RESUMO
Progress in earlier detection and clinical management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available as a result of technical challenges. We developed a transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein-coding genes. RNA-seq of neonatal forebrains demonstrates that TcHSA21rat expresses HSA21 genes and has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a "Down syndrome karyotype" in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, which is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.
Assuntos
Ansiedade/genética , Cromossomos Humanos Par 21 , Síndrome de Down/genética , Efeito Fundador , Hipercinese/genética , Animais , Ansiedade/metabolismo , Ansiedade/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Modelos Animais de Doenças , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Feminino , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hipercinese/metabolismo , Hipercinese/patologia , Cariótipo , Aprendizagem , Masculino , Mutagênese Insercional , Tamanho do Órgão , Postura , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Ratos , Ratos TransgênicosRESUMO
Cocaine blocks dopamine uptake via dopamine transporter (DAT) on plasma membrane of neuron cells and, as a result, produces the high and induces DAT trafficking to plasma membrane which contributes to the drug seeking or craving. In this study, we first examined the dose dependence of cocaine-induced DAT trafficking and hyperactivity in rats, demonstrating that cocaine at an intraperitoneal dose of 10 mg/kg or higher led to redistribution of most DAT to the plasma membrane while inducing significant hyperactivity in rats. However, administration of 5-mg/kg cocaine (ip) did not significantly induce DAT trafficking or hyperactivity in rats. So the threshold (intraperitoneal) dose of cocaine that can significantly induce DAT trafficking or hyperactivity should be between 5 and 10 mg/kg. These data suggest that when a cocaine dose is high enough to induce significant hyperactivity, it can also significantly induce DAT trafficking to the plasma membrane. Further, the threshold brain cocaine concentration required to induce significant hyperactivity and DAT trafficking was estimated to be ~2.0 ± 0.8 µg/g. Particularly, for treatment of cocaine abuse, previous studies demonstrated that an exogenous cocaine-metabolizing enzyme, for example, CocH3-Fc(M3), can effectively block cocaine-induced hyperactivity. However, it was unknown whether an enzyme could also effectively block cocaine-induced DAT trafficking to the plasma membrane. This study demonstrates, for the first time, that the enzyme is also capable of effectively blocking cocaine from reaching the brain even with a lethal dose of 60-mg/kg cocaine (ip) and, thus, powerfully preventing cocaine-induced physiological effects such as the hyperactivity and DAT trafficking.
Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Membrana Celular/efeitos dos fármacos , Cocaína/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Hipercinese/patologia , Proteínas Recombinantes/metabolismo , Animais , Transtornos Relacionados ao Uso de Cocaína , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
There is evidence that glycemic fluctuations trigger vascular-mediated dysfunction in both the retina and the striatopallidal regions in patients with diabetes. The latter is associated with a variety of hyperkinetic disorders that are rare but disabling and potentially preventable. We conducted a systematic review of the potential association between diabetic retinopathy and the risk and prognosis of hyperkinetic disorders in patients with diabetes. We identified a total of 461 articles and 147 were eligible for review. Nine out of 147 articles (6.12%) reported 13 patients with information on diabetic retinopathy. Glycemic fluctuations were present at onset in 10 patients (77%) and retinopathy was present in nine of them (69.23%). The degree of retinopathy was reported in four patients. Two had severe, bilateral proliferative retinopathy, one had moderate-to-severe non-proliferative retinopathy and one had non-proliferative retinopathy. In the nine patients with retinopathy, hyperkinesia persisted, required higher doses of dopamine receptor antagonists or deep brain stimulation. Retinopathy was absent in four cases (30.77%). In these patients, hyperkinesia resolved spontaneously or with lower doses of dopamine receptor antagonists. Diabetic retinopathy could be an indirect marker of striatopallidal microangiopathy in patients with diabetes. The severity of retinopathy may be associated with increased risk or worse prognosis for patients who develop hyperkinetic disorders of the diabetic striatopathy spectrum. Early detection of retinopathy could identify patients in which avoiding glycemic fluctuations may prevent the development of striatopathy and hyperkinetic disorders.
Assuntos
Doenças dos Gânglios da Base/patologia , Corpo Estriado/patologia , Complicações do Diabetes/patologia , Retinopatia Diabética/patologia , Hipercinese/patologia , Doenças dos Gânglios da Base/etiologia , Complicações do Diabetes/complicações , Retinopatia Diabética/etiologia , Humanos , Hipercinese/etiologiaRESUMO
BACKGROUND: This is the first case-control study investigating an association between gallbladder hyperkinesia and symptomatic acalculous chronic cholecystitis. METHODS: This retrospective study in a single academic center compared resolution of biliary pain in adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction ≥80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy (control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of 296 adults without gallstones had an ejection fraction ≥80%, of whom 46 patients met predetermined eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity of pain, and resolution of pain were compared between groups. RESULTS: Demographics (mean ± standard deviation) in the control group (n = 25) and in the study group (n = 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/m2, with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18 of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean follow-up of 36 ± 28 months (range 10-120 months) (P < .01). Pain resolution with cholecystectomy was independent of demographic variables, hepatobiliary iminodiacetic acid scan ejection fraction, and chronicity of pain. The odds of pain resolution was 19.7 times greater with cholecystectomy than without (odds ratio, 19.7; 95% confidence interval, 4.34, 89.43; P < .01), and remained robust even with the odds adjusted for each covariate. Gallbladder histopathology confirmed chronic cholecystitis in all 21 cholecystectomy specimens. CONCLUSION: Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in adults.
Assuntos
Colecistite/etiologia , Doenças da Vesícula Biliar/complicações , Hipercinese/complicações , Adulto , Idoso , Colecistectomia , Colecistite/cirurgia , Doença Crônica , Feminino , Doenças da Vesícula Biliar/patologia , Humanos , Hipercinese/patologia , Iminoácidos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders.
Assuntos
Síndromes Epilépticas/genética , Hipercinese/genética , Proteínas Serina-Treonina Quinases/genética , Espasmos Infantis/genética , Animais , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Síndromes Epilépticas/patologia , Transtornos Neurológicos da Marcha/genética , Transtornos Neurológicos da Marcha/metabolismo , Transtornos Neurológicos da Marcha/patologia , Humanos , Hipercinese/metabolismo , Hipercinese/patologia , Metilfenidato/metabolismo , Camundongos , Camundongos Knockout , Espasmos Infantis/patologiaAssuntos
Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/farmacologia , Hipercinese/tratamento farmacológico , Hipercinese/genética , Maconha Medicinal/farmacologia , Proteínas Mitocondriais/genética , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/genética , Fatores de Alongamento de Peptídeos/genética , Núcleo Subtalâmico/patologia , Adulto , Agonistas de Receptores de Canabinoides/administração & dosagem , Consanguinidade , Dronabinol/administração & dosagem , Humanos , Hipercinese/patologia , Hipercinese/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Maconha Medicinal/administração & dosagem , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/fisiopatologia , Núcleo Subtalâmico/diagnóstico por imagem , Adulto JovemRESUMO
Developmental ethanol exposure is a well-known cause of lifelong cognitive deficits, behavioral hyperactivity, emotional dysregulation, and more. In healthy adults, sleep is thought to have a critical involvement in each of these processes. Our previous work has demonstrated that some aspects of cognitive impairment in adult mice exposed at postnatal day 7 (P7) to ethanol (EtOH) correlate with slow-wave sleep (SWS) fragmentation (Wilson et al., 2016). We and others have also previously demonstrated that co-treatment with LiCl on the day of EtOH exposure prevents many of the anatomical and physiological impairments observed in adults. Here we explored cognitive function, diurnal rhythms (activity, temperature), SWS, and parvalbumin (PV) and perineuronal net (PNN)-positive cell densities in adult mice that had received a single day of EtOH exposure on P7 and saline-treated littermate controls. Half of the animals also received a LiCl injection on P7. The results suggest that developmental EtOH resulted in adult behavioral hyperactivity, cognitive impairment, and reduced SWS compared to saline controls. Both of these effects were reduced by LiCl treatment on the day of EtOH exposure. Finally, developmental EtOH resulted in decreased PV/PNN-expressing cells in retrosplenial (RS) cortex and dorsal CA3 hippocampus at P90. As with sleep and behavioral activity, LiCl treatment reduced this decrease in PV expression. Together, these results further clarify the long-lasting effects of developmental EtOH on adult behavior, physiology, and anatomy. Furthermore, they demonstrate the neuroprotective effects of LiCl co-treatment on this wide range of developmental EtOH's long-lasting consequences.
