RESUMEN
Mouse models of various neuropsychiatric disorders, such as schizophrenia, often display an immature dentate gyrus, characterized by increased numbers of immature neurons and neuronal progenitors and a dearth of mature neurons. We previously demonstrated that the CRMP5-associated GTPase (CRAG), a short splice variant of Centaurin-γ3/AGAP3, is highly expressed in the dentate gyrus. CRAG promotes cell survival and antioxidant defense by inducing the activation of serum response factors at promyelocytic leukemia protein bodies, which are nuclear stress-responsive domains, during neuronal development. However, the physiological role of CRAG in neuronal development remains unknown. Here, we analyzed the role of CRAG using dorsal forebrain-specific CRAG/Centaurin-γ3 knockout mice. The mice revealed maturational abnormality of the hippocampal granule cells, including increased doublecortin-positive immature neurons and decreased calbindin-positive mature neurons, a typical phenotype of immature dentate gyri. Furthermore, the mice displayed hyperactivity in the open-field test, a common measure of exploratory behavior, suggesting that these mice may serve as a novel model for neuropsychiatric disorder associated with hyperactivity. Thus, we conclude that CRAG is required for the maturation of neurons in the dentate gyrus, raising the possibility that its deficiency might promote the development of psychiatric disorders in humans.
Asunto(s)
Giro Dentado/patología , GTP Fosfohidrolasas/fisiología , Células-Madre Neurales/patología , Neurogénesis , Neuronas/patología , Prosencéfalo/patología , Agitación Psicomotora/patología , Animales , Giro Dentado/metabolismo , Conducta Exploratoria , Femenino , Masculino , Ratones , Ratones Noqueados , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Prosencéfalo/metabolismo , Agitación Psicomotora/etiología , Agitación Psicomotora/metabolismoRESUMEN
The core symptoms of many neurological disorders have traditionally been thought to be caused by genetic variants affecting brain development and function. However, the gut microbiome, another important source of variation, can also influence specific behaviors. Thus, it is critical to unravel the contributions of host genetic variation, the microbiome, and their interactions to complex behaviors. Unexpectedly, we discovered that different maladaptive behaviors are interdependently regulated by the microbiome and host genes in the Cntnap2-/- model for neurodevelopmental disorders. The hyperactivity phenotype of Cntnap2-/- mice is caused by host genetics, whereas the social-behavior phenotype is mediated by the gut microbiome. Interestingly, specific microbial intervention selectively rescued the social deficits in Cntnap2-/- mice through upregulation of metabolites in the tetrahydrobiopterin synthesis pathway. Our findings that behavioral abnormalities could have distinct origins (host genetic versus microbial) may change the way we think about neurological disorders and how to treat them.
Asunto(s)
Microbioma Gastrointestinal , Locomoción , Conducta Social , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores , Trasplante de Microbiota Fecal , Heces/microbiología , Limosilactobacillus reuteri/metabolismo , Limosilactobacillus reuteri/fisiología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/microbiología , Trastornos del Neurodesarrollo/patología , Trastornos del Neurodesarrollo/terapia , Análisis de Componente Principal , Agitación Psicomotora/patología , Transmisión SinápticaRESUMEN
BACKGROUND: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of three neuroleptic strategies on refractory agitation in patients with cancer with terminal delirium. METHODS: In this single-centre, double-blind, parallel-group, randomised trial, patients with advanced cancer, aged at least 18 years, admitted to the palliative and supportive care unit at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), with refractory agitation, despite low-dose haloperidol, were randomly assigned to receive intravenous haloperidol dose escalation at 2 mg every 4 h, neuroleptic rotation with chlorpromazine at 25 mg every 4 h, or combined haloperidol at 1âmg and chlorpromazine at 12·5 mg every 4 h, until death or discharge. Rescue doses identical to the scheduled doses were administered at inception, and then hourly as needed. Permuted block randomisation (block size six; 1:1:1) was done, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients, and caregivers were masked to group assignment. The primary outcome was change in RASS score from time 0 to 24 h. Comparisons among group were done by modified intention-to-treat analysis. This completed study is registered with ClinicalTrials.gov, NCT03021486. FINDINGS: Between July 5, 2017, and July 1, 2019, 998 patients were screened for eligibility, with 68 being enrolled and randomly assigned to treatment; 45 received the masked study interventions (escalation n=15, rotation n=16, combination n=14). RASS score decreased significantly within 30 min and remained low at 24 h in the escalation group (n=10, mean RASS score change between 0 h and 24 h -3·6 [95% CI -5·0 to -2·2]), rotation group (n=11, -3·3 [-4·4 to -2·2]), and combination group (n=10, -3·0 [-4·6 to -1·4]), with no difference among groups (p=0·71). The most common serious toxicity was hypotension (escalation n=6 [40%], rotation n=5 [31%], combination n=3 [21%]); there were no treatment-related deaths. INTERPRETATION: Our data provide preliminary evidence that the three strategies of neuroleptics might reduce agitation in patients with terminal agitation. These findings are in the context of the single-centre design, small sample size, and lack of a placebo-only group. FUNDING: National Institute of Nursing Research.
