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1.
Cell ; 175(5): 1177-1179, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445036

RESUMO

In Drosophila, well-delineated circuits control circadian rhythms, but the electrophysiological patterns that occur within these circuits are not well understood. In this issue, Tabuchi et al. clarify the temporal coding within a circuit, linking patterns of neural activity to sleep behavior.


Assuntos
Proteínas de Drosophila , Animais , Ritmo Circadiano , Drosophila , Plasticidade Neuronal , Sono
2.
J Neurosci ; 43(48): 8126-8139, 2023 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-37821228

RESUMO

Subcortical white matter stroke (WMS) is a progressive disorder which is demarcated by the formation of small ischemic lesions along white matter tracts in the CNS. As lesions accumulate, patients begin to experience severe motor and cognitive decline. Despite its high rate of incidence in the human population, our understanding of the cause and outcome of WMS is extremely limited. As such, viable therapies for WMS remain to be seen. This study characterizes myelin recovery following stroke and motor learning-based rehabilitation in a mouse model of subcortical WMS. Following WMS, a transient increase in differentiating oligodendrocytes occurs within the peri-infarct in young male adult mice, which is completely abolished in male aged mice. Compound action potential recording demonstrates a decrease in conduction velocity of myelinated axons at the peri-infarct. Animals were then tested on one of three distinct motor learning-based rehabilitation strategies (skilled reach, restricted access to a complex running wheel, and unrestricted access to a complex running wheel) for their capacity to induce repair. These studies determined that unrestricted access to a complex running wheel alone increases the density of differentiating oligodendrocytes in infarcted white matter in young adult male mice, which is abolished in aged male mice. Unrestricted access to a complex running wheel was also able to enhance conduction velocity of myelinated axons at the peri-infarct to a speed comparable to naive controls suggesting functional recovery. However, there was no evidence of motor rehabilitation-induced remyelination or myelin protection.SIGNIFICANCE STATEMENT White matter stroke is a common disease with no medical therapy. A form of motor rehabilitation improves some aspects of white matter repair and recovery.


Assuntos
Acidente Vascular Cerebral , Substância Branca , Humanos , Masculino , Camundongos , Animais , Idoso , Substância Branca/patologia , Acidente Vascular Cerebral/patologia , Bainha de Mielina/patologia , Oligodendroglia/fisiologia , Infarto/patologia , Atividade Motora
3.
J Neurosci Res ; 102(1): e25290, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38284849

RESUMO

Sleep and circadian rhythm disturbances are common features of Huntington's disease (HD). HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies as well as preclinical work indicate there may be sex differences in disease presentation and progression. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s), we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in sleep/wake cycles are detectable in an animal model of the disease. Electroencephalography/electromyography (EEG/EMG) was used to measure sleep/wake states and polysomnographic patterns in young adult (12-week-old) male and female wild-type and BACHD mice. Our findings show that male, but not female, BACHD mice exhibited increased variation in phases of the rhythms as compared to age- and sex-matched wild-types. For both rapid-eye movement (REM) and non-rapid eye movement (NREM) sleep, genotypic and sex differences were detected. In particular, the BACHD males spent less time in NREM sleep and exhibited a more fragmented sleep than the other groups. Finally, in response to 6 h of sleep deprivation, both genotypes and sexes displayed the predicted homeostatic responses to sleep loss. These findings suggest that females are relatively protected early in disease progression in this HD model.


Assuntos
Doença de Huntington , Caracteres Sexuais , Adulto Jovem , Feminino , Masculino , Humanos , Animais , Camundongos , Doença de Huntington/genética , Sono , Modelos Animais de Doenças , Camundongos Transgênicos
4.
J Exp Biol ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38873751

