RESUMO
In Alzheimer's disease (AD), characterized by cognitive deterioration, synaptic alterations are frequently reported. The TgCRND8 model, in which mice develop AD-like amyloid ß plaque formation, has been used to investigate the effects of amyloidosis on synaptic function. Background strain impacts the behavioral and neuropathological phenotype of mice in this model, but whether this extends to synaptic function is unknown. We investigated the influence of background strain on basal synaptic transmission and long-term potentiation (LTP) in the hippocampus of TgCRND8 mice (13-16â¯months) on hybrid backgrounds of (129SvEv/Tac) x (C3H/C57/129SvEv/Tac) (aka "129") or (C57) x (C3H/C57) (aka "C3H"). In littermate controls, basal synaptic transmission was significantly reduced, whereas the amplitude of excitatory postsynaptic potentials was significantly higher after LTP induction in 129 vs. C3H mice. In 129 TgCRND8 mice, deficits in hippocampal LTP were more severe than in C3H TgCRND8 relative to controls. Compared to controls, network excitability was decreased in transgenics from both strains. These data suggest that 129 TgCRND8 mice are the more appropriate model to evaluate the efficacy of potential AD treatments on synaptic function, owing to their significant deficit in LTP. Such studies are critical in order to improve the translational capacity of basic science research.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/fisiologia , Camundongos , Transmissão Sináptica/fisiologiaRESUMO
Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. Although neurofibrillary tangles and amyloid beta are classic hallmarks of AD, the earliest deficits in AD progression may be caused by unknown factors. One suspected factor has to do with brain energy metabolism. To investigate this factor, brain metabolic activity in 3xTg-AD mice and age-matched controls were measured with FDG-PET. Significant hypometabolic changes (pâ¯<â¯.01) in brain metabolism were detected in the cortical piriform and insular regions of AD brains relative to controls. These regions are associated with olfaction, which is a potential clinical marker for AD progression as well as neurogenesis. The activity of the terminal component of the mitochondrial respiratory chain (complex IV) and the expression of complex I-V were significantly decreased (pâ¯<â¯.05), suggesting that impaired metabolic activity coupled with impaired oxidative phosphorylation leads to decreased mitochondrial bioenergetics and subsequent Neurodegeneration. Although there is an association between neuroinflammatory pathological markers (microglial) and hypometabolism in AD, there was no association found between neuropathological (Aß, tau, and astrocytes) and functional changes in AD sensitive brain regions, also suggesting that brain hypometabolism occurs prior to AD pathology. Therefore, targeting metabolic mechanisms in cortical piriform and insular regions at early stages may be a promising approach for preventing, slowing, and/or blocking the onset of AD and preserving neurogenesis.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Mitocôndrias/metabolismo , Emaranhados Neurofibrilares/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Fosforilação Oxidativa , Proteínas tau/metabolismoRESUMO
The brain has a high demand for energy, of which creatine (Cr) is an important regulator. Studies document neurocognitive benefits of oral Cr in mammals, yet little is known regarding their physiological basis. This study investigated the effects of Cr supplementation (3%, w/w) on hippocampal function in male C57BL/6 mice, including spatial learning and memory in the Morris water maze and oxygen consumption rates from isolated mitochondria in real time. Levels of transcription factors and related proteins (CREB, Egr1, and IκB to indicate NF-κB activity), proteins implicated in cognition (CaMKII, PSD-95, and Egr2), and mitochondrial proteins (electron transport chain Complex I, mitochondrial fission protein Drp1) were probed with Western blotting. Dietary Cr decreased escape latency/time to locate the platform (P < 0.05) and increased the time spent in the target quadrant (P < 0.01) in the Morris water maze. This was accompanied by increased coupled respiration (P < 0.05) in isolated hippocampal mitochondria. Protein levels of CaMKII, PSD-95, and Complex 1 were increased in Cr-fed mice, whereas IκB was decreased. These data demonstrate that dietary supplementation with Cr can improve learning, memory, and mitochondrial function and have important implications for the treatment of diseases affecting memory and energy homeostasis.
