RESUMO
Motor learning depends on synaptic plasticity between corticostriatal projections and striatal medium spiny neurons. Retrograde tracing from the dorsolateral striatum reveals that both layer II/III and V neurons in the motor cortex express BDNF as a potential regulator of plasticity in corticostriatal projections in male and female mice. The number of these BDNF-expressing cortical neurons and levels of BDNF protein are highest in juvenile mice when adult motor patterns are shaped, while BDNF levels in the adult are low. When mice are trained by physical exercise in the adult, BDNF expression in motor cortex is reinduced, especially in layer II/III projection neurons. Reduced expression of cortical BDNF in 3-month-old mice results in impaired motor learning while space memory is preserved. These findings suggest that activity regulates BDNF expression differentially in layers II/III and V striatal afferents from motor cortex and that cortical BDNF is essential for motor learning.SIGNIFICANCE STATEMENT Motor learning in mice depends on corticostriatal BDNF supply, and regulation of BDNF expression during motor learning is highest in corticostriatal projection neurons in cortical layer II/III.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Aprendizagem/fisiologia , Atividade Motora , Córtex Motor/fisiologia , Neurônios/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Corpo Estriado/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vias Neurais/fisiologia , Plasticidade Neuronal , Condicionamento Físico AnimalRESUMO
BACKGROUND: Cytokines are signaling molecules operating within complex cascade patterns and having exceptional modulatory functions. They impact various physiological processes such as neuroendocrine and metabolic interactions, neurotrophins' metabolism, neuroplasticity, and may affect behavior and cognition. In our previous study, we found that sex and Cytomegalovirus (CMV)-serostatus may modulate levels of circulating pro- and anti-inflammatory cytokines, metabolic factors, immune cells, and cognitive performance, as well as associations between them. RESULTS: In the present study, we used a graph-theoretical approach to investigate the network topology dynamics of 22 circulating biomarkers and 11 measures of cognitive performance in 161 older participants recruited to undergo a six-months training intervention. For network construction, we applied coefficient of determination (R 2 ) that was calculated for all possible pairs of variables (N = 33) in four groups (CMV- men and women; CMV+ men and women). Network topology has been evaluated by clustering coefficient (CC) and characteristic path length (CPL) as well as local (E local ) and global (E global ) efficiency, showing the degree of network segregation (CC and E local ) and integration (CPL and E global ). We found that networks under consideration showed small-world networks properties with more random characteristics. Mean CC, as well as local and global efficiency were highest and CPL shortest in CMV- males (having lowest inflammatory status and highest cognitive performance). CMV- and CMV+ females did not show any significant differences. Modularity analyses showed that the networks exhibit in all cases highly differentiated modular organization (with Q-value ranged between 0.397 and 0.453). CONCLUSIONS: In this work, we found that segregation and integration properties of the network were notably stronger in the group with balanced inflammatory status. We were also able to confirm our previous findings that CMV-infection and sex modulate multiple circulating biomarkers and cognitive performance and that balanced inflammatory and metabolic status in elderly contributes to better cognitive functioning. Thus, network analyses provide a useful strategy for visualization and quantitative description of multiple interactions between various circulating pro- and anti-inflammatory biomarkers, hormones, neurotrophic and metabolic factors, immune cells, and measures of cognitive performance and can be in general applied for analyzing interactions between different physiological systems.
RESUMO
Insulin-like growth factor 1 (IGF-1) is a pluripotent growth factor with multiple functions in the peripheral and central nervous system. It supports neuronal survival and axon growth, and also acts on myelinating Schwann cells and oligodendroglia. The biological functions of IGF-1 are modulated by IGF-binding proteins (IGFBPs). Expression of IGF-1 and its corresponding IGF-1 receptor (IGF-1R) are dysregulated in patients with diabetes and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). IGFBP5, an inhibitory binding protein for IGF-1, is also substantially increased in nerve biopsies of patients with sensorimotor diabetic neuropathy (DNP). We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which IGF-1R was conditionally depleted in motoneurons, indicating that reduced activity of IGF-1 on IGF-1R in motoneurons is responsible for the observed effect. The upregulation of IGFBP5 has possibly contributed to the lack of efficacy found in previous clinical trials with systemically administered IGF-1 in patients with other forms of motoneuron disease such as ALS. Thus, strategies aiming at circumventing these inhibitory effects could be of benefit for development of new therapies for ALS and DNP. However, these strategies have to be built on a better understanding of the metabolic processes that contribute to neurodegeneration, and on the role of IGF-1 in these metabolic processes that go beyond protection from axonal degeneration and cell death.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Neuropatias Diabéticas/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Animais , HumanosRESUMO
Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.
Assuntos
Axônios/fisiologia , Proteínas de Transporte/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Neurônios Motores/fisiologia , Degeneração Neural/fisiopatologia , Animais , Axônios/patologia , Crescimento Celular , Sobrevivência Celular/fisiologia , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/patologia , Humanos , Camundongos Transgênicos , Atividade Motora/fisiologia , Neurônios Motores/patