RESUMO
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.
Assuntos
Microbioma Gastrointestinal , Locomoção , Comportamento Social , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores , Transplante de Microbiota Fecal , Fezes/microbiologia , Limosilactobacillus reuteri/metabolismo , Limosilactobacillus reuteri/fisiologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/microbiologia , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/terapia , Análise de Componente Principal , Agitação Psicomotora/patologia , Transmissão SinápticaRESUMO
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.
Assuntos
Giro Denteado/patologia , GTP Fosfo-Hidrolases/fisiologia , Células-Tronco Neurais/patologia , Neurogênese , Neurônios/patologia , Prosencéfalo/patologia , Agitação Psicomotora/patologia , Animais , Giro Denteado/metabolismo , Comportamento Exploratório , Feminino , Masculino , Camundongos , Camundongos Knockout , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Prosencéfalo/metabolismo , Agitação Psicomotora/etiologia , Agitação Psicomotora/metabolismoRESUMO
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.
Assuntos
Antipsicóticos/uso terapêutico , Delírio/tratamento farmacológico , Haloperidol/uso terapêutico , Neoplasias/complicações , Cuidados Paliativos , Agitação Psicomotora/tratamento farmacológico , Idoso , Delírio/etiologia , Delírio/patologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/psicologia , Neoplasias/terapia , Prognóstico , Agitação Psicomotora/etiologia , Agitação Psicomotora/patologiaRESUMO
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.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Adolescente , Adulto , Atenção/fisiologia , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Agitação Psicomotora/diagnóstico por imagem , Agitação Psicomotora/patologia , Adulto JovemRESUMO
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.
Assuntos
Transtorno Autístico/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Mutação , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Agitação Psicomotora/genética , Sinapses/metabolismo , Adulto , Animais , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Criança , Feminino , Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/deficiência , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Neurogênese , Neurônios/patologia , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/deficiência , Agitação Psicomotora/metabolismo , Agitação Psicomotora/patologia , Ratos , Análise de Sequência de DNA , Índice de Gravidade de Doença , Sinapses/patologiaRESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Transtorno Autístico/genética , Comportamento Animal/fisiologia , Proteínas do Tecido Nervoso/genética , Agitação Psicomotora/genética , Animais , Transtorno Autístico/patologia , Espinhas Dendríticas/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Agitação Psicomotora/patologia , Receptores Ionotrópicos de Glutamato/metabolismo , Sinapses/metabolismo , Regulação para Cima , Vocalização Animal/fisiologiaRESUMO
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.
Assuntos
Transtornos do Humor/genética , Mutação/genética , Receptores de Glucocorticoides/genética , Análise de Variância , Animais , Animais Geneticamente Modificados , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Arginina/genética , Encéfalo/metabolismo , Linhagem Celular Transformada , Chlorocebus aethiops , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Cisteína/genética , Diazepam/farmacologia , Diazepam/uso terapêutico , Modelos Animais de Doenças , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Reação de Congelamento Cataléptica/fisiologia , Antagonistas de Hormônios/farmacologia , Humanos , Hidrocortisona/sangue , Relações Interpessoais , Mifepristona/farmacologia , Transtornos do Humor/dietoterapia , Transtornos do Humor/metabolismo , Transtornos do Humor/patologia , Agitação Psicomotora/genética , Agitação Psicomotora/patologia , Radioimunoensaio , Receptores de Glucocorticoides/metabolismo , Serotonina/genética , Serotonina/metabolismo , Transfecção , Peixe-ZebraRESUMO
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.
Assuntos
Envelhecimento/genética , Hipocampo/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Agitação Psicomotora/metabolismo , Transdução de Sinais/fisiologia , Tri-Iodotironina/metabolismo , Fatores Etários , Envelhecimento/patologia , Animais , Aprendizagem da Esquiva/fisiologia , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos ICR , Camundongos Mutantes , Fibras Nervosas Mielinizadas/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Agitação Psicomotora/genética , Agitação Psicomotora/patologia , Transdução de Sinais/genética , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/genéticaRESUMO
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.
