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1.
Proc Natl Acad Sci U S A ; 120(19): e2220911120, 2023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-37126681

RESUMEN

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.


Asunto(s)
Cataplejía , Narcolepsia , Neuropéptidos , Ratones , Animales , Orexinas/metabolismo , Cataplejía/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neuropéptidos/metabolismo , Narcolepsia/genética , Hipotálamo/metabolismo , Epigénesis Genética , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo
2.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33737391

RESUMEN

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.


Asunto(s)
Citocinas/genética , Susceptibilidad a Enfermedades , Variación Genética , Síndrome de Kleine-Levin/complicaciones , Síndrome de Kleine-Levin/genética , Complicaciones del Trabajo de Parto/epidemiología , Complicaciones del Trabajo de Parto/etiología , Trastorno Bipolar/etiología , Trastornos de Somnolencia Excesiva/etiología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Síndrome de Kleine-Levin/epidemiología , Masculino , Oportunidad Relativa , Polimorfismo Genético , Embarazo , Medición de Riesgo , Factores de Riesgo
3.
J Hum Genet ; 67(6): 377-380, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35034961

RESUMEN

Excessive daytime sleepiness is characterized by a persistent feeling of having trouble staying awake, typically with inappropriate sleep episodes. Orexin (hypocretin) is a neuropeptide that regulates sleep-wake cycles and rapid eye movement sleep. Several large-scale genome-wide association studies (GWASs) in European populations have found genetic variants in orexin receptor-1 (OX1R) and -2 (OX2R) that are associated with sleep traits including daytime sleepiness. To identify genetic variants associated with daytime sleepiness, we performed an association study of genetic variants in prepro-orexin, OX1R, and OX2R in 14,329 Japanese individuals from the Tohoku Medical Megabank Project cohort. A genetic variant in OX2R was significantly associated with self-reported daytime sleepiness after Bonferroni correction (rs188018846: P = 8.4E-05). In addition, a missense variant in OX2R identified by the European GWASs showed a nominally significant association with daytime sleepiness in a Japanese population (p.Ile308Val, rs2653349: P = 0.044). Multiple genetic variants in OX2R can affect daytime sleepiness in general populations.


Asunto(s)
Trastornos de Somnolencia Excesiva , Estudio de Asociación del Genoma Completo , Receptores de Orexina/metabolismo , Trastornos de Somnolencia Excesiva/epidemiología , Trastornos de Somnolencia Excesiva/genética , Humanos , Japón/epidemiología , Receptores de Orexina/genética , Orexinas/genética , Autoinforme
4.
J Hum Genet ; 64(12): 1219-1225, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31527662

RESUMEN

Delayed sleep-wake phase disorder (DSWPD) is a subtype of circadian rhythm sleep-wake disorders, and is characterized by an inability to fall asleep until late at night and wake up at a socially acceptable time in the morning. The study aim was to identify low-frequency nonsense and missense variants that are associated with DSWPD. Candidate variants in circadian rhythm-related genes were extracted by integration of genetic variation databases and in silico assessment. We narrowed down the candidates to six variants. To examine whether the six variants are associated with DSWPD, we performed an association study in 236 Japanese patients with DSWPD and 1436 controls. A low-frequency missense variant (p.Val1205Met) in PER2 showed a significant association with DSWPD (2.5% in cases and 1.1% in controls, P = 0.026, odds ratio (OR) = 2.32). The variant was also associated with idiopathic hypersomnia known to have a tendency toward phase delay (P = 0.038, OR = 2.07). PER2 forms a heterodimer with CRY, and the heterodimer plays an important role in the regulation of circadian rhythms. Val1205 is located in the CRY-binding domain of PER2 and was hypothesized to interact with CRY. The p.Val1205Met substitution could be a potential genetic marker for DSWPD.