Assuntos
Creatina/administração & dosagem , Suplementos Nutricionais , Hipocampo/metabolismo , Mitocôndrias/metabolismo , Memória Espacial/fisiologia , Animais , Metabolismo Energético , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Plasticidade Neuronal/fisiologia , Oxigênio/metabolismo , Distribuição AleatóriaRESUMO
Cerebellar subregions are recognized as having specialized roles, with lateral cerebellum considered crucial for cognitive processing, whereas vermal cerebellum is more strongly associated with motor control. In human Duchenne muscular dystrophy, loss of the cytoskeletal protein dystrophin is thought to cause impairments in cognition, including learning and memory. Previous studies demonstrate that loss of dystrophin causes dysfunctional signaling at γ-aminobutyric acid (GABA) synapses on Purkinje neurons, presumably by destabilization of GABAA receptors. However, potential differences in the intrinsic electrophysiological properties of Purkinje neurons, including membrane potential and action potential firing rates, have not been investigated. Here, using a 2×2 analysis of variance (ANOVA) experimental design, we employed patch clamp analysis to compare membrane properties and action potentials generated by acutely dissociated Purkinje neurons from vermal and lateral cerebellum in wild-type (WT) mice and mdx dystrophin-deficient mice. Compared to Purkinje neurons from WT mice, neurons from mdx mice exhibited more irregular action potential firing and a hyperpolarization of the membrane potential. Firing frequency was also lower in Purkinje neurons from the lateral cerebellum of mdx mice relative to those from WT mice. Several action potential waveform parameters differed between vermal and lateral Purkinje neurons, irrespective of dystrophin status, including action potential amplitude, slope (both larger in the vermal region), and duration (shorter in the vermal region). Moreover, the membrane potential of Purkinje neurons from the vermal region of WT mice exhibited a significant hyperpolarization and concurrent reduction in the frequency of spontaneous action potentials compared to Purkinje neurons from the lateral region. This regional hyperpolarization and reduction in spontaneous action potential frequency was abolished in mdx mice. These results from mice demonstrate the presence of differential electrophysiological properties between Purkinje neurons from different regions of the WT mouse cerebellum and altered intrinsic membrane properties in the absence of dystrophin. These findings provide a possible mechanism for the observations that absence of cerebellar dystrophin contributes to deficits in mental function observed in humans and mouse models of muscular dystrophy. Moreover, these results highlight the importance of distinguishing functional zones of the cerebellum in future work characterizing Purkinje neuron electrophysiology and studies using the model of dissociated Purkinje neurons from mice.
Assuntos
Cerebelo/fisiologia , Distrofina/fisiologia , Células de Purkinje/fisiologia , Potenciais de Ação/fisiologia , Análise de Variância , Animais , Distrofina/genética , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdxRESUMO
BACKGROUND: Loss of dystrophin profoundly affects muscle function and cognition. Changes in the dystrophin-glycoprotein complex (DGC) including disruption of nitric oxide synthase (NOS-1) may result from loss of dystrophin or secondarily after muscle damage. Disruptions in NOS-1 and beta-dystroglycan (bDG) were examined in developing diaphragm, quadriceps, and two brain regions between control and mdx mice at embryonic day E18 and postnatal days P1, P10, and P28. Age-dependent differential muscle loading allowed us to test the hypothesis that DGC changes are dependent on muscle use. RESULTS: Muscle development, including loss of central nucleation and the localization of NOS-1 and bDG, was earlier in diaphragm than quadriceps; these features were differentially disrupted in dystrophic muscles. The NOS-1/bDG ratio, an index of DGC stability, was higher in dystrophic diaphragm (P10-P28) and quadriceps (P28) than controls. There were also distinct regional differences in NOS-1 and bDG in brain tissues with age and strain. NOS-1 increased with age in control forebrain and cerebellum, and in mdx cerebellum; NOS-1 and bDG were higher in control than mdx mouse forebrain. CONCLUSIONS: Important developmental changes in structure and muscle DGC preceded the hallmarks of dystrophy, and are consistent with the impact of muscle-specific differential loading during maturation.