Assuntos
Sintomas Afetivos/fisiopatologia , Doenças Cerebelares/fisiopatologia , Função Executiva/fisiologia , Transtornos do Humor/fisiopatologia , Agitação Psicomotora/fisiopatologia , Adulto , Sintomas Afetivos/complicações , Sintomas Afetivos/patologia , Idoso , Idoso de 80 Anos ou mais , Doenças Cerebelares/complicações , Doenças Cerebelares/patologia , Feminino , Humanos , Inibição Psicológica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Agitação Psicomotora/complicações , Agitação Psicomotora/patologia , Índice de Gravidade de DoençaRESUMO
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".
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/classificação , Doença de Alzheimer/patologia , Transtornos Cognitivos/classificação , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Delusões/classificação , Delusões/diagnóstico , Delusões/patologia , Delusões/psicologia , Transtorno Depressivo/classificação , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/patologia , Transtorno Depressivo/psicologia , Progressão da Doença , Feminino , Lobo Frontal/patologia , Alucinações/classificação , Alucinações/diagnóstico , Alucinações/patologia , Alucinações/psicologia , Hipocampo/patologia , Humanos , Humor Irritável , Imageamento por Ressonância Magnética , Masculino , Transtornos Mentais/classificação , Transtornos Mentais/patologia , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Neocórtex/patologia , Testes Neuropsicológicos/estatística & dados numéricos , Psicometria , Agitação Psicomotora/classificação , Agitação Psicomotora/diagnóstico , Agitação Psicomotora/patologia , Agitação Psicomotora/psicologia , Transtornos do Sono-Vigília/classificação , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/patologia , Transtornos do Sono-Vigília/psicologiaRESUMO
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.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Agitação Psicomotora/metabolismo , Sinapses/metabolismo , Animais , Neurônios Dopaminérgicos/patologia , Potenciais Pós-Sinápticos Excitadores , Feminino , Humanos , Potenciais Pós-Sinápticos Inibidores , Proteínas com Homeodomínio LIM/metabolismo , Camundongos , Camundongos Knockout , Gravidez , Cultura Primária de Células , Agitação Psicomotora/patologia , Sinapses/patologia , Fatores de Transcrição/metabolismo , TransfecçãoRESUMO
Alzheimer's disease research has largely concentrated on the study of cognitive decline, but the associated behavioural and neuropsychiatric symptoms are of equal importance in the clinical profile of the disease. There is emerging evidence that regional differences in brain atrophy may align with variant disease presentations. The objective of this study was to identify the regions of decreased grey matter (GM) volume which were associated with specific neuropsychiatric behaviours in patients with mild Alzheimer's disease. Voxel-based morphometry was used to correlate GM derived from T(1)-weighted MRI images of 31 patients with mild Alzheimer's disease and specific neuropsychiatric symptoms and behaviours measured by the Neuropsychiatric Inventory. Delusions were associated with decreased GM density in the left frontal lobe, in the right frontoparietal cortex and in the left claustrum. Apathy was associated with GM density loss in the anterior cingulate and frontal cortex bilaterally, the head of the left caudate nucleus and in bilateral putamen. Agitation was associated with decreased GM values in the left insula, and in anterior cingulate cortex bilaterally. Neuropsychiatric symptoms of Alzheimer's disease seem to associate with neurodegeneration of specific neural networks supporting personal memory, reality monitoring, processing of reward, interoceptive sensations and subjective emotional experience. The study of neurodegenerative disorders such as Alzheimer's disease using voxel-based morphometry and other imaging modalities may further the understanding of the neural structures that mediate the genesis of abnormal behaviours.
Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Encéfalo/patologia , Idoso , Idoso de 80 Anos ou mais , Atrofia/patologia , Mapeamento Encefálico/métodos , Delusões/etiologia , Delusões/patologia , Feminino , Humanos , Letargia/etiologia , Letargia/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Agitação Psicomotora/etiologia , Agitação Psicomotora/patologiaRESUMO
Although previous studies have reported a role for phosphoinositide-3 kinase (PI3K) in axonal definition and growth in vitro, it is not clear whether PI3K regulates axonal formation and synaptogenesis in vivo. The goal of the present study was to clarify the role of PI3K in behavioral functions and some underlying neuroanatomical structures. Immunohistochemistry, an electron-microscopic analysis and behavioral tests were carried out. Knockout mice lacking the p85alpha regulatory subunit of PI3K (p85alpha-/- mice) significantly showed learning deficits, restlessness and motivation deficit. Expression of phosphorylated Akt, which indirectly shows the activity of PI3K, was high in myelinated axons, especially in axonal bundles in the striatum of wild-type mice, but was significantly low in the striatum, cerebral cortex and the hippocampal CA3 of p85alpha-/- mice. The axonal marker protein level decreased mainly in the striatum and cerebral cortex of p85alpha-/- mice. In these two regions, myelinated axons are rich in the wild-type mice. However, the density of myelinated axons and myelin thickness were significantly low in the striatum and cerebral cortex of p85alpha-/- mice. Synaptic protein level was clearly decreased in the striatum, cerebral cortex, and hippocampus of p85alpha-/- mice when compared with wild mice. The present results suggest that PI3K plays a role in the generation and/or maintenance of synapses and myelinated axons in the brain and that deficiencies in PI3K activity result in abnormalities in several neuronal functions, including learning, restlessness and motivation.
Assuntos
Axônios/ultraestrutura , Encéfalo/enzimologia , Deficiências da Aprendizagem/enzimologia , Bainha de Mielina/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Agitação Psicomotora/enzimologia , Sinapses/ultraestrutura , Animais , Encéfalo/patologia , Feminino , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/patologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Motivação , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/deficiência , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Agitação Psicomotora/genética , Agitação Psicomotora/patologia , Organismos Livres de Patógenos Específicos , NataçãoRESUMO
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.
Assuntos
Eletrocoagulação/efeitos adversos , Hipercinese/tratamento farmacológico , Cloreto de Lítio/administração & dosagem , Agitação Psicomotora/tratamento farmacológico , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/patologia , Animais , Ansiolíticos/administração & dosagem , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Ansiedade/psicologia , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/patologia , Transtornos de Ansiedade/psicologia , Eletrocoagulação/métodos , Hipercinese/patologia , Hipercinese/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Agitação Psicomotora/patologia , Agitação Psicomotora/psicologia , Comportamento Estereotipado/efeitos dos fármacos , Resultado do TratamentoRESUMO
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.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Córtex Auditivo/fisiopatologia , Cerebelo/fisiopatologia , Hipocampo/fisiopatologia , Hiperacusia/fisiopatologia , Formação Reticular/fisiopatologia , Zumbido/fisiopatologia , Tonsila do Cerebelo/patologia , Animais , Córtex Auditivo/patologia , Mapeamento Encefálico , Cerebelo/patologia , Cóclea/patologia , Cóclea/fisiopatologia , Modelos Animais de Doenças , Corpos Geniculados/patologia , Corpos Geniculados/fisiopatologia , Hipocampo/patologia , Humanos , Hiperacusia/induzido quimicamente , Hiperacusia/patologia , Colículos Inferiores/patologia , Colículos Inferiores/fisiopatologia , Imageamento por Ressonância Magnética , Modelos Psicológicos , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Agitação Psicomotora/patologia , Agitação Psicomotora/fisiopatologia , Ratos , Ratos Sprague-Dawley , Formação Reticular/patologia , Ácido Salicílico , Zumbido/induzido quimicamente , Zumbido/patologiaRESUMO
Four patients presented with hemiballism-hemichorea as a clinical manifestation of white matter ischemia. These patients illustrate "positive" motor phenomena rather than limb weakness as a consequence of cerebral ischemia. In each patient, the involuntary movements disappeared following worsening of paresis. Subcortical white matter infarction in three patients and hemodynamic hypo-perfusion in the cerebral hemisphere contralateral to dyskinetic movements were possible causes. Neuroradiologically, none had pathological changes in the vicinity of the subthalamic nucleus. We presume from these observations that ischemia of the subcortical white matter, without involvement of the basal ganglia or the subthalamic nucleus, may cause hemiballism-hemichorea.