Asunto(s)
Pueblo Asiatico/genética , Variación Genética/genética , Mutación Missense/genética , Proteínas Circadianas Period/genética , Trastornos del Sueño del Ritmo Circadiano/genética , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes/genética , Humanos
5.
Hum Mol Genet ; 24(3): 891-8, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25256355

RESUMEN

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.


Asunto(s)
Pueblo Asiatico/genética , Genes MHC Clase II , Cadenas beta de HLA-DP/genética , Cadenas beta de HLA-DQ/genética , Narcolepsia/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Japón
6.
Biochem Biophys Res Commun ; 469(3): 587-92, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26687948

RESUMEN

Cellular disease models are useful tools for Alzheimer's disease (AD) research. Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are promising materials for creating cellular models of such diseases. In the present study, we established cellular models of AD in hESCs that overexpressed the mutant Presenilin 1 (PS1) gene with the use of a site-specific gene integration system. The overexpression of PS1 did not affect the undifferentiated status or the neural differentiation ability of the hESCs. We found increases in the ratios of amyloid-ß 42 (Aß42)/Aß40 and Aß43/Aß40. Furthermore, synaptic dysfunction was observed in a cellular model of AD that overexpressed mutant PS1. These results suggest that the AD phenotypes, in particular, the electrophysiological abnormality of the synapses in our AD models might be useful for AD research and drug discovery.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Células Madre Embrionarias Humanas/metabolismo , Neuronas/metabolismo , Neuronas/patología , Presenilina-1/metabolismo , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Células Madre Embrionarias Humanas/patología , Humanos , Mutación , Presenilina-1/genética , Regulación hacia Arriba
7.
J Hum Genet ; 61(10): 873-878, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27305985

RESUMEN

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*06:02=2.30 × 10-48, Pwhole genome without HLA-DQB1*06:02=6.73 × 10-2) including HLA-DQB1*06:02 effects and 1.3% (Pwhole genome without HLA-DQB1*06:02=2.43 × 10-2) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*06:02=9.74 × 10-2). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, PHLA-DQB1*06:02=7.02 × 10-14, Pwhole genome without HLA-DQB1*06:02=1.34 × 10-1, EHS without HLA-DQB1*06:02: 0.4%, Pwhole genome without HLA-DQB1*06:02=3.06 × 10-1). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.


Asunto(s)
Trastornos de Somnolencia Excesiva/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Narcolepsia/genética , Alelos , Hibridación Genómica Comparativa , Trastornos de Somnolencia Excesiva/diagnóstico , Genotipo , Cadenas beta de HLA-DQ/genética , Humanos , Narcolepsia/diagnóstico , Fenotipo , Polimorfismo de Nucleótido Simple , Riesgo
9.
Brain Behav Immun ; 49: 148-55, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25986216

RESUMEN

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.


Asunto(s)
Narcolepsia/genética , Polimorfismo de Nucleótido Simple , Receptores CCR1/genética , Receptores CCR3/genética , Pueblo Asiatico , Estudio de Asociación del Genoma Completo , Humanos , Japón
10.
J Hum Genet ; 59(5): 235-40, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24694762

RESUMEN

In humans, narcolepsy with cataplexy (narcolepsy) is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Narcolepsy is caused by a reduction in the number of neurons that produce hypocretin (orexin) neuropeptide. Both genetic and environmental factors contribute to the development of narcolepsy.Rare and large copy number variations (CNVs) reportedly play a role in the etiology of a number of neuropsychiatric disorders. Narcolepsy is considered a neurological disorder; therefore, we sought to investigate any possible association between rare and large CNVs and human narcolepsy. We used DNA microarray data and a CNV detection software application, PennCNV-Affy, to detect CNVs in 426 Japanese narcoleptic patients and 562 healthy individuals. Overall, we found a significant enrichment of rare and large CNVs (frequency ≤1%, size ≥100 kb) in the patients (case-control ratio of CNV count=1.54, P=5.00 × 10(-4)). Next, we extended a region-based association analysis by including CNVs with its size ≥30 kb. Rare and large CNVs in PARK2 region showed a significant association with narcolepsy. Four patients were assessed to carry duplications of the gene region, whereas no controls carried the duplication, which was further confirmed by quantitative PCR assay. This duplication was also found in 2 essential hypersomnia (EHS) patients out of 171 patients. Furthermore, a pathway analysis revealed enrichments of gene disruptions by rare and large CNVs in immune response, acetyltransferase activity, cell cycle regulation and regulation of cell development. This study constitutes the first report on the risk association between multiple rare and large CNVs and the pathogenesis of narcolepsy. In the future, replication studies are needed to confirm the associations.