Asunto(s)
Antipsicóticos/uso terapéutico , Delirio/tratamiento farmacológico , Haloperidol/uso terapéutico , Neoplasias/complicaciones , Cuidados Paliativos , Agitación Psicomotora/tratamiento farmacológico , Anciano , Delirio/etiología , Delirio/patología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/psicología , Neoplasias/terapia , Pronóstico , Agitación Psicomotora/etiología , Agitación Psicomotora/patologíaRESUMEN
The neurodevelopmental origin of hyperactivity disorder has been suggested to involve the dopaminergic system, but the underlying mechanisms are still unknown. Here, transcription factors Lmx1a and Lmx1b are shown to be essential for midbrain dopaminergic (mDA) neuron excitatory synaptic inputs and dendritic development. Strikingly, conditional knockout (cKO) of Lmx1a/b in postmitotic mDA neurons results in marked hyperactivity. In seeking Lmx1a/b target genes, we identify positively regulated Slitrk2 and negatively regulated Slitrk5. These two synaptic adhesion proteins promote excitatory and inhibitory synapses on mDA neurons, respectively. Knocking down Slitrk2 reproduces some of the Lmx1a/b cKO cellular and behavioral phenotypes, whereas Slitrk5 knockdown has opposite effects. The hyperactivity caused by this imbalance in excitatory/inhibitory synaptic inputs on dopamine neurons is reproduced by chronically inhibiting the ventral tegmental area during development using pharmacogenetics. Our study shows that alterations in developing dopaminergic circuits strongly impact locomotor activity, shedding light on mechanisms causing hyperactivity behaviors.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Agitación Psicomotora/metabolismo , Sinapsis/metabolismo , Animales , Neuronas Dopaminérgicas/patología , Potenciales Postsinápticos Excitadores , Femenino , Humanos , Potenciales Postsinápticos Inhibidores , Proteínas con Homeodominio LIM/metabolismo , Ratones , Ratones Noqueados , Embarazo , Cultivo Primario de Células , Agitación Psicomotora/patología , Sinapsis/patología , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
Youths with attention-deficit/hyperactivity disorder symptomatology often exhibit residual inattention and/or hyperactivity in adulthood; however, this is not true for all individuals. We recently reported that dimensional, multi-informant ratings of hyperactive/inattentive symptoms are associated with ventromedial prefrontal cortex (vmPFC) structure. Herein, we investigate the degree to which vmPFC structure during adolescence predicts hyperactive/inattentive symptomatology at 5-year follow-up. Structural equation modeling was used to test the extent to which adolescent vmPFC volume predicts hyperactive/inattentive symptomatology 5 years later in early adulthood. 1104 participants (M = 14.52 years, standard deviation = 0.42; 583 females) possessed hyperactive/inattentive symptom data at 5-year follow-up, as well as quality controlled neuroimaging data and complete psychometric data at baseline. Self-reports of hyperactive/inattentive symptomatology were obtained during adolescence and at 5-year follow-up using the Strengths and Difficulties Questionnaire (SDQ). At baseline and 5-year follow-up, a hyperactive/inattentive latent variable was derived from items on the SDQ. Baseline vmPFC volume predicted adult hyperactive/inattentive symptomatology (standardized coefficient = -0.274, P < 0.001) while controlling for baseline hyperactive/inattentive symptomatology. These results are the first to reveal relations between adolescent brain structure and adult hyperactive/inattentive symptomatology, and suggest that early structural development of the vmPFC may be consequential for the subsequent expression of hyperactive/inattentive symptoms.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Trastorno por Déficit de Atención con Hiperactividad/patología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patología , Adolescente , Adulto , Atención/fisiología , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos , Agitación Psicomotora/diagnóstico por imagen , Agitación Psicomotora/patología , Adulto JovenRESUMEN
Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline ID combined with behavioral problems consisting of autistic, hyperactive and/or aggressive behavior. Studies in dissociated rat hippocampal neurons demonstrated the enhancement of dendritic formation by suppressing endogenous TRIO, and similarly decreasing endogenous TRIO in organotypic hippocampal brain slices significantly increased synaptic strength by increasing functional synapses. Together, our findings provide new mechanistic insight into how genetic deficits in TRIO can lead to early neuronal network formation by directly affecting both neurite outgrowth and synapse development.