RESUMO

The influence of light spectral properties on circadian rhythms is of substantial interest to laboratory-based investigation of the circadian system and to field-based understanding of the effects of artificial light at night. The tradeoffs between intensity and spectrum regarding masking behaviors are largely unknown, even for well-studied organisms. We used a custom LED illumination system to document the response of wild type house mice (Mus musculus) to 1-hr nocturnal exposure of all combinations of four intensity levels (0.01, 0.5, 5, and 50 lx) and three correlated color temperatures (CCT; 1750, 1950, and 3000 K). Higher intensities of light (50 lx) suppressed cage activity substantially, and consistently more for the higher CCT light (91% for 3000 K; 53% for 1750 K). At the lower intensities (0.01 lx), mean activity was increased, with the greatest increases for the lowest CCT (12.3% increase at 1750 K; 3% increase at 3000 K). Multiple linear regression confirmed the influence of both CCT (p<0.001) and intensity (p<0.001) on changes in activity (r2=0.66, F9,171=3.33; p<0.001) with the scaled effect size of intensity 3.6 times greater than CCT. Activity suppression was significantly lower for male than female mice (p<0.0001). Assessment of light-evoked cFos expression in the suprachiasmatic nucleus at 50 lx showed no significant difference between high and low CCT exposure. The significant differences by spectral composition illustrate a need to account for light spectrum in circadian studies of behavior and confirm that spectral controls can mitigate some, but certainly not all, of the effects of light pollution on species in the wild.

5.
Neurobiol Dis ; 176: 105944, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36493974

RESUMO

Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycles, and they may be particularly vulnerable to the impact of circadian disruptors. We have previously shown that a 2-weeks exposure to dim light at night (DLaN) disrupts diurnal rhythms, increases repetitive behaviors and reduces social interactions in contactin-associated protein-like 2 knock out (Cntnap2 KO) mice. The deleterious effects of DLaN may be mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin, which is maximally sensitive to blue light (480 nm). In this study, the usage of a light-emitting diode array enabled us to shift the spectral properties of the DLaN while keeping the intensity of the illumination at 10 lx. First, we confirmed that the short-wavelength enriched lighting produced strong acute suppression of locomotor activity (masking), robust light-induced phase shifts, and cFos expression in the suprachiasmatic nucleus in wild-type (WT) mice, while the long-wavelength enriched lighting evoked much weaker responses. Opn4DTA mice, lacking the melanopsin expressing ipRGCs, were resistant to DLaN effects. Importantly, shifting the DLaN stimulus to longer wavelengths mitigated the negative impact on the activity rhythms and 'autistic' behaviors (i.e. reciprocal social interactions, repetitive grooming) in the Cntnap2 KO as well as in WT mice. The short-, but not the long-wavelength enriched, DLaN triggered cFos expression in in the basolateral amygdala (BLA) as well as in the peri-habenula region raising that possibility that these cell populations may mediate the effects. Broadly, our findings are consistent with the recommendation that spectral properties of light at night should be considered to optimize health in neurotypical as well as vulnerable populations.


Assuntos
Ritmo Circadiano , Células Ganglionares da Retina , Camundongos , Animais , Ritmo Circadiano/fisiologia , Células Ganglionares da Retina/metabolismo , Núcleo Supraquiasmático , Luz , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo
6.
J Clin Psychol ; 78(7): 1516-1539, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35150595

RESUMO

OBJECTIVE: This study examined sleep disorders and sleep medication use rates, nighttime tics, and sleep and chronotype in relation to tic and co-occurring symptoms in adults with persistent tic disorders (PTDs), including Tourette's disorder (TD). METHODS: One hundred twenty-five adult internet survey respondents rated sleep history, sleep, chronotype, tic severity, impairment, attention deficit hyperactivity disorder, obsessive-compulsive symptoms, anxiety, depression, and emotional and behavioral dyscontrol. RESULTS: Bruxism, insomnia, tic-related difficulty falling asleep, and melatonin use were commonly endorsed. Sleep disturbance correlated with impairment, obsessive-compulsive symptoms, and emotional and behavioral dyscontrol. Eveningness correlated with vocal and total tic severity only in TD. Controlling for age and sex, age, impairment, and obsessive-compulsive symptoms predicted sleep disturbance, and age and tic severity predicted chronotype. CONCLUSIONS: Impairment and obsessive-compulsive symptoms play a role in sleep disturbance in adults with PTDs, and may be intervention targets. Eveningness relates to tic severity, which may suggest the utility of interventions to advance chronotype.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Obsessivo-Compulsivo , Transtornos de Tique , Tiques , Síndrome de Tourette , Adulto , Humanos , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/epidemiologia , Sono , Transtornos de Tique/diagnóstico , Transtornos de Tique/epidemiologia
7.
J Mol Cell Cardiol ; 150: 12-22, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33011158