Assuntos
Encéfalo/metabolismo , Diafragma/metabolismo , Distroglicanas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Distrofias Musculares/fisiopatologia , Óxido Nítrico Sintase Tipo I/metabolismo , Músculo Quadríceps/metabolismo , Fatores Etários , Análise de Variância , Animais , Encéfalo/crescimento & desenvolvimento , Citoesqueleto/metabolismo , Diafragma/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Técnicas Histológicas , Camundongos , Camundongos Endogâmicos mdx , Músculo Quadríceps/crescimento & desenvolvimentoRESUMO
Dystrophin, present in muscle, also resides in the brain, including cerebellar Purkinje neurons. The cerebellum, although historically associated with motor abilities, is also implicated in cognition. An absence of brain dystrophin in Duchenne muscular dystrophy (DMD) and in the mdx mouse model results in cognitive impairments. Localization studies of cerebellar dystrophin, however, have focused on the vermal cerebellum, associated with motor function, and have not investigated dystrophin distribution in the lateral cerebellum, considered to mediate cognitive function. The present study examined dystrophin localization in vermal and lateral cerebellar regions and across subcellular areas of Purkinje neurons in the mouse using immunohistochemistry. In both vermal and lateral cerebellum, dystrophin was restricted to puncta on somatic and dendritic membranes of Purkinje neurons. The density of dystrophin puncta was greater in the lateral than the vermal region. Neither the size of puncta nor the area of Purkinje neuron somata differed between regions. Results support the view that cognitive deficits in the DMD and the mdx model may be mediated by the loss of dystrophin, particularly in the lateral cerebellum. Findings have important implications for future studies examining the neurophysiological sequelae of neuronal dystrophin deficiency and the role of the lateral cerebellum in cognition.
Assuntos
Cerebelo/metabolismo , Distrofina/metabolismo , Animais , Crioultramicrotomia , Imunofluorescência , Camundongos , Camundongos Endogâmicos C57BL , Células de Purkinje/metabolismoRESUMO
Purpose: This mixed-methods systematic review synthesized findings from studies published between January 1, 2006 and July 31, 2018 on the social inclusion experiences of children with and without disabilities, as viewed from their own perspective, with a focus on how typically developing peers promote social inclusion.Method: Forty-five studies met the inclusion criteria. Data from included studies were synthesized by means of content analysis.Results: The findings detail the inner social inclusion experiences (e.g., feeling included, different) of children with disabilities and provide information regarding the influence of disability type (e.g., physical, social, affective) on typically developing peers' responses (e.g., acceptance vs. rejection), peers' explanations for social inclusion/exclusion, and peers' relationships with children with disabilities. Barriers to social inclusion, supports, as well as strategies used to promote social inclusion, as perceived by peers and children with disabilities, are also reported.Conclusion: The findings of this review provide evidence that despite society's efforts to promote social inclusion, children with disabilities continue to report feeling lonely and excluded, having limited contact socially outside of home, and encountering systemic barriers (e.g., bullying, discrimination). More research on the social inclusion experiences of children with disabilities beyond educational settings is needed, such as in the contexts of recreation and leisure, community, and employment.Implications for rehabilitationThe perspectives of children with and without disabilities need to be integrated in activities and programs aimed at promoting social inclusion.Teaching social inclusion strategies to children with and without disabilities is needed to help them deal with barriers.In addition to educational settings, rehabilitation clinicians need to promote social inclusion strategies in other contexts such as recreation and leisure, community, and employment contexts.