Asunto(s)
Trastorno Autístico/genética , Factores de Intercambio de Guanina Nucleótido/genética , Discapacidad Intelectual/genética , Mutación , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Agitación Psicomotora/genética , Sinapsis/metabolismo , Adulto , Animales , Trastorno Autístico/metabolismo , Trastorno Autístico/patología , Niño , Femenino , Expresión Génica , Factores de Intercambio de Guanina Nucleótido/deficiencia , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Masculino , Neurogénesis , Neuronas/patología , Cultivo Primario de Células , Proteínas Serina-Treonina Quinasas/deficiencia , Agitación Psicomotora/metabolismo , Agitación Psicomotora/patología , Ratas , Análisis de Secuencia de ADN , Índice de Severidad de la Enfermedad , Sinapsis/patologíaRESUMEN
Hearing loss often triggers an inescapable buzz (tinnitus) and causes everyday sounds to become intolerably loud (hyperacusis), but exactly where and how this occurs in the brain is unknown. To identify the neural substrate for these debilitating disorders, we induced both tinnitus and hyperacusis with an ototoxic drug (salicylate) and used behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) techniques to identify the tinnitus-hyperacusis network. Salicylate depressed the neural output of the cochlea, but vigorously amplified sound-evoked neural responses in the amygdala, medial geniculate, and auditory cortex. Resting-state fMRI revealed hyperactivity in an auditory network composed of inferior colliculus, medial geniculate, and auditory cortex with side branches to cerebellum, amygdala, and reticular formation. Functional connectivity revealed enhanced coupling within the auditory network and segments of the auditory network and cerebellum, reticular formation, amygdala, and hippocampus. A testable model accounting for distress, arousal, and gating of tinnitus and hyperacusis is proposed.
Asunto(s)
Amígdala del Cerebelo/fisiopatología , Corteza Auditiva/fisiopatología , Cerebelo/fisiopatología , Hipocampo/fisiopatología , Hiperacusia/fisiopatología , Formación Reticular/fisiopatología , Acúfeno/fisiopatología , Amígdala del Cerebelo/patología , Animales , Corteza Auditiva/patología , Mapeo Encefálico , Cerebelo/patología , Cóclea/patología , Cóclea/fisiopatología , Modelos Animales de Enfermedad , Cuerpos Geniculados/patología , Cuerpos Geniculados/fisiopatología , Hipocampo/patología , Humanos , Hiperacusia/inducido químicamente , Hiperacusia/patología , Colículos Inferiores/patología , Colículos Inferiores/fisiopatología , Imagen por Resonancia Magnética , Modelos Psicológicos , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Agitación Psicomotora/patología , Agitación Psicomotora/fisiopatología , Ratas , Ratas Sprague-Dawley , Formación Reticular/patología , Ácido Salicílico , Acúfeno/inducido químicamente , Acúfeno/patologíaRESUMEN
RATIONALE: Alterations in brainstem circuits have been proposed as a possible mechanism underlying the etiology of mood disorders. Projections from the median raphe nucleus (MnR) modulate dopaminergic activity in the forebrain and are also part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder. OBJECTIVE: The aim of this study is to assess the effect of chronic lithium treatment on behavioral disinhibition induced by MnR lesions. METHODS: MnR electrolytic lesions were performed in C57BL/6J mice, with sham-operated and intact animals as control groups. Following recovery, mice were chronically treated with lithium (LiCl, added in chow) followed by behavioral testing. RESULTS: MnR lesion induced manic-like behavioral alterations including hyperactivity in the open field (OF), stereotyped circling, anxiolytic/risk taking in the elevated plus maze (EPM) and light/dark box (LDB) tests, and increased basal body temperature. Lithium was specifically effective in reducing OF hyperactivity and stereotypy but did not reverse (EPM) or had a nonspecific effect (LDB) on anxiety/risk-taking measures. Additionally, lithium decreased saccharin preference and prevented weight loss during single housing. CONCLUSIONS: Our data support electrolytic lesions of the MnR as an experimental model of a hyper-excitable/disinhibited phenotype consistent with some aspects of mania that are attenuated by the mood stabilizer lithium. Given lithium's relatively specific efficacy in treating mania, these data support the hypothesis that manic symptoms derive not only from the stimulation of excitatory systems but also from inactivation or decreased activity of inhibitory mechanisms.