Assuntos
Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Cloreto de Lítio/farmacologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Animais , Animais Recém-Nascidos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Feminino , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/patologia , Transtornos do Espectro Alcoólico Fetal/psicologia , Hipercinese/etiologia , Hipercinese/metabolismo , Hipercinese/patologia , Hipercinese/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , Parvalbuminas/metabolismo , Sono/efeitos dos fármacos , Privação do Sono/etiologia , Privação do Sono/metabolismo , Privação do Sono/patologia , Privação do Sono/prevenção & controleRESUMO
The zinc-finger SWIM domain-containing protein 6 (ZSWIM6) is a protein of unknown function that has been associated with schizophrenia and limited educational attainment by three independent genome-wide association studies. Additionally, a putatively causal point mutation in ZSWIM6 has been identified in several cases of acromelic frontonasal dysostosis with severe intellectual disability. Despite the growing number of studies implicating ZSWIM6 as an important regulator of brain development, its role in this process has never been examined. Here, we report the generation of Zswim6 knockout mice and provide a detailed anatomical and behavioral characterization of the resulting phenotype. We show that Zswim6 is initially expressed widely during embryonic brain development but becomes restricted to the striatum postnatally. Loss of Zswim6 causes a reduction in striatal volume and changes in medium spiny neuron morphology. These changes are associated with alterations in motor control, including hyperactivity, impaired rotarod performance, repetitive movements, and behavioral hyperresponsiveness to amphetamine. Together, our results show that Zswim6 is indispensable to normal brain function and support the notion that Zswim6 might serve as an important contributor to the pathogenesis of schizophrenia and other neurodevelopmental disorders.
Assuntos
Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteínas de Ligação a DNA/deficiência , Hipercinese/metabolismo , Hipercinese/patologia , Animais , Corpo Estriado/crescimento & desenvolvimento , Proteínas de Ligação a DNA/genética , Hipercinese/genética , Locomoção/fisiologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologiaRESUMO
The programming of cell fate by transcription factors requires precise regulation of their time and level of expression. The LIM-homeodomain transcription factor Islet1 (Isl1) is involved in cell-fate specification of motor neurons, and it may play a similar role in the inner ear. In order to study its role in the regulation of vestibulo-motor development, we investigated a transgenic mouse expressing Isl1 under the Pax2 promoter control (Tg +/- ). The transgenic mice show altered level, time, and place of expression of Isl1 but are viable. However, Tg +/- mice exhibit hyperactivity, including circling behavior, and progressive age-related decline in hearing, which has been reported previously. Here, we describe the molecular and morphological changes in the cerebellum and vestibular system that may cause the hyperactivity of Tg +/- mice. The transgene altered the formation of folia in the cerebellum, the distribution of calretinin labeled unipolar brush cells, and reduced the size of the cerebellum, inferior colliculus, and saccule. Age-related progressive reduction of calbindin expression was detected in Purkinje cells in the transgenic cerebella. The hyperactivity of Tg +/- mice is reduced upon the administration of picrotoxin, a non-competitive channel blocker for the γ-aminobutyric acid (GABA) receptor chloride channels. This suggests that the overexpression of Isl1 significantly affects the functions of GABAergic neurons. We demonstrate that the overexpression of Isl1 affects the development and function of the cerebello-vestibular system, resulting in hyperactivity.