Assuntos
Crianças com Deficiência , Criança , Emprego , Humanos , Grupo Associado , Distância Psicológica , Inclusão SocialRESUMO
Alzheimer's disease (AD) is a major public health concern worldwide. Advanced age and female sex are two of the most prominent risk factors for AD. AD is characterized by progressive neuronal loss, especially in the cortex and hippocampus, and mitochondrial dysfunction has been proposed to be an early event in the onset and progression of the disease. Our results showed early perturbations in mitochondrial function in 3xTg mouse brain, with the cortex being more susceptible to mitochondrial changes than the hippocampus. In the cortex of 3xTg females, decreased coupled and uncoupled respiration were evident early (at 2 months of age), while in males it appeared later at 6 months of age. We observed increased coupled respiration in the hippocampus of 2-month-old 3xTg females, but no changes were detected later in life. Changes in mitochondrial dynamics were indicated by decreased mitofusin (Mfn2) and increased dynamin related protein 1 (Drp1) (only in females) in the hippocampus and cortex of 3xTg mice. Our findings highlight the importance of controlling and accounting for sex, brain region, and age in studies examining brain bioenergetics using this common AD model in order to more accurately evaluate potential therapies and improve the sex-specific translatability of preclinical findings.
Assuntos
Doença de Alzheimer/genética , Encéfalo/patologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/imunologia , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos TransgênicosRESUMO
The creatine (Cr) energy system has been implicated in Alzheimer's disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8-9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enhancements with Cr supplementation in both sexes. In females, Cr supplementation increased CREB phosphorylation and levels of IκB (NF-κB suppressor), CaMKII, PSD-95, and high-molecular-weight amyloid ß (Aß) species, whereas Aß trimers were reduced. These data suggest a beneficial preventative effect of Cr supplementation in females and warrant caution against Cr supplementation in males in the AD-like brain.
Assuntos
Doença de Alzheimer/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Creatina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Memória Espacial/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Animais , Comportamento Animal/fisiologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Fatores Sexuais , Memória Espacial/fisiologiaRESUMO
BACKGROUND: research has reliably demonstrated cardioprotection from regular alcohol use. Heavy episodic drinking (HED), however, negates these beneficial effects and increases the risk of cardiovascular disease (CVD). The impact of age on the health effects of episodic drinking has not been evaluated. OBJECTIVE: to examine the association between alcohol volume and pattern of consumption on the risk of cardiovascular morbidity and mortality across the lifespan. DESIGN AND SETTING: prospective, community-based cohort study of adults in Winnipeg, Manitoba, Canada. SUBJECTS: a total of 1,154 participants (580 men and 574 women) aged 18-64 surveyed at baseline (1990-91) on alcohol consumption levels and pattern of use. METHODS: usual alcohol consumption was measured using a quantity-frequency approach. HED was estimated by asking participants how often they consumed eight or more drinks in one sitting in the past year. Questions were asked separately for wine, beer and spirits. Surveillance for cardiovascular events was conducted for 10 years (i.e. up to age 74 years). Diagnoses of CVD were obtained via health utilization records. Cox proportional hazard models were derived for both genders and for 'young adults' (baseline age 18-34), 'middle-aged adults' (baseline age 35-49) and 'older adults' (baseline 50-64). Models were adjusted for marital status, cigarette smoking status and educational level. RESULTS: Reduced risk of CVD was associated with usual consumption, whereas an increased risk was associated with HED. Among male usual drinkers, cardioprotection was afforded only to middle and older age groups. The benefits of regular consumption were seen only in the youngest age group among women. The heaviest usual consumption category was associated with a decreased risk of CVD in men. Heavy episodic drinking increased the risk of coronary heart disease in middle-aged men and was marginally significant in middle-aged women. Risk of hypertension was elevated in older men with heavy episodic drinking. CONCLUSIONS: The well-established relationship between regular alcohol consumption and decreased risk of CVD may not become evident until middle age or older in men. Women may benefit from usual consumption at a much younger age. In both sexes, however, these beneficial effects of alcohol use are negated when alcohol is consumed in a heavy episodic drinking pattern, particularly for middle-aged and older men.
