found to attenuate the expression of long-term potentiation (108+/-3% of baseline 1 h following tetanic stimulation), and this effect was not blocked by pre-treatment with SB203580. To investigate a possible role for interleukin-1beta in the normal expression of long-term potentiation, the interleukin-1 receptor antagonist (25 ng/ml) was applied during the maintenance phase of long-term potentiation. This was found to depress the sustained expression of long-term potentiation (116+/-6% of baseline 1 h following tetanic stimulation). Our results indicate possible signalling mechanisms by which interleukin-1beta at pathophysiological concentrations may serve to inhibit long-term potentiation, and also suggests a role for IL-1beta in the physiological expression of synaptic plasticity in the rat dentate gyrus in vitro.