RESUMO

Salt sensitivity of blood pressure (SSBP) is a trait carrying strong prognostic implications for various cardiovascular diseases. To test the hypothesis that excessive maternal salt intake causes SSBP in offspring through a mechanism dependent upon arginine-vasopressin (AVP), we performed a series of experiments using offspring of the rat dams salt-loaded during pregnancy and lactation with 1.5% saline drink ("experimental offspring") and those with normal perinatal salt exposure ("control offspring"). Salt challenge, given at 7-8 weeks of age with either 2% saline drink (3 days) or 8% NaCl-containing chow (4 weeks), had little or no effect on systolic blood pressure (SBP) in female offspring, whereas the salt challenge significantly raised SBP in male offspring, with the magnitude of increase being greater in experimental, than control, rats. Furthermore, the salt challenge not only raised plasma AVP level more and caused greater depressor responses to V1a and V2 AVP receptor antagonists to occur in experimental, than control, males, but it also made GABA excitatory in a significant proportion of magnocellular AVP neurons of experimental males by depolarizing GABA equilibrium potential. The effect of the maternal salt loading on the salt challenge-elicited SBP response in male offspring was precluded by maternal conivaptan treatment (non-selective AVP receptor antagonist) during the salt-loading period, whereas it was mimicked by neonatal AVP treatment. These results suggest that the excessive maternal salt intake brings about SSBP in male offspring, both the programming and the expression of which depend on increased AVP secretion that may partly result from excitatory GABAergic action.


Assuntos
Pressão Sanguínea , Efeitos Tardios da Exposição Pré-Natal/patologia , Cloreto de Sódio na Dieta/efeitos adversos , Vasopressinas/metabolismo , Animais , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Feminino , Lactação/efeitos dos fármacos , Masculino , Neurônios/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/líquido cefalorraquidiano , Ratos Sprague-Dawley , Receptores de GABA/metabolismo , Sódio/sangue , Sódio/líquido cefalorraquidiano , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/patologia , Sístole/efeitos dos fármacos , Vasopressinas/sangue , Ácido gama-Aminobutírico/metabolismo
8.
Neurobiol Dis ; 145: 105064, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32889171

RESUMO

Nighttime light pollution is linked to metabolic and cognitive dysfunction. Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycle, and may be particularly vulnerable to the impact of circadian disruptors. In this study, we examined the impact of exposure to dim light at night (DLaN, 5 lx) in a model of ASD: the contactin associated protein-like 2 knock out (Cntnap2 KO) mice. DLaN was sufficient to disrupt locomotor activity rhythms, exacerbate the excessive grooming and diminish the social preference in Cntnap2 mutant mice. On a molecular level, DLaN altered the phase and amplitude of PER2:LUC rhythms in a tissue-specific manner in vitro. Daily treatment with melatonin reduced the excessive grooming of the mutant mice to wild-type levels and improved activity rhythms. Our findings suggest that common circadian disruptors such as light at night should be considered in the management of ASD.


Assuntos
Transtorno do Espectro Autista , Depressores do Sistema Nervoso Central/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Iluminação/efeitos adversos , Melatonina/farmacologia , Animais , Transtorno do Espectro Autista/genética , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética
9.
Kidney Int ; 97(4): 728-740, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31948598