Asunto(s)
Pueblo Asiatico/genética , Variaciones en el Número de Copia de ADN , Estudio de Asociación del Genoma Completo , Narcolepsia/genética , Estudios de Casos y Controles , Redes Reguladoras de Genes , Humanos , Japón , Narcolepsia/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Transducción de Señal , Ubiquitina-Proteína Ligasas/genética
11.
Intern Med ; 63(5): 733-737, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-37468246

RESUMEN

An 81-year-old man experienced acute progression of weakness in the extremities accompanied by a fever, tenderness, and swelling in distal parts of the extremities. He had flaccid tetraparesis with fasciculations and general hyporeflexia. Nerve conduction studies indicated demyelinating sensorimotor neuropathy. A cerebrospinal fluid examination revealed elevated proteins without pleocytosis. Immunological treatments were effective, but his symptoms exhibited repeated relapse and remission phases. He was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with an acute onset. The highlight of this case is pain with inflammatory reaction recognized as red flags of CIDP, with the clinical course and electrophysiological findings compatible with CIDP.


Asunto(s)
Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Polirradiculoneuropatía , Masculino , Humanos , Anciano de 80 o más Años , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/complicaciones , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Enfermedad Crónica , Edema/complicaciones , Extremidades , Dolor/complicaciones , Polirradiculoneuropatía/complicaciones , Polirradiculoneuropatía/terapia
12.
Sci Rep ; 14(1): 10422, 2024 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-38710727

RESUMEN

Anticipating positive outcomes is a core cognitive function in the process of reward prediction. However, no neurophysiological method objectively assesses reward prediction in basic medical research. In the present study, we established a physiological paradigm using cortical direct current (DC) potential responses in rats to assess reward prediction. This paradigm consisted of five daily 1-h sessions with two tones, wherein the rewarded tone was followed by electrical stimulation of the medial forebrain bundle (MFB) scheduled at 1000 ms later, whereas the unrewarded tone was not. On day 1, both tones induced a negative DC shift immediately after auditory responses, persisting up to MFB stimulation. This negative shift progressively increased and peaked on day 4. Starting from day 3, the negative shift from 600 to 1000 ms was significantly larger following the rewarded tone than that following the unrewarded tone. This negative DC shift was particularly prominent in the frontal cortex, suggesting its crucial role in discriminative reward prediction. During the extinction sessions, the shift diminished significantly on extinction day 1. These findings suggest that cortical DC potential is related to reward prediction and could be a valuable tool for evaluating animal models of depression, providing a testing system for anhedonia.


Asunto(s)
Extinción Psicológica , Recompensa , Animales , Ratas , Masculino , Extinción Psicológica/fisiología , Estimulación Eléctrica , Estimulación Acústica , Haz Prosencefálico Medial/fisiología , Ratas Sprague-Dawley
13.
J Cereb Blood Flow Metab ; 44(9): 1591-1607, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38477254