Asunto(s)
Electrocoagulación/efectos adversos , Hipercinesia/tratamiento farmacológico , Cloruro de Litio/administración & dosificación , Agitación Psicomotora/tratamiento farmacológico , Núcleos del Rafe/efectos de los fármacos , Núcleos del Rafe/patología , Animales , Ansiolíticos/administración & dosificación , Ansiedad/tratamiento farmacológico , Ansiedad/patología , Ansiedad/psicología , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/patología , Trastornos de Ansiedad/psicología , Electrocoagulación/métodos , Hipercinesia/patología , Hipercinesia/psicología , Masculino , Ratones , Ratones Endogámicos C57BL , Agitación Psicomotora/patología , Agitación Psicomotora/psicología , Conducta Estereotipada/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a rare heritable disease marked by dystonia and loss of movement control. In contrast to the well-known "Eye-of-the-Tiger" sign affecting the globus pallidus, little is known about other deviations of brain morphology, especially about grey matter changes. METHODS: We investigated 29 patients with PKAN and 29 age-matched healthy controls using Magnet Resonance Imaging and Voxel-Based Morphometry. RESULTS: As compared to controls, children with PKAN showed increased grey matter density in the putamen and nucleus caudatus and adults with PKAN showed increased grey matter density in the ventral part of the anterior cingulate cortex. A multiple regression analysis with dystonia score as predictor showed grey matter reduction in the cerebellum, posterior cingulate cortex, superior parietal lobule, pars triangularis and small frontal and temporal areas and an analysis with age as predictor showed grey matter decreases in the putamen, nucleus caudatus, supplementary motor area and anterior cingulate cortex. CONCLUSIONS: The grey matter increases may be regarded as a secondary phenomenon compensating the increased activity of the motor system due to a reduced inhibitory output of the globus pallidus. With increasing age, the grey matter reduction of cortical midline structures however might contribute to the progression of dystonic symptoms due to loss of this compensatory control.
Asunto(s)
Sustancia Gris/patología , Neurodegeneración Asociada a Pantotenato Quinasa/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Agitación Psicomotora/patología , Adolescente , Adulto , Factores de Edad , Cerebelo/patología , Niño , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neurodegeneración Asociada a Pantotenato Quinasa/enzimología , Neurodegeneración Asociada a Pantotenato Quinasa/fisiopatología , Agitación Psicomotora/fisiopatología , Adulto JovenRESUMEN
Cigarette smoking remains a significant health threat for smokers and nonsmokers alike. Secondhand smoke (SHS) is intrinsically more toxic than directly inhaled smoke. Recently, a new threat has been discovered - Thirdhand smoke (THS) - the accumulation of SHS on surfaces that ages with time, becoming progressively more toxic. THS is a potential health threat to children, spouses of smokers and workers in environments where smoking is or has been allowed. The goal of this study is to investigate the effects of THS on liver, lung, skin healing, and behavior, using an animal model exposed to THS under conditions that mimic exposure of humans. THS-exposed mice show alterations in multiple organ systems and excrete levels of NNAL (a tobacco-specific carcinogen biomarker) similar to those found in children exposed to SHS (and consequently to THS). In liver, THS leads to increased lipid levels and non-alcoholic fatty liver disease, a precursor to cirrhosis and cancer and a potential contributor to cardiovascular disease. In lung, THS stimulates excess collagen production and high levels of inflammatory cytokines, suggesting propensity for fibrosis with implications for inflammation-induced diseases such as chronic obstructive pulmonary disease and asthma. In wounded skin, healing in THS-exposed mice has many characteristics of the poor healing of surgical incisions observed in human smokers. Lastly, behavioral tests show that THS-exposed mice become hyperactive. The latter data, combined with emerging associated behavioral problems in children exposed to SHS/THS, suggest that, with prolonged exposure, they may be at significant risk for developing more severe neurological disorders. These results provide a basis for studies on the toxic effects of THS in humans and inform potential regulatory policies to prevent involuntary exposure to THS.