RESUMO

Chronic Kidney Disease (CKD) is increasing in incidence and has become a worldwide health problem. Sleep disorders are prevalent in patients with CKD raising the possibility that these patients have a disorganized circadian timing system. Here, we examined the effect of adenine-induced tubulointerstitial nephropathy on the circadian system in mice. Compared to controls, adenine-treated mice showed serum biochemistry evidence of CKD as well as increased kidney expression of inflammation and fibrosis markers. Mice with CKD exhibited fragmented sleep behavior and locomotor activity, with lower degrees of cage activity compared to mice without CKD. On a molecular level, mice with CKD exhibited low amplitude rhythms in their central circadian clock as measured by bioluminescence in slices of the suprachiasmatic nucleus of PERIOD 2::LUCIFERASE mice. Whole animal imaging indicated that adenine treated mice also exhibited dampened oscillations in intact kidney, liver, and submandibular gland. Consistently, dampened circadian oscillations were observed in several circadian clock genes and clock-controlled genes in the kidney of the mice with CKD. Finally, mice with a genetically disrupted circadian clock (Clock mutants) were treated with adenine and compared to wild type control mice. The treatment evoked worse kidney damage as indicated by higher deposition of gelatinases (matrix metalloproteinase-2 and 9) and adenine metabolites in the kidney. Adenine also caused non-dipping hypertension and lower heart rate. Thus, our data indicate that central and peripheral circadian clocks are disrupted in the adenine-treated mice, and suggest that the disruption of the circadian clock accelerates CKD progression.


Assuntos
Relógios Circadianos , Adenina/toxicidade , Animais , Ritmo Circadiano , Humanos , Metaloproteinase 2 da Matriz , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Supraquiasmático
10.
Neurochem Res ; 45(3): 591-605, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30906970

RESUMO

Oligodendrocytes (OL) are the only myelinating cells of the central nervous system thus interferences, either environmental or genetic, with their maturation or function have devastating consequences. Albeit so far neglected, one of the less appreciated, nevertheless possible, regulators of OL maturation and function is the circadian cycle. Yet, disruptions in these rhythms are unfortunately becoming a common "disorder" in the today's world. The temporal patterning of behaviour and physiology is controlled by a circadian timing system based in the anterior hypothalamus. At the molecular level, circadian rhythms are generated by a transcriptional/translational feedback system that regulates transcription and has a major impact on cellular function(s). Fundamental cellular properties/functions in most cell types vary with the daily circadian cycle: OL are unlikely an exception! To be clear, the presence of circadian oscillators or the cell-specific function(s) of the circadian clock in OL has yet to be defined. Furthermore, we wish to entertain the idea of links between the "thin" evidence on OL intrinsic circadian rhythms and their interjection(s) at different stages of lineage progression as well as in supporting/regulating OL crucial function: myelination. Individuals with intellectual and developmental syndromes as well as neurodegenerative diseases present with a disrupted sleep/wake cycle; hence, we raise the possibility that these disturbances in timing can contribute to the loss of white matter observed in these disorders. Preclinical and clinical work in this area is needed for a better understanding of how circadian rhythms influence OL maturation and function(s), to aid the development of new therapeutic strategies and standards of care for these patients.


Assuntos
Ritmo Circadiano , Oligodendroglia/metabolismo , Sono/fisiologia , Animais , Humanos
11.
J Neurosci Res ; 97(12): 1606-1623, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31359503

RESUMO

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock-in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature (CBT), reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, CBT, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD.


Assuntos
Ritmo Circadiano/fisiologia , Proteína Huntingtina/fisiologia , Doença de Huntington/fisiopatologia , Doença de Huntington/psicologia , Locomoção/fisiologia , Animais , Ritmo Circadiano/genética , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Proteína Huntingtina/genética , Doença de Huntington/genética , Locomoção/genética , Masculino , Camundongos Transgênicos , Atividade Motora/genética , Atividade Motora/fisiologia , Neurônios/fisiologia , Sono/genética , Sono/fisiologia , Núcleo Supraquiasmático/fisiologia
12.
Cephalalgia ; 39(14): 1855-1866, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31142137