Assuntos
Consumo de Bebidas Alcoólicas/mortalidade , Doença das Coronárias/mortalidade , Hipertensão/mortalidade , Adolescente , Adulto , Distribuição por Idade , Envelhecimento , Estudos de Coortes , Doença das Coronárias/prevenção & controle , Coleta de Dados , Feminino , Humanos , Hipertensão/prevenção & controle , Masculino , Manitoba/epidemiologia , Pessoa de Meia-Idade , Morbidade , Fatores de Risco , Distribuição por Sexo , Adulto JovemRESUMO
Autism occurs in 1 in 1,000 children and incidence may be increasing. Investigating brain development and developmental injury in humans is difficult. As such, many studies rely on animal models of disorders. We chose to investigate the valproic acid-exposed rat, as this model shares many similarities with autism. Pregnant Long-Evans rats were administered either valproic acid (VPA) or saline during fetal neural tube development. Morphological analyses of cells in layer II of the golgi impregnated motor cortex were done to determine dendritic length, volume, and complexity in both groups. No differences were found in length or volume of cortical dendrites, but dendritic arborization was more complex in apical dendrites of pyramidal cells in VPA-exposed animals than controls. The implication of this finding is that pruning in the VPA-exposed rat is not occurring, which is consistent with theories related to abnormal human brain development in autism.
Assuntos
Transtorno Autístico/patologia , Modelos Animais de Doenças , Córtex Motor/patologia , Neurônios/patologia , Fatores Etários , Animais , Transtorno Autístico/induzido quimicamente , Dendritos/efeitos dos fármacos , Dendritos/patologia , Feminino , Masculino , Córtex Motor/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Gravidez , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , Ratos , Ratos Long-Evans , Ácido ValproicoRESUMO
Participant attrition and attendance at follow-up were examined in a multicenter, randomized, clinical trial. The Lung Health Study (LHS) enrolled a total of 5887 adults to examine the impact of smoking cessation coupled with the use of an inhaled bronchodilator on chronic obstructive pulmonary disease (COPD). Of the initial LHS 1 volunteers still living at the time of enrolment in LHS 3 (5332), 4457 (84%) attended the LHS 3 clinic visit, a follow-up session to determine current smoking status and lung function. The average period between the beginning of LHS 1 and baseline interview for LHS 3 was 11 years. In univariate analyses, attenders were older, more likely female, more likely to be married, smoked fewer cigarettes per day, and were more likely to have children who smoked at the start of LHS 1 than non-attenders. Attenders were also less likely to experience respiratory symptoms, such as cough, but had decreased baseline lung function compared with non-attenders. Volunteers recruited via mass mailing were more likely to attend the long-term follow-up visit. Those recruited by public site, worksite, or referral methods were less likely to attend. In multivariate models, age, gender, cigarettes smoked per day, married status, and whether participants' children smoked were identified as significant predictors of attendance versus non-attendance at LHS 3 using stepwise logistic regression. Treatment condition (smoking intervention or usual care) was not a significant predictor of attendance at LHS 3. Older females who smoked less heavily were most likely to participate. These findings may be applied to improve participant recruitment and retention in future clinical trials.