Asunto(s)
Hígado Graso/etiología , Agitación Psicomotora/etiología , Fibrosis Pulmonar/etiología , Contaminación por Humo de Tabaco/efectos adversos , Animales , Biomarcadores/orina , Preescolar , Colágeno/biosíntesis , Hígado Graso/patología , Hígado Graso/orina , Humanos , Lactante , Hígado/patología , Pulmón/patología , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Nitrosaminas/orina , Enfermedad del Hígado Graso no Alcohólico , Agitación Psicomotora/patología , Agitación Psicomotora/orina , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/orina , Piridinas/orina , Piel/patología , Cicatrización de HeridasRESUMEN
Intrauterine growth restriction and premature delivery decrease circulating levels of the neurotrophic hormone leptin and increase the risk of adult psychiatric disease. In mouse models, neonatal leptin replacement normalizes brain growth and improves the neurodevelopmental outcomes of growth restricted mice, but leptin supplementation of well-grown mice decreases adult locomotor activity. We hypothesized isolated neonatal leptin deficiency is sufficient to reduce adult brain volumes and program behavioral outcomes, including hyperactivity. C57Bl/6 pups were randomized to daily injections of saline or PEG-leptin antagonist (LX, 12.5 mg/kg) from postnatal day 4 to 14. After 4 months, fear conditioning and open field testing were performed followed by carotid radiotelemetry for the measurement of baseline activity and blood pressure. Neonatal LX did not significantly increase cue-based fear or blood pressure, but increased adult locomotor activity during assessment in both the open field (beam breaks: control 930 ± 40, LX 1099 ± 42, P<0.01) and the home cage (radiotelemetry counts: control 4.5 ± 0.3, LX 5.6 ± 0.3, P=0.02). Follow-up MRI revealed significant reductions in adult frontal cortex volumes following neonatal LX administration (control 45. 1 ± 0.4 mm(3), LX 43.8 ± 0.4 mm(3), P=0.04). This was associated with a significant increase in cerebral cortex leptin receptor mRNA expression. In conclusion, isolated neonatal leptin deficiency increases cerebral cortex leptin receptor expression and reduces frontal cortex volumes in association with increased adult locomotor activity. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with perinatal growth restriction, and postnatal leptin therapy may be protective.
Asunto(s)
Lóbulo Frontal/crecimiento & desarrollo , Lóbulo Frontal/fisiopatología , Agitación Psicomotora/fisiopatología , Receptores de Leptina/antagonistas & inhibidores , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Encéfalo/fisiopatología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Señales (Psicología) , Ingestión de Alimentos/efectos de los fármacos , Miedo/efectos de los fármacos , Miedo/fisiología , Femenino , Lóbulo Frontal/patología , Frecuencia Cardíaca/efectos de los fármacos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Tamaño de los Órganos , Agitación Psicomotora/patología , ARN Mensajero/metabolismo , Receptores de Leptina/metabolismo , Factores SexualesRESUMEN
Rising neurodegenerative and depressive disease prevalence combined with the lack of effective pharmaceutical treatments and dangerous side effects, has created an urgent need for the development of effective therapies. Considering that these disorders are multifactorial in origin, treatments designed to interfere at different mechanistic levels may be more effective than the traditional single-targeted pharmacological concepts. To that end, an experimental diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine, and choline was formulated. This diet was tested on the olfactory bulbectomized rat (OBX), an established animal model of depression and cognitive decline. The ingredients of the diet have been individually shown to attenuate glutamate excitoxicity, exert potent anti-oxidant/anti-inflammatory properties, and improve synaptogenesis; processes that all have been implicated in neurodegenerative diseases and in the cognitive deficits following OBX in rodents. Dietary treatment started 2 weeks before OBX surgery, continuing for 6 weeks in total. The diet attenuated OBX-induced cognitive and behavioral deficits, except long-term spatial memory. Ameliorating effects of the diet extended to the control animals. Furthermore, the experimental diet reduced hippocampal atrophy and decreased the peripheral immune activation in the OBX rats. The ameliorating effects of the diet on the OBX-induced changes were comparable to those of the NMDA receptor antagonist, memantine, a drug used for the management of Alzheimer's disease. This proof-of-concept study suggests that a diet, which simultaneously targets multiple disease etiologies, can prevent/impede the development of a neurodegenerative and depressive disorders and the concomitant cognitive deficits.