RESUMO

OBJECTIVE: To review and discuss the putative role of light, sleep, and the biological clock in cluster headache. DISCUSSION: Cluster headache attacks are believed to be modulated in the hypothalamus; moreover, the severe pain and typical autonomic cranial features associated with cluster headache are caused by abnormal activity of the trigeminal-autonomic reflex. The temporal pattern of cluster headache attacks suggests involvement of the biological clock, and the seasonal pattern is influenced by the number of daylight hours. Although sleep is often reported as a trigger for cluster headache attacks, to date no clear correlation has been established between these attacks and sleep stage. CONCLUSIONS: We hypothesize that light, sleep, and the biological clock can change the brain's state, thereby lowering the threshold for activating the trigeminal-autonomic reflex, resulting in a cluster headache attack. Understanding the mechanisms that contribute to the daily and seasonal fluctuations in cluster headache attacks may provide new therapeutic targets.


Assuntos
Relógios Biológicos/fisiologia , Ritmo Circadiano/fisiologia , Cefaleia Histamínica/diagnóstico , Cefaleia Histamínica/fisiopatologia , Humanos
13.
Yale J Biol Med ; 92(2): 291-303, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249490

RESUMO

Huntington's disease (HD) patients suffer from a progressive neurodegenerative disorder that inflicts both motor and non-motor symptoms. HD is caused by a CAG repeat expansion within the first exon of the huntingtin (HTT) gene that produces a polyglutamine repeat that leads to protein misfolding, soluble aggregates, and inclusion bodies detected throughout the body. Both clinical and preclinical research indicate that cardiovascular dysfunction should be considered a core symptom in at least a subset of HD patients. There is strong evidence for dysautonomia (dysfunctional autonomic nervous system, ANS) in HD patients that can be detected early in the disease progression. The temporal patterning of ANS function is controlled by the circadian timing system based in the anterior hypothalamus. Patients with neurodegenerative diseases including HD exhibit disrupted sleep/wake cycle and, in preclinical models, there is compelling evidence that the circadian timing system is compromised early in the disease process. Here we review data from preclinical models of HD that explore the intersection between disruption of circadian rhythms and dysautonomia. This work will lead to new therapeutic strategies and standards of care for HD and other neurodegenerative diseases.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Doença de Huntington/fisiopatologia , Disautonomias Primárias/fisiopatologia , Animais , Humanos , Hipotálamo Anterior/fisiopatologia , Modelos Biológicos , Doenças Neurodegenerativas/fisiopatologia , Fatores de Tempo
14.
J Neurosci Res ; 96(12): 1862-1875, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30168855

RESUMO

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, are not well established. The BACHD mouse model of HD exhibits disrupted behavioral and physiological rhythms, including decreased electrical activity in the central circadian clock (suprachiasmatic nucleus, SCN). In this study, electrophysiological techniques were used to explore the ionic underpinning of the reduced spontaneous neural activity in male mice. We found that SCN neural activity rhythms were lost early in the disease progression and was accompanied by loss of the normal daily variation in resting membrane potential in the mutant SCN neurons. The low neural activity could be transiently reversed by direct current injection or application of exogenous N-methyl-d-aspartate (NMDA) thus demonstrating that the neurons have the capacity to discharge at WT levels. Exploring the potassium currents known to regulate the electrical activity of SCN neurons, our most striking finding was that these cells in the mutants exhibited an enhancement in the large-conductance calcium activated K+ (BK) currents. The expression of the pore forming subunit (Kcnma1) of the BK channel was higher in the mutant SCN. We found a similar decrease in daytime electrical activity and enhancement in the magnitude of the BK currents early in disease in another HD mouse model (Q175). These findings suggest that SCN neurons of both HD models exhibit early pathophysiology and that dysregulation of BK current may be responsible.


Assuntos
Relógios Circadianos/fisiologia , Doença de Huntington/fisiopatologia , Núcleo Supraquiasmático/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Modelos Animais de Doenças , Antagonistas de Receptores de GABA-A/farmacologia , Doença de Huntington/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/fisiologia , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Piridazinas/farmacologia
15.
Am J Physiol Endocrinol Metab ; 313(2): E213-E221, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28465284

RESUMO

Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1) behavioral circadian rhythms, 2) photic entrainment of circadian activity, 3) SCN and peripheral tissue molecular clock function, and 4) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM.