Assuntos
Cerebelo/metabolismo , Cerebelo/patologia , Hipercinese/metabolismo , Hipercinese/patologia , Proteínas com Homeodomínio LIM/biossíntese , Fator de Transcrição PAX2/biossíntese , Fatores de Transcrição/biossíntese , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Vestíbulo do Labirinto/metabolismo , Vestíbulo do Labirinto/patologiaRESUMO
The adolescent period in mammals is a critical period of brain maturation and thus represents a time of susceptibility to environmental insult, e.g. psychosocial stress and/or drugs of abuse, which may cause lasting impairments in brain function and behavior and even precipitate symptoms in at-risk individuals. One likely effect of these environmental insults is to increase oxidative stress in the developing adolescent brain. Indeed, there is increasing evidence that redox dysregulation plays an important role in the development of schizophrenia and other neuropsychiatric disorders and that GABA interneurons are particularly susceptible to alterations in oxidative stress. The current study sought to model this adolescent neurochemical "stress" by exposing mice to the dopamine transporter inhibitor GBR12909 (5mg/kg; IP) during adolescence (postnatal day 35-44) and measuring the resultant effect on locomotor behavior and probabilistic reversal learning as well as GABAergic interneurons and oxidative stress in adulthood. C57BL6/J mice exposed to GBR12909 showed increased activity in a novel environment and increased impulsivity as measured by premature responding in the probabilistic reversal learning task. Adolescent GBR12909-exposed mice also showed decreased parvalbumin (PV) immunoreactivity in the prefrontal cortex, which was accompanied by increased oxidative stress in PV+ neurons. These findings indicate that adolescent exposure to a dopamine transporter inhibitor results in loss of PV in GABAergic interneurons, elevations in markers of oxidative stress, and alterations in behavior in adulthood.
Assuntos
Comportamento Impulsivo/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Hipercinese/metabolismo , Hipercinese/patologia , Comportamento Impulsivo/fisiologia , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Estresse Oxidativo/fisiologia , Parvalbuminas/metabolismo , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Aprendizagem por Probabilidade , Reversão de Aprendizagem/efeitos dos fármacos , Reversão de Aprendizagem/fisiologiaRESUMO
BACKGROUND: Cervical dystonias have a variable presentation and underlying etiology, but collectively represent the most common form of focal dystonia. There are a number of known genetic forms of dystonia (DYT1-27); however the heterogeneity of disease presentation does not always make it easy to categorize the disease by phenotype-genotype comparison. CASE PRESENTATION: In this report, we describe a 53-year-old female who presented initially with hand tremor following a total hip arthroplasty. The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm. Whole exome sequencing of the patient revealed a novel heterozygous missense variant (Chr11(GRCh38): g.26525644C > G; NM_031418.2(ANO3): c.702C > G; NP_113606.2. p.C234W) in exon 7 in the ANO3 gene. CONCLUSIONS: ANO3 encodes anoctamin-3, a Ca+2-dependent phospholipid scramblase expressed in striatal-neurons, that has been implicated in autosomal dominant craniocervical dystonia (Dystonia-24, DYT24, MIM# 615034). To date, only a handful of cases of DYT-24 have been described in the literature. The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24. This report highlights the utility of using clinical whole exome sequencing in patients with complex neurological phenotypes that would not normally fit a classical presentation of a defined genetic disease.
Assuntos
Blefarospasmo/genética , Canais de Cloreto/genética , Disartria/genética , Distonia/genética , Hipercinese/genética , Tiques/genética , Abdome/diagnóstico por imagem , Sequência de Aminoácidos , Anoctaminas , Blefarospasmo/complicações , Blefarospasmo/patologia , Disartria/complicações , Disartria/patologia , Distonia/complicações , Distonia/patologia , Eletrofisiologia , Éxons , Feminino , Heterozigoto , Humanos , Hipercinese/complicações , Hipercinese/patologia , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Polimorfismo Genético , Alinhamento de Sequência , Tiques/complicações , Tiques/patologiaRESUMO
UNLABELLED: Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditional tryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep-wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior. SIGNIFICANCE STATEMENT: Serotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep-wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder.