Asunto(s)
Trastornos del Conocimiento/dietoterapia , Trastornos del Conocimiento/tratamiento farmacológico , Memantina/uso terapéutico , Enfermedades Neurodegenerativas/dietoterapia , Enfermedades Neurodegenerativas/tratamiento farmacológico , Nootrópicos/uso terapéutico , Animales , Atrofia/dietoterapia , Atrofia/tratamiento farmacológico , Atrofia/patología , Atrofia/fisiopatología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Trastorno Depresivo , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Trastornos de la Memoria/dietoterapia , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/fisiopatología , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , Fármacos Neuroprotectores/uso terapéutico , Trastornos del Olfato/patología , Trastornos del Olfato/fisiopatología , Bulbo Olfatorio/fisiopatología , Agitación Psicomotora/dietoterapia , Agitación Psicomotora/tratamiento farmacológico , Agitación Psicomotora/patología , Agitación Psicomotora/fisiopatología , Ratas , Ratas Sprague-Dawley , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiología , Sulfato de ZincRESUMEN
Upon binding of cortisol, the glucocorticoid receptor (GR) regulates the transcription of specific target genes, including those that encode the stress hormones corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone. Dysregulation of the stress axis is a hallmark of major depression in human patients. However, it is still unclear how glucocorticoid signaling is linked to affective disorders. We identified an adult-viable zebrafish mutant in which the negative feedback on the stress response is disrupted, due to abolition of all transcriptional activity of GR. As a consequence, cortisol is elevated, but unable to signal through GR. When placed into an unfamiliar aquarium ('novel tank'), mutant fish become immobile ('freeze'), show reduced exploratory behavior and do not habituate to this stressor upon repeated exposure. Addition of the antidepressant fluoxetine to the holding water and social interactions restore normal behavior, followed by a delayed correction of cortisol levels. Fluoxetine does not affect the overall transcription of CRH, the mineralocorticoid receptor (MR), the serotonin transporter (Serta) or GR itself. Fluoxetine, however, suppresses the stress-induced upregulation of MR and Serta in both wild-type fish and mutants. Our studies show a conserved, protective function of glucocorticoid signaling in the regulation of emotional behavior and reveal novel molecular aspects of how chronic stress impacts vertebrate brain physiology and behavior. Importantly, the zebrafish model opens up the possibility of high-throughput drug screens in search of new classes of antidepressants.
Asunto(s)
Trastornos del Humor/genética , Mutación/genética , Receptores de Glucocorticoides/genética , Análisis de Varianza , Animales , Animales Modificados Genéticamente , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Arginina/genética , Encéfalo/metabolismo , Línea Celular Transformada , Chlorocebus aethiops , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Cisteína/genética , Diazepam/farmacología , Diazepam/uso terapéutico , Modelos Animales de Enfermedad , Reacción de Fuga/efectos de los fármacos , Reacción de Fuga/fisiología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Reacción Cataléptica de Congelación/fisiología , Antagonistas de Hormonas/farmacología , Humanos , Hidrocortisona/sangre , Relaciones Interpersonales , Mifepristona/farmacología , Trastornos del Humor/dietoterapia , Trastornos del Humor/metabolismo , Trastornos del Humor/patología , Agitación Psicomotora/genética , Agitación Psicomotora/patología , Radioinmunoensayo , Receptores de Glucocorticoides/metabolismo , Serotonina/genética , Serotonina/metabolismo , Transfección , Pez CebraRESUMEN
The senescence-accelerated mouse (SAM) strains were established through selective inbreeding of the AKR/J strain based on phenotypic variations of aging and consist of senescence-prone (SAMP) and senescence-resistant (SAMR) strains. Among them, SAMP8 is considered as a model of neurodegeneration displaying age-associated learning and memory impairment and altered emotional status. Because adult hypothyroidism is one of the common causes of cognitive impairment and various psychiatric disorders, we examined the possible involvement of thyroid hormone (TH) signaling in the pathological aging of SAMP8 using the senescence-resistant SAMR1 as control. Although plasma TH levels were similar in both strains, a significant decrease in type 2 deiodinase (D2) gene expression was observed in the SAMP8 hippocampus from 1 to 8 months of age, which led to a 35-50% reductions at the protein level and 20% reduction of its enzyme activity at 1, 3, and 5 months. D2 is responsible for local conversion of thyroxine into transcriptionally active 3,5,3'-triiodothyronine (T3), so the results suggest a reduction in T3 level in the SAMP8 hippocampus. Attenuation of local TH signaling was confirmed by downregulation of TH-dependent genes and by immunohistochemical demonstration of delayed and reduced accumulation of myelin basic protein, the expression of which is highly dependent on TH. Furthermore, we found that hyperactivity and reduced anxiety were not age-associated but were characteristic of young SAMP8 before they start showing impairments in learning and memory. Early alterations in local TH signaling may thus underlie behavioral abnormalities as well as the pathological aging of SAMP8.