Assuntos
Comportamento Animal/fisiologia , Ritmo Circadiano/genética , Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Luz , Masculino , Proteínas Circadianas Period/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/patologia
16.
Nat Rev Neurosci ; 12(10): 553-69, 2011 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-21886186

RESUMO

Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. A hallmark feature of SCN neuronal populations is that they are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Sets of currents are responsible for this daily rhythm, with the strongest evidence for persistent Na(+) currents, L-type Ca(2+) currents, hyperpolarization-activated currents (I(H)), large-conductance Ca(2+) activated K(+) (BK) currents and fast delayed rectifier (FDR) K(+) currents. These rhythms in electrical activity are crucial for the function of the circadian timing system, including the expression of clock genes, and decline with ageing and disease. This article reviews our current understanding of the ionic and molecular mechanisms that drive the rhythmic firing patterns in the SCN.


Assuntos
Relógios Biológicos/fisiologia , Ritmo Circadiano/fisiologia , Neurônios/fisiologia , Núcleo Supraquiasmático/fisiologia , Potenciais de Ação/fisiologia , Animais , Humanos , Potenciais da Membrana/fisiologia
17.
Neurobiol Dis ; 77: 155-64, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25779967

RESUMO

Disturbances in the sleep/wake cycle are prevalent in patients with Rett syndrome (RTT). We sought to determine whether the circadian system is disrupted in a RTT model, Mecp2(-/y) mice. We found that MeCP2 mutants showed decreased strength and precision of daily rhythms of activity coupled with extremely fragmented sleep. The central circadian clock (suprachiasmatic nucleus) exhibited significant reduction in the number of neurons expressing vasoactive intestinal peptide (VIP) as well as compromised spontaneous neural activity. The molecular clockwork was disrupted both centrally in the SCN and in peripheral organs, indicating a general disorganization of the circadian system. Disruption of the molecular clockwork was observed in fibroblasts of RTT patients. Finally, MeCP2 mutant mice were vulnerable to circadian disruption as chronic jet lag accelerated mortality. Our finds suggest an integral role of MeCP2 in the circadian timing system and provides a possible mechanistic explanation for the sleep/wake distrubances observed in RTT patients. The work raises the possibility that RTT patients may benefit from a temporally structured environment.


Assuntos
Transtornos Cronobiológicos/etiologia , Modelos Animais de Doenças , Síndrome de Rett/complicações , Potenciais de Ação/genética , Animais , Células Cultivadas , Transtornos Cronobiológicos/genética , Embrião de Mamíferos , Regulação da Expressão Gênica/genética , Técnicas In Vitro , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Mutação/genética , Técnicas de Patch-Clamp , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Síndrome de Rett/genética , Transtornos do Sono-Vigília/etiologia
18.
Eur J Neurosci ; 42(2): 1839-48, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25885685

RESUMO

The neuropeptide vasoactive intestinal peptide (VIP) is expressed at high levels in a subset of neurons in the ventral region of the suprachiasmatic nucleus (SCN). While VIP is known to be important for the synchronization of the SCN network, the role of VIP in photic regulation of the circadian system has received less attention. In the present study, we found that the light-evoked increase in electrical activity in vivo was unaltered by the loss of VIP. In the absence of VIP, the ventral SCN still exhibited N-methyl-d-aspartate-evoked responses in a brain slice preparation, although the absolute levels of neural activity before and after treatment were significantly reduced. Next, we used calcium imaging techniques to determine if the loss of VIP altered the calcium influx due to retinohypothalamic tract stimulation. The magnitude of the evoked calcium influx was not reduced in the ventral SCN, but did decline in the dorsal SCN regions. We examined the time course of the photic induction of Period1 in the SCN using in situ hybridization in VIP-mutant mice. We found that the initial induction of Period1 was not reduced by the loss of this signaling peptide. However, the sustained increase in Period1 expression (after 30 min) was significantly reduced. Similar results were found by measuring the light induction of cFOS in the SCN. These findings suggest that VIP is critical for longer-term changes within the SCN circuit, but does not play a role in the acute light response.