RESUMEN

Neurovascular coupling (NVC) is the functional hyperemia of the brain responding to local neuronal activity. It is mediated by astrocytes and affected by subcortical ascending pathways in the cortex that convey information, such as sensory stimuli and the animal condition. Here, we investigate the influence of the raphe serotonergic system, a subcortical ascending arousal system in animals, on the modulation of cortical NVC and cerebral blood flow (CBF). Raphe serotonergic neurons were optogenically activated for 30 s, which immediately awakened the mice from non-rapid eye movement sleep. This caused a biphasic cortical hemodynamic change: a transient increase for a few seconds immediately after photostimulation onset, followed by a large progressive decrease during the stimulation period. Serotonergic neuron activation increased intracellular Ca2+ levels in cortical pyramidal neurons and astrocytes, demonstrating its effect on the NVC components. Pharmacological inhibition of cortical neuronal firing activity and astrocyte metabolic activity had small hypovolemic effects on serotonin-induced biphasic CBF changes, while blocking 5-HT1B receptors expressed primarily in cerebral vasculature attenuated the decreasing CBF phase. This suggests that serotonergic neuron activation leading to animal awakening could allow the NVC to exert a hyperemic function during a biphasic CBF response, with a predominant decrease in the cortex.


Asunto(s)
Astrocitos , Circulación Cerebrovascular , Hemodinámica , Acoplamiento Neurovascular , Neuronas Serotoninérgicas , Serotonina , Vigilia , Animales , Acoplamiento Neurovascular/fisiología , Ratones , Circulación Cerebrovascular/fisiología , Serotonina/metabolismo , Hemodinámica/fisiología , Vigilia/fisiología , Masculino , Neuronas Serotoninérgicas/fisiología , Neuronas Serotoninérgicas/metabolismo , Astrocitos/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/fisiología , Sueño/fisiología , Núcleos del Rafe/metabolismo , Núcleos del Rafe/fisiología , Ratones Endogámicos C57BL
14.
Sci Adv ; 10(4): eadj5279, 2024 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-38266094

RESUMEN

In neurological and neuropsychiatric diseases, different brain regions are affected, and differences in gene expression patterns could potentially explain this mechanism. However, limited studies have precisely explored gene expression in different regions of the human brain. In this study, we performed long-read RNA sequencing on three different brain regions of the same individuals: the cerebellum, hypothalamus, and temporal cortex. Despite stringent filtering criteria excluding isoforms predicted to be artifacts, over half of the isoforms expressed in multiple samples across multiple regions were found to be unregistered in the GENCODE reference. We then especially focused on genes with different major isoforms in each brain region, even with similar overall expression levels, and identified that many of such genes including GAS7 might have distinct roles in dendritic spine and neuronal formation in each region. We also found that DNA methylation might, in part, drive different isoform expressions in different regions. These findings highlight the significance of analyzing isoforms expressed in disease-relevant sites.


Asunto(s)
Encéfalo , Transcriptoma , Humanos , Cerebelo , Análisis de Secuencia de ARN , Isoformas de Proteínas/genética
15.
J Autoimmun ; 45: 24-30, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23834844

RESUMEN

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy (a sudden weakening of posture muscle tone usually triggered by emotion) caused by the loss of orexin neurons in the hypothalamus. Autoimmune mechanisms are implicated in narcolepsy by increased frequency of specific HLA alleles and the presence of specific autoantibody (anti-Tribbles homolog 2 (TRIB2) antibodies) in the sera of patients with narcolepsy. Presently, we passively transferred narcolepsy to naïve mice by injecting intra-cerebra-ventricularly (ICV) pooled IgG positive for anti-TRIB2 antibodies. Narcolepsy-IgG-injected mice had a loss of the NeuN (neuronal marker), synaptophysin (synaptic marker) and orexin-positive neurons in the lateral hypothalamus area in narcolepsy compared to control-IgG-injected mice and these changes were associated with narcolepsy-like immobility attacks at four weeks post injection and with hyperactivity and long term memory deficits in the staircase and novel object recognition tests. Similar behavioral and cognitive deficits are observed in narcoleptic patients. This is the first report of passive transfer of experimental narcolepsy to naïve mice induced by autoantibodies and supports the autoimmune pathogenesis in narcolepsy.