Assuntos
Encéfalo/metabolismo , Transtornos Cronobiológicos/genética , Proteínas de Fluorescência Verde/deficiência , Hipercinese/genética , Parassonias/genética , Serotonina/deficiência , Análise de Variância , Animais , Cromatografia Líquida de Alta Pressão , Transtornos Cronobiológicos/patologia , Comportamento Exploratório , Feminino , Proteínas de Fluorescência Verde/genética , Hipercinese/patologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Transdução Genética , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismoRESUMO
We report the case of a 4-year-old girl who presented with paroxysmal sympathetic hyperactivity (PSH), after developing severe hypoxic-ischemic-encephalopathy because of cardiopulmonary arrest. She showed dramatic paroxysmal sympathetic activity with dystonia. She was treated with wide variety of medications against PSH, which were found to be effective in previous studies. Among them, morphine, bromocriptine, propranolol, and clonidine were effective in reducing the frequency of her attacks while gabapentin, baclofen, dantrolene, and benzodiazepine were ineffective. Though the paroxysms decreased markedly after the treatment, they could not be completely controlled beyond 500 days. Following the treatment, levels of plasma catecholamines and their urinary metabolites decreased to normal during inter- paroxysms. However, once a paroxysm had recurred, these levels were again very high. This case study is considered significant for two rea- sons. One is that PSH among children have been rarely reported, and the other is that this case of prolonged PSH delineated the transition of plasma catecholamines during the treatment. The excitatory: inhibitory ratio (EIR) model proposed by Baguley was considered while dis- cussing drug sensitivity in this case. Accumulation of similar case studies will help establish more effective treatment strategies and elucidate the pathophysiology of PSH.
Assuntos
Hipercinese , Pré-Escolar , Feminino , Humanos , Hipercinese/patologia , Hipercinese/fisiopatologia , Imageamento por Ressonância Magnética , Proibitinas , Vasoconstrição , Sinais VitaisRESUMO
Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.
Assuntos
Corpo Estriado/patologia , Hipercinese/genética , Mutação , Diester Fosfórico Hidrolases/genética , Alelos , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Variação Genética , Células HEK293 , Humanos , Hipercinese/diagnóstico , Hipercinese/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Linhagem , Inibidores de Fosfodiesterase/metabolismo , Alinhamento de SequênciaRESUMO
Head direction (HD) cells fire when an animal faces a particular direction in its environment, and they are thought to represent the neural correlate of the animal's perceived spatial orientation. Previous studies have shown that vestibular information is critical for generating the HD signal but have not delineated whether information from all three semicircular canals or just the horizontal canals, which are primarily sensitive to angular head rotation in the horizontal (yaw) plane, are critical for the signal. Here, we monitored cell activity in the anterodorsal thalamus (ADN), an area known to contain HD cells, in epstatic circler (Ecl) mice, which have a bilateral malformation of the horizontal (lateral) semicircular canals. Ecl mice and their littermates that did not express the mutation (controls) were implanted with recording electrodes in the ADN. Results confirm the important role the horizontal canals play in forming the HD signal. Although normal HD cell activity (Raleigh's r > 0.4) was recorded in control mice, no such activity was found in Ecl mice, although some cells had activity that was mildly modulated by HD (0.4 > r > 0.2). Importantly, we also observed activity in Ecl mice that was best characterized as bursty--a pattern of activity similar to an HD signal but without any preferred firing direction. These results suggest that the neural structure for the HD network remains intact in Ecl mice, but the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable HD signal. Significance statement: Cells in the anterior dorsal thalamic nucleus normally fire in relation to the animal's directional heading with respect to the environment--so-called head direction cells. To understand how these head direction cells generate their activity, we recorded single-unit activity from the anterior dorsal thalamus in transgenic mice that lack functional horizontal semicircular canals. We show that the neural network for the head direction signal remains intact in these mice, but that the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable head direction signal.