Assuntos
Isquemia Encefálica/complicações , Coreia/etiologia , Agitação Psicomotora/etiologia , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Infarto Cerebral/patologia , Coreia/diagnóstico por imagem , Coreia/patologia , Feminino , Lateralidade Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Agitação Psicomotora/diagnóstico por imagem , Agitação Psicomotora/patologia , Tomografia Computadorizada por Raios XRESUMO
Rats with intrahippocampal lesions produced by infusion of colchicine showed an impairment of learning ability and a decrease in local choline acetyl-transferase activity. In addition, these rats showed bizarre excitable behavior from 3 days after infusion for about an average of 10 days. This included daytime arousal, and easy jumping and squeak reactions against external stimuli as compared to the sham-operated control rats. Moreover, three-dimensional behavioral analysis disclosed: (i) the lesioned rats showed an increase ambulation compared to the control rats, (ii) a more centrally oriented sequence of wandering, while the control rats tended to display peripheral movement around the wall of the test cage, and (iii) they showed a decrease movement associated with rearing compared to the control rats. Neuropathologically, pyramidal neurons and fascia dentata of the lesioned hippocampus showed degeneration from 3 days with a marked astrocytic reaction. In addition, transient over expression of synaptophysin-immunoreactive material was seen in early stage of degeneration and this corresponded ultrastructurally to the presence of swollen synaptic boutons containing numerous non-core synaptic vesicles. These findings appeared to represent in part an abnormal excitement seen in patients with organic brain lesions, in which the excitement has been considered to correspond with neuronal death. Thus, the hippocampus-lesioned rats may provide an animal model to analyse the abnormal behaviors associated with neuronal death.
Assuntos
Comportamento Animal , Hipocampo/patologia , Atividade Motora , Acatisia Induzida por Medicamentos , Animais , Colina O-Acetiltransferase/deficiência , Ritmo Circadiano , Colchicina , Emoções , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Masculino , Microscopia Eletrônica , Degeneração Neural , Agitação Psicomotora/patologia , Agitação Psicomotora/psicologia , Ratos , Ratos Endogâmicos F344RESUMO
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.
Assuntos
Substância Cinzenta/patologia , Neurodegeneração Associada a Pantotenato-Quinase/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Agitação Psicomotora/patologia , Adolescente , Adulto , Fatores Etários , Cerebelo/patologia , Criança , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Neurodegeneração Associada a Pantotenato-Quinase/enzimologia , Neurodegeneração Associada a Pantotenato-Quinase/fisiopatologia , Agitação Psicomotora/fisiopatologia , Adulto JovemRESUMO
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.
Assuntos
Fígado Gorduroso/etiologia , Agitação Psicomotora/etiologia , Fibrose Pulmonar/etiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Biomarcadores/urina , Pré-Escolar , Colágeno/biossíntese , Fígado Gorduroso/patologia , Fígado Gorduroso/urina , Humanos , Lactente , Fígado/patologia , Pulmão/patologia , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Nitrosaminas/urina , Hepatopatia Gordurosa não Alcoólica , Agitação Psicomotora/patologia , Agitação Psicomotora/urina , Fibrose Pulmonar/patologia , Fibrose Pulmonar/urina , Piridinas/urina , Pele/patologia , CicatrizaçãoRESUMO
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.