Assuntos
Ensaios Clínicos como Assunto/métodos , Pneumopatias Obstrutivas/prevenção & controle , Cooperação do Paciente/estatística & dados numéricos , Projetos de Pesquisa , Abandono do Hábito de Fumar , Adulto , Idoso , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Casamento/estatística & dados numéricos , Pessoa de Meia-Idade , Razão de Chances , Fumar/epidemiologiaRESUMO
A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-ß (Aß) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both Aß plaques and neurofibrillary tangles. Mean diffusivity did not differ between 3xTg and control mice in any region. Decreased fractional anisotropy (pâ<â0.01) and axial diffusivity (pâ<â0.05) were detected only in the hippocampus, in which both congophilic Aß plaques and hyperphosphorylated tau accumulation, consistent with neurofibrillary tangle formation, were detected. Pathological tau accumulation was seen in the cortex. The entorhinal cortex was largely spared from AD-related neuropathology. This is the first study to demonstrate DTI abnormalities in gray matter in a mouse model of AD in which both pathological hallmarks are present, suggesting the feasibility of DTI as a non-invasive means of detecting brain pathology in vivo in early-stage AD.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Imagem de Tensor de Difusão , Substância Cinzenta/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Emaranhados Neurofibrilares , Placa Amiloide/diagnóstico por imagemRESUMO
Alzheimer's disease (AD) is the most common late onset neurodegenerative disorder with indications that women are disproportionately affected. Mitochondrial dysfunction has been one of the most discussed hypotheses associated with the early onset and progression of AD, and it has been attributed to intraneuronal accumulation of amyloid ß (Aß). It was suggested that one of the possible mediators for Aß-impaired mitochondrial function is the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays important roles in brain inflammation and antioxidant defense, as well as in the regulation of mitochondrial function, and studies have confirmed altered NF-κB signaling in AD brain. In this study, we looked for sex-based differences in impaired bioenergetic processes and NF-κB signaling in the AD-like brain using transgenic (Tg) CRND8 mice that express excessive brain Aß, but without tau pathology. Our results show that mitochondrial dysfunction is not uniform in affected brain regions. We observed increased basal and coupled respiration in the hippocampus of TgCRND8 females only, along with a decreased Complex II-dependent respiratory activity. Cortical mitochondria from TgCRND8 mice have reduced uncoupled respiration capacity, regardless of sex. The pattern of changes in NF-κB signaling was the same in both brain structures, but was sex specific. Whereas in females there was an increase in all three subunits of NF-κB, in males we observed increase in p65 and p105, but no changes in p50 levels. These results demonstrate that mitochondrial function and inflammatory signaling in the AD-like brain is region- and sex-specific, which is an important consideration for therapeutic strategies.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/patologia , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Caracteres Sexuais , Transdução de Sinais/genéticaRESUMO
Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.
RESUMO
Research has identified several transcription factors that regulate activity-dependent plasticity and memory, with cAMP-response element binding protein (CREB) being the most well-studied. In neurons, CREB activation is influenced by the transcription factor nuclear factor kappa B (NF-κB), considered central to immunity but more recently implicated in memory. The transcription factor early growth response-2 (Egr-2), an NF-κB gene target, is also associated with learning and memory. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an antioxidant transcription factor linked to NF-κB in pathological conditions, has not been studied in normal memory. Given that numerous transcription factors implicated in activity-dependent plasticity demonstrate connections to NF-κB, this study simultaneously evaluated protein levels of NF-κB, CREB, Egr-2, Nrf2, and actin in hippocampi from young (1 month-old) weanling CD1 mice after training in the Morris water maze, a hippocampal-dependent spatial memory task. After a 6-day acquisition period, time to locate the hidden platform decreased in the Morris water maze. Mice spent more time in the target vs. non-target quadrants of the maze, suggestive of recall of the platform location. Western blot data revealed a decrease in NF-κB p50 protein after training relative to controls, whereas NF-κB p65, Nrf2 and actin increased. Nrf2 levels were correlated with platform crosses in nearly all tested animals. These data demonstrate that training in a spatial memory task results in alterations in and associations with particular transcription factors in the hippocampus, including upregulation of NF-κB p65 and Nrf2. Training-induced increases in actin protein levels caution against its use as a loading control in immunoblot studies examining activity-dependent plasticity, learning, and memory.