Assuntos
Movimentos da Cabeça/fisiologia , Orientação/fisiologia , Canais Semicirculares/patologia , Canais Semicirculares/fisiologia , Animais , Feminino , Hipercinese/patologia , Hipercinese/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Canais Semicirculares/anormalidadesRESUMO
Traumatic brain injury (TBI) often results in structural damage and a loss of neurons that is commonly accompanied by early changes in neuronal electrical activity. Loss of neuronal activity has been hypothesized to contribute to post-traumatic epileptogenesis through the regulation of homeostatic plasticity. The existence of activity loss in cortical neurons after TBI and its subsequent transition into hyperactivity over time is not well characterized, however, particularly in models of TBI in vivo. In the current study, changes in neuronal activity in the primary motor cortex after moderate controlled cortical impact (CCI) in mice were studied using a single-unit recording technique in vivo. Recordings were made at different time points after CCI from cortical layer V pyramidal neurons that were within 1-2 mm from the anterior edge of the injured foci. Within 1-4 h after CCI, the frequency of spontaneous single-unit activity depressed significantly, with the mean firing frequency decreasing from 2.59 ± 0.18 Hz in the sham group to 1.05 ± 0.20 Hz of the injured group. The firing frequencies recovered to the normal level at 1 day and 7 days post-CCI, but became significantly higher at 3 days and 14 days post-CCI. The results suggest that TBI caused initial loss of activity in neurons of the perilesional cortical region, which was followed by compensatory recovery and enhancement of activity. These time-dependent changes in neuronal activity may contribute to the development of hyperexcitability through homeostatic activity regulation.
Assuntos
Lesões Encefálicas Traumáticas/patologia , Hipercinese/patologia , Locomoção , Córtex Motor/patologia , Células Piramidais/patologia , Animais , Lesões Encefálicas Traumáticas/complicações , Hipercinese/etiologia , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Motor/fisiologia , Células Piramidais/fisiologia , Ratos Sprague-DawleyRESUMO
Selenoprotein T (SelT) is a newly discovered thioredoxin-like protein, which is abundantly but transiently expressed in the neural lineage during brain ontogenesis. Because its physiological function in the brain remains unknown, we developed a conditional knockout mouse line (Nes-Cre/SelTfl/fl) in which SelT gene is specifically disrupted in nerve cells. At postnatal day 7 (P7), these mice exhibited reduced volume of different brain structures, including hippocampus, cerebellum, and cerebral cortex. This phenotype, which is observed early during the first postnatal week, culminated at P7 and was associated with increased loss of immature neurons but not glial cells, through apoptotic cell death. This phenomenon was accompanied by elevated levels of intracellular reactive oxygen species, which may explain the increased neuron demise and reduced brain structure volumes. At the second postnatal week, an increase in neurogenesis was observed in the cerebellum of Nes-Cre/SelTfl/fl mice, suggesting the occurrence of developmental compensatory mechanisms in the brain. In fact, the brain volume alterations observed at P7 were attenuated in adult mice. Nevertheless, SelT mutant mice exhibited a hyperactive behavior, suggesting that despite an apparent morphological compensation, SelT deficiency leads to cerebral malfunction in adulthood. Altogether, these results demonstrate that SelT exerts a neuroprotective role which is essential during brain development, and that its loss impairs mice behavior.
Assuntos
Comportamento Animal , Hipercinese/metabolismo , Malformações do Sistema Nervoso/metabolismo , Sistema Nervoso/embriologia , Sistema Nervoso/metabolismo , Selenoproteínas/deficiência , Animais , Animais Recém-Nascidos , Apoptose , Astrócitos/metabolismo , Encéfalo/patologia , Proliferação de Células , Sobrevivência Celular , Homeostase , Hipercinese/patologia , Integrases/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sistema Nervoso/patologia , Malformações do Sistema Nervoso/patologia , Nestina/metabolismo , Neurogênese , Neurônios/metabolismo , Neurônios/patologia , Tamanho do Órgão , Oxirredução , Ratos , Espécies Reativas de Oxigênio/metabolismo , Selenoproteínas/genéticaRESUMO
PURPOSE: Paroxysmal sympathetic hyperactivity is a complication of brain injury that has mainly been described in the adult brain injury literature. METHODS: We present a case series of three pediatric patients that developed paroxysmal sympathetic hyperactivity of varying severity following hypoxic brain injury. RESULTS: Comparison of brain magnetic resonance imaging revealed bilateral and symmetric global ischemic changes in all three cases. However, the thalamus was not affected in the patient with the mild case of paroxysmal sympathetic hyperactivity. In contrast, bilateral and symmetric damage to the thalamus was observed in the two severe cases. CONCLUSIONS: Our case series suggests that in hypoxic brain injury, evidence of bilateral ischemic injury to the thalamus on magnetic resonance imaging may be an important early predictor of severity and length of paroxysmal sympathetic hyperactivity. While this is an interesting observation, definite proof of our hypothesis requires further research including analysis of larger numbers of patients and comparison of MRI findings in children with hypoxic brain injury that do not develop paroxysmal sympathetic hyperactivity.