Assuntos
Regulação da Expressão Gênica/genética , Luz , Neurônios/fisiologia , Núcleo Supraquiasmático/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Escuridão , Agonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , N-Metilaspartato/farmacologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Proteínas Oncogênicas v-fos/metabolismo , Técnicas de Patch-Clamp , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/genética
19.
Eur J Neurosci ; 42(7): 2467-77, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26215659

RESUMO

Histamine, a neurotransmitter/neuromodulator implicated in the control of arousal state, exerts a potent phase-shifting effect on the circadian clock in the rodent suprachiasmatic nucleus (SCN). In this study, the mechanisms by which histamine resets the circadian clock in the mouse SCN were investigated. As a first step, Ca(2+) -imaging techniques were used to demonstrate that histamine increases intracellular Ca(2+) concentration ([Ca(2+) ]i ) in acutely dissociated SCN neurons and that this increase is blocked by the H1 histamine receptor (H1R) antagonist pyrilamine, the removal of extracellular Ca(2+) and the L-type Ca(2+) channel blocker nimodipine. The histamine-induced Ca(2+) transient is reduced, but not blocked, by application of the ryanodine receptor (RyR) blocker dantrolene. Immunohistochemical techniques indicated that CaV 1.3 L-type Ca(2+) channels are expressed mainly in the somata of SCN cells along with the H1R, whereas CaV 1.2 channels are located primarily in the processes. Finally, extracellular single-unit recordings demonstrated that the histamine-elicited phase delay of the circadian neural activity rhythm recorded from SCN slices is blocked by pyrilamine, nimodipine and the knockout of CaV 1.3 channel. Again, application of dantrolene reduced but did not block the histamine-induced phase delays. Collectively, these results indicate that, to reset the circadian clock, histamine increases [Ca(2+) ]i in SCN neurons by activating CaV 1.3 channels through H1R, and secondarily by causing Ca(2+) -induced Ca(2+) release from RyR-mediated internal stores.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Relógios Circadianos/fisiologia , Histamina/fisiologia , Receptores Histamínicos H1/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Núcleo Supraquiasmático/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Dantroleno/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nimodipina/farmacologia , Pirilamina/farmacologia , Transdução de Sinais
20.
Horm Behav ; 75: 55-63, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26226656

RESUMO

We measured diurnal rhythms of food intake, as well as body weight and composition, while varying three major classes of sex-biasing factors: activational and organizational effects of gonadal hormones, and sex chromosome complement (SCC). Four Core Genotypes (FCG) mice, comprising XX and XY gonadal males and XX and XY gonadal females, were either gonad-intact or gonadectomized (GDX) as adults (2.5months); food intake was measured second-by-second for 7days starting 5weeks later, and body weight and composition were measured for 22weeks thereafter. Gonadal males weighed more than females. GDX increased body weight/fat of gonadal females, but increased body fat and reduced body weight of males. After GDX, XX mice had greater body weight and more fat than XY mice. In gonad-intact mice, males had greater total food intake and more meals than females during the dark phase, but females had more food intake and meals and larger meals than males during the light phase. GDX reduced overall food intake irrespective of gonad type or SCC, and eliminated differences in feeding between groups with different gonads. Diurnal phase of feeding was influenced by all three sex-biasing variables. Gonad-intact females had earlier onset and acrophase (peak) of feeding relative to males. GDX caused a phase-advance of feeding, especially in XX mice, leading to an earlier onset of feeding in GDX XX vs. XY mice, but earlier acrophase in GDX males relative to females. Gonadal hormones and SCC interact in the control of diurnal rhythms of food intake.


Assuntos
Ritmo Circadiano , Ingestão de Alimentos/fisiologia , Hormônios Gonadais/sangue , Caracteres Sexuais , Cromossomos Sexuais/fisiologia , Animais , Composição Corporal/fisiologia , Peso Corporal , Ritmo Circadiano/genética , Ingestão de Alimentos/genética , Feminino , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores Sexuais
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