Asunto(s)
Cataplejía/inmunología , Hipotálamo/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Narcolepsia/inmunología , Neuronas/metabolismo , Neuropéptidos/metabolismo , Animales , Autoanticuerpos/administración & dosificación , Autoanticuerpos/sangre , Autoantígenos/inmunología , Proteínas Quinasas Dependientes de Calcio-Calmodulina , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunización Pasiva , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/sangre , Péptidos y Proteínas de Señalización Intracelular/inmunología , Ratones , Ratones Endogámicos C3H , Neuronas/efectos de los fármacos , Neuronas/patología , Orexinas , Patrones de Reconocimiento Fisiológico
16.
Neurosci Res ; 191: 48-56, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36549387

RESUMEN

The ventrolateral striatum (VLS), a subregion of the ventral striatum (VS), possesses distinct neuronal Ca2+ activities and functions in reward-oriented behavior, compared with the ventromedial striatum (VMS) based on the anatomical feature. We hypothesized that the VLS exhibits unique neuronal activity and function in nociceptive processing, a part of aversive processing. Using fiber photometry to monitor the neuronal Ca2+ activities, we demonstrated that acute noxious mechanical stimuli like tail-pinch increased the Ca2+ activity of dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) in the VLS in correlation with the stimulus intensities in mice, whereas mechanical stimuli increased the VMS D2-MSN activity independent of the stimulus intensities. Likewise, thermal stimuli decreased the VLS and VMS D2-MSN Ca2+ activities during nociceptive behaviors in the hot plate test. Furthermore, the VLS D2-MSNs increased their Ca2+ activity accompanied by formalin-induced nociceptive behaviors in mice, whereas the VMS D2-MSNs decreased it. The optogenetic inhibition of VLS D2-MSN activity increased the formalin-induced pain-related behavior in mice, thus suggesting the inhibitory effect of VLS D2-MSN activity on chemical nociceptive behavior, in contrast to previous reports that the VMS D2-MSNs could not involve the behavior. Therefore, the VLS D2-MSNs exhibited region-specific roles in nociception.


Asunto(s)
Nocicepción , Estriado Ventral , Ratones , Animales , Neuronas Espinosas Medianas , Receptores de Dopamina D2/metabolismo , Cuerpo Estriado/metabolismo , Neuronas/fisiología , Receptores de Dopamina D1/metabolismo , Ratones Transgénicos , Ratones Endogámicos C57BL
17.
Clin Neurophysiol ; 155: 99-106, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37596134

RESUMEN

OBJECTIVE: To elucidate long-term potentiation (LTP)-like effects on the primary motor cortical (M1) in progressive supranuclear palsy (PSP) and its relationships with clinical features. METHODS: Participants were 18 probable/possible PSP Richardson syndrome (PSP-RS) patients and 17 healthy controls (HC). We used quadripulse stimulation (QPS) over the M1 with an interstimulus interval of 5 ms (QPS-5) to induce LTP-like effect and analyzed the correlations between the degree of LTP-like effect and clinical features. We also evaluated cortical excitability using short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF) in 15 PSP patients and 17 HC. RESULTS: LTP-like effect after QPS in PSP was smaller than HC and negatively correlated with Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score, especially bradykinesia, but not with either age or any scores of cognitive functions. The SICI was abnormally reduced in PSP, but neither ICF nor SICF differed from those of normal subjects. None of these cortical excitability parameters correlated with any clinical features. CONCLUSIONS: LTP induction was impaired in PSP. The degree of LTP could reflect the severity of bradykinesia. The bradykinesia may partly relate with the motor cortical dysfunction. SIGNIFICANCE: The degree of motor cortical LTP could relate with the severity of motor symptoms in PSP.