Assuntos
Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/patologia , Hipercinese/patologia , Imageamento por Ressonância Magnética , Tálamo/diagnóstico por imagem , Criança , Feminino , Humanos , Hipercinese/complicações , Processamento de Imagem Assistida por Computador , Lactente , MasculinoRESUMO
High levels of impulsivity have been linked to a number of psychiatric disorders, including attention-deficit/hyperactivity disorder, drug abuse and schizophrenia. Additionally, schizophrenia patients commonly show deficits in another rather preattentive form of response inhibition, called sensorimotor gating. Given that higher-order functions, such as impulse control, are protected by early and preattentive processes, disturbed gating mechanisms may hamper more complex cognitive-executive functions. In the present study, we therefore tested whether high levels of impulsivity are accompanied by impaired sensorimotor gating in rats. High (HI) and low impulsive (LI) rats were identified based on the number of premature responses in the 5-choice serial reaction time task. Here, LI rats showed higher numbers of omission errors which may suggest attentional deficits while HI rats completed significantly less trials which could indicate a decrease in motivation. However, HI and LI rats did not differ in terms of impulsive decision-making in a delay-based decision-making T-maze task, prepulse inhibition of the acoustic startle response (a measure of sensorimotor gating mechanisms) or locomotor activity levels. Overall, our data indicate that high motor impulsivity is not a suitable predictor of deficient sensorimotor gating and is further not necessarily associated with attentional deficits and/or locomotor hyperactivity in rats.
Assuntos
Comportamento Impulsivo/fisiologia , Atividade Motora/fisiologia , Filtro Sensorial/fisiologia , Estimulação Acústica , Animais , Comportamento de Escolha/fisiologia , Hipercinese/patologia , Masculino , Inibição Pré-Pulso/fisiologia , Ratos , Ratos Wistar , Tempo de Reação/fisiologia , Reflexo de Sobressalto/fisiologiaRESUMO
Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2(-/-) mice. Using the in vivo microdialysis technique we found that the ability of amphetamine to stimulate noradrenaline (NA) release in the striatum was reduced by about 50% in Tph2(-/-) mice while the release of dopamine (DA) was not affected. Tph2 deletion did not affect the release of NA and DA in the prefrontal cortex. The role of endogenous 5-HT in enhancing the effect of amphetamine was confirmed showing that treatment with the 5-HT precursor 5-hydroxytryptophan (10 mg/kg) restored tissue and extracellular levels of brain 5-HT and the effects of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. Treatment with the NA precursor dihydroxyphenylserine (400 mg/kg) was sufficient to restore the effect of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. These findings indicate that amphetamine-induced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2(-/-) mice may be a useful preclinical model to assess the role of 5-HT-dependent mechanisms in the action of psychostimulants. Acute sensitivity to the motor effects of amphetamine has been associated to increased risk of psychostimulant abuse. Here, we show that deletion of Tph2, the gene responsible for brain 5-HT synthesis, enhances the motor effect of amphetamine in mice through the inhibition of striatal NA release. This suggests that Tph2(-/-) mice is a useful preclinical model to assess the role of 5-HT-dependent mechanisms in psychostimulants action. Tph2, tryptophan hydroxylase-2.