RESUMO
Although traditionally associated with immune function, the transcription factor nuclear factor kappa B (NF-κB) has garnered much attention in recent years as an important regulator of memory. Specifically, research has found that NF-κB, localized in both neurons and glia, is activated during the induction of long-term potentiation (LTP), a paradigm of synaptic plasticity and correlate of memory. Further, experimental manipulation of NF-κB activation or its blockade results in altered memory and spatial navigation abilities. Genetic knockout of specific NF-κB subunits in mice results in memory alterations. Collectively, such data suggest that NF-κB may be a requirement for memory, although the direction of the response (i.e., memory enhancement or deficit) is inconsistent. A limited number of gene targets of NF-κB have been recently identified in neurons, including neurotrophic factors, calcium-regulating proteins, other transcription factors, and molecules associated with neuronal outgrowth and remodeling. In turn, several key molecules are activators of NF-κB, including protein kinase C and [Ca(++)]i. Thus, NF-κB signaling is complex and under the regulation of numerous proteins involved in activity-dependent synaptic plasticity. The purpose of this review is to highlight the literature detailing a role for NF-κB in synaptic plasticity, memory, and spatial navigation. Secondly, this review will synthesize the research evaluating gene targets of NF-κB in synaptic plasticity and memory. Although there is ample evidence to suggest a critical role for NF-κB in memory, our understanding of its gene targets in neurons is limited and only beginning to be appreciated.
Assuntos
Marcação de Genes/métodos , Memória/fisiologia , NF-kappa B/fisiologia , Plasticidade Neuronal/fisiologia , Comportamento Espacial/fisiologia , Sinapses/fisiologia , Animais , Humanos , Potenciação de Longa Duração/fisiologia , CamundongosAssuntos
População Rural , Apoio Social , Esportes , Saúde da Mulher , Feminino , Humanos , Manitoba , Saúde Mental , Qualidade de VidaRESUMO
Humans are intensely social animals, and healthy social relationships are vital for proper mental health (see Lim and Young, 2006). By using animal models, the behavior, mental, and physiological processes of humans can be understood at a level that cannot be attained by studying human behavior and the human brain alone. The goals of this review are threefold. First, we define affiliative social behavior and describe the primary relationship types in which affiliative relationships are most readily observed--the mother-infant bond and pair-bonding. Second, we summarize neurophysiological studies that have investigated the role of neurohypophyseal nanopeptides (oxytocin and vasopressin) and the catecholamine dopamine in regulating affiliative social behavior and the implications of said research for our understanding of human social behavior. Finally, we discuss the merits and limitations of the using a comparative approach to enhance our understanding of the mechanisms underlying human affiliative social behavior.
Assuntos
Encéfalo/fisiologia , Neurotransmissores/fisiologia , Apego ao Objeto , Psicologia Comparada , Comportamento Social , Animais , Dopamina/fisiologia , Humanos , Relações Interpessoais , Modelos Animais , Ocitocina/fisiologia , Relações Pais-Filho , Vasopressinas/fisiologiaRESUMO
Duchenne muscular dystrophy (DMD) is a genetic condition affecting predominantly boys that is characterized by fatal muscle weakness. While there is no cure, recent therapeutic advances have extended the lifespan of those with DMD considerably. Although the physiological basis of muscle pathology is well-documented, less is known regarding the cognitive, behavioral, and psychosocial functioning of those afflicted. Several lines of evidence point to central nervous system involvement as an organic feature of DMD, challenging our view of the disorder as strictly neuromuscular. This report provides a review of the literature on neuropsychological and neurobehavioral functioning in DMD. Recent research identifying associations with DMD and neuropsychiatric disorders is also discussed. Lastly, the review presents implications of findings related to nonmotor aspects of DMD for improving the quality of life in those affected. While the literature is often contradictory in nature, this review highlights some key findings for consideration by clinicians, educators and parents when developing therapeutic interventions for this population.