Asunto(s)
Envejecimiento/genética , Hipocampo/metabolismo , Fibras Nerviosas Mielínicas/metabolismo , Agitación Psicomotora/metabolismo , Transducción de Señal/fisiología , Triyodotironina/metabolismo , Factores de Edad , Envejecimiento/patología , Animales , Reacción de Prevención/fisiología , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos ICR , Ratones Mutantes , Fibras Nerviosas Mielínicas/patología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Agitación Psicomotora/genética , Agitación Psicomotora/patología , Transducción de Señal/genética , Hormonas Tiroideas/metabolismo , Triyodotironina/genéticaRESUMEN
Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αß(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.
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Proteínas Adaptadoras Transductoras de Señales/genética , Trastorno Autístico/genética , Conducta Animal/fisiología , Proteínas del Tejido Nervioso/genética , Agitación Psicomotora/genética , Animales , Trastorno Autístico/patología , Espinas Dendríticas/genética , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Agitación Psicomotora/patología , Receptores Ionotrópicos de Glutamato/metabolismo , Sinapsis/metabolismo , Regulación hacia Arriba , Vocalización Animal/fisiologíaRESUMEN
INTRODUCTION: The early diagnosis of Alzheimer's disease is a new challenge. This study concerns 50 patients, 34 females (68 %) and 16 males (32 %) with Alzheimer (AD), according to NINCDS-ADRDA diagnostic criteria. OBJECTIVES: To systematically evaluate in all patients behavioral and psychological signs and symptoms of dementia (BPSSD), according to the stage of AD, with the patients of our population separated into two MMS groups. METHODS: The first group was composed of patients with an MMS score from 10 to 20 (eight males and 19 females). Patients of the second group had an MMS score between 21 and 28 (eight males and 19 females). The Neuro-Psychiatric Inventory (NPI) was used to collect information on the presence of BPSSD in AD patients. NPI scores were correlated to the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-Cog) that permits evaluation of the severity of cognitive impairment in AD patients. Before starting the study, all patients gave their informed consent to participate in the study of BPSSD in AD. Statistical treatment of data was performed using STATVIEW. RESULTS: Our study demonstrates that BPSSD are present not only in early but also in moderate stages of AD. As cognitive impairment, BPSSD are an integrate part of the clinical picture. With a frequency of 74 % for the whole population, "anxiety" represented the more predominant BPSSD for all our patients at all stages of AD. At the very early stages of AD, BPSSD appeared to precede cognitive disorders. CONCLUSION: The symptomatic association of "depression", "agitation", and "irritability of mood" may remain in a steady state for a few months before the appearance of verbal episodic memory impairment, which is characteristic of hippocampus involvement. "Irritability" seems to specifically characterise the initial phase of AD. On the other hand, two BPSSD are characteristic of the late stages of AD: "sleep disorder" and "hallucinations".
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Trastornos Mentales/diagnóstico , Trastornos Mentales/psicología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/clasificación , Enfermedad de Alzheimer/patología , Trastornos del Conocimiento/clasificación , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/psicología , Deluciones/clasificación , Deluciones/diagnóstico , Deluciones/patología , Deluciones/psicología , Trastorno Depresivo/clasificación , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/patología , Trastorno Depresivo/psicología , Progresión de la Enfermedad , Femenino , Lóbulo Frontal/patología , Alucinaciones/clasificación , Alucinaciones/diagnóstico , Alucinaciones/patología , Alucinaciones/psicología , Hipocampo/patología , Humanos , Genio Irritable , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/clasificación , Trastornos Mentales/patología , Escala del Estado Mental , Persona de Mediana Edad , Neocórtex/patología , Pruebas Neuropsicológicas/estadística & datos numéricos , Psicometría , Agitación Psicomotora/clasificación , Agitación Psicomotora/diagnóstico , Agitación Psicomotora/patología , Agitación Psicomotora/psicología , Trastornos del Sueño-Vigilia/clasificación , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/patología , Trastornos del Sueño-Vigilia/psicologíaRESUMEN
OBJECTIVE: The authors studied mood disorder and neurobehavioral correlates of solitary focal cerebellar (CB) lesions. BACKGROUND: CB function has been correlated with cognitive, behavioral, and psychiatric conditions. Systematic study of uncomplicated CB pathology can further our understanding of these correlates. METHOD: Magnetic Resonance Images were blindly selected from 20,000 scans for solitary focal CB lesions after excluding other pathology. "Secondary" conditions (developing after lesion onset) were determined using structured clinical interviews (DIS and SCID) for psychiatric diagnoses while blind to MRI findings. Clinical correlates of lesions and a priori hypotheses were examined in 13 participants while controlling for alternative attributions (atrophy, hyperintensities, ventriculomegaly, disability, etc.). RESULTS: Bipolar disorders after CB lesions were more common than expected in normal populations (OR 28.62, 95% CI 3.51 < - >233.34, P=0.0001), replicating a previous finding. Secondary DSM-III and -IV depressive disorders correlated with posterolateral lesions of the right CB posterior lobe (P=0.0035); severity correlated with lesion size. Other lesion correlates included hypomania (anterolateral left CB posterior lobe), apathy (medial left anterior lobe, anterolateral right posterior lobe), disinhibition and dysexecution (medial left anterior lobe), agitation (central left and anterolateral right posterior lobe), and elation (anterolateral right posterior lobe). Although other structural cerebral and psychosocial variables did not explain the findings, much larger sample sizes will be needed to adequately control for these variables. CONCLUSIONS: Review of the literature reveals support for these findings, suggesting CB control of mood, behavior, and frontal cognition.