18.
Sci Rep ; 13(1): 10464, 2023 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-37380713

RESUMEN

Narcolepsy type 1 (NT1) is caused by a loss of hypothalamic orexin-producing cells, and autoreactive CD4+ and CD8+ T cells have been suggested to play a role in the autoimmune mechanism. Although NT1 showed a strong association with human leukocyte antigen (HLA)-DQB1*06:02, the responsible antigens remain unidentified. We analyzed array-based DNA methylation and gene expression data for the HLA region in CD4+ and CD8+ T cells that were separated from the peripheral blood mononuclear cells of Japanese subjects (NT1, N = 42; control, N = 42). As the large number of SNPs in the HLA region might interfere with the affinity of the array probes, we conducted a comprehensive assessment of the reliability of each probe. The criteria were based on a previous study reporting that the presence of frequent SNPs, especially on the 3' side of the probe, makes the probe unreliable. We confirmed that 90.3% of the probes after general filtering in the HLA region do not include frequent SNPs, and are thus suitable for analysis, particularly in Japanese subjects. We then performed an association analysis, and found that several CpG sites in the HLA class II region of the patients were significantly hypomethylated in CD4+ and CD8+ T cells. This association was not detected when the effect of HLA-DQB1*06:02 was considered, suggesting that the hypomethylation was possibly derived from HLA-DQB1*06:02. Further RNA sequencing revealed reduced expression levels of HLA-DQB1 alleles other than HLA-DQB1*06:02 in the patients with NT1. Our results suggest the involvement of epigenetic and expressional changes in HLA-DQB1 in the pathogenesis of NT1.


Asunto(s)
Linfocitos T CD8-positivos , Narcolepsia , Humanos , Metilación de ADN , Leucocitos Mononucleares , Reproducibilidad de los Resultados , Antígenos de Histocompatibilidad , Antígenos de Histocompatibilidad Clase II , Narcolepsia/genética , Expresión Génica
19.
iScience ; 26(1): 105830, 2023 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-36713262

RESUMEN

The central serotonergic system has multiple roles in animal physiology and behavior, including sleep-wake control. However, its function in controlling brain energy metabolism according to the state of animals remains undetermined. Through in vivo monitoring of energy metabolites and signaling, we demonstrated that optogenetic activation of raphe serotonergic neurons increased cortical neuronal intracellular concentration of ATP, an indispensable cellular energy molecule, which was suppressed by inhibiting neuronal uptake of lactate derived from astrocytes. Raphe serotonergic neuronal activation induced cortical astrocytic Ca2+ and cAMP surges and increased extracellular lactate concentrations, suggesting the facilitation of lactate release from astrocytes. Furthermore, chemogenetic inhibition of raphe serotonergic neurons partly attenuated the increase in cortical neuronal intracellular ATP levels as arousal increased in mice. Serotonergic neuronal activation promoted an increase in cortical neuronal intracellular ATP levels, partly mediated by the facilitation of the astrocyte-neuron lactate shuttle, contributing to state-dependent optimization of neuronal intracellular energy levels.

20.
eNeurologicalSci ; 29: 100422, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36097517

RESUMEN

Background: The relationship between abnormal cortical plasticity and parkinsonian symptoms remains unclear in Parkinson's disease (PD). Objective: We studied the relationship between their symptoms and degree of Long-term potentiation (LTP)-like effects induced by quadripulse magnetic stimulation (QPS) over the primary motor cortex, which has a small inter-individual variability in humans. Methods: Participants were 16 PD patients (drug-naïve or treated with L-DOPA monotherapy) and 13 healthy controls (HC). LTP-like effects by QPS were compared between three conditions (HC、PD with or without L-DOPA). In PD, correlation analyses were performed between clinical scores (MDS-UPDRS, MMSE and MoCA-J) and the degree of LTP-like effects induced by QPS. Results: In PD, QPS-induced LTP-like effect was reduced and restored by L-DOPA. The degree of the LTP was negatively correlated with MDS-UPDRS Part I and III scores, but not with MMSE and MoCA-J. In the sub-scores, upper limb bradykinesia and rigidity showed a negative correlation with the LTP-like effect whereas the tremor had no correlation. Conclusions: Our results suggest that motor cortical plasticity relate with mechanisms underlying bradykinesia and rigidity in the upper limb muscles. LTP induced by QPS may be used as an objective marker of parkinsonian symptoms.

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