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Síntomas Afectivos/fisiopatología , Enfermedades Cerebelosas/fisiopatología , Función Ejecutiva/fisiología , Trastornos del Humor/fisiopatología , Agitación Psicomotora/fisiopatología , Adulto , Síntomas Afectivos/complicaciones , Síntomas Afectivos/patología , Anciano , Anciano de 80 o más Años , Enfermedades Cerebelosas/complicaciones , Enfermedades Cerebelosas/patología , Femenino , Humanos , Inhibición Psicológica , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos del Humor/complicaciones , Agitación Psicomotora/complicaciones , Agitación Psicomotora/patología , Índice de Severidad de la EnfermedadRESUMEN
Delirium is a term used variously to characterize a change in behavior. Neurologists most often use the term to describe a patient who has acutely developed a hyperactive agitated state. In many patients, agitation and overactivity are explained by toxic and metabolic factors and infections. Lesions, especially strokes, in some brain regions have been reported to cause sudden agitation and a hyperactive state, often with an increased amount of speech output, the topics of which flit from one subject to another. Strokes and other lesions that involve the temporal lobes, fusiform and lingual gyri, caudate nucleus, and anterior cingulum have been reported to cause an acute hyperactive state similar to that found in patients with delirium tremens related to alcohol withdrawal.
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Encéfalo/patología , Delirio/patología , Neurología , Médicos , Agitación Psicomotora/patología , Infarto Cerebral/complicaciones , Infarto Cerebral/patología , Delirio/etiología , Humanos , Sistema Límbico/patología , Neurología/métodos , Agitación Psicomotora/etiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patología , Lóbulo Temporal/patologíaAsunto(s)
Dopamina/metabolismo , Neuronas/patología , Lóbulo Parietal/patología , Agitación Psicomotora/patología , Animales , Benserazida/farmacología , Núcleo Celular/química , Núcleo Celular/patología , Citoplasma/química , Citoplasma/patología , Dopaminérgicos/farmacología , Combinación de Medicamentos , Levodopa/farmacología , Neuronas/química , Neuronas/efectos de los fármacos , Lóbulo Parietal/química , Lóbulo Parietal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
BACKGROUND: We investigated structural brain morphology of intellectually disabled children with Williams (WS) syndrome and its relationship to the behavioural phenotype. METHODS: We compared the neuroanatomy of 15 children (mean age:13+/-2) with WS and 15 age/gender-matched healthy children using a manual region-of-interest analysis to measure bulk (white+grey) tissue volumes and unbiased fully-automated voxel-based morphometry to assess differences in grey/white matter throughout the brain. Ratings of abnormal behaviours were correlated with brain structure. RESULTS: Compared to controls, the brains of children with WS had a decreased volume of the right parieto-occipital regions and basal ganglia. We identified reductions of grey matter of the parieto-occipital regions, left putamen/globus pallidus and thalamus; and in white matter of the basal ganglia and right posterior cingulate gyrus. In contrast, significant increases of grey matter were identified in the frontal lobes, anterior cingulate gyrus, left temporal lobe, and of white matter bilaterally in the anterior cingulate. Inattention in WS was correlated with volumetric differences in the frontal lobes, caudate nucleus and cerebellum, and hyperactivity was related to differences in the left temporal and parietal lobes and cerebellum. Finally, ratings of peer problems were related to differences in the temporal lobes, right basal ganglia and frontal lobe. CONCLUSIONS: In one of the first studies of brain structure in intellectually disabled children with WS using voxel-based morphometry, our findings suggest that this group has specific differences in grey/white matter morphology. In addition, it was found that structural differences were correlated to ratings of inattention, hyperactivity and peer problems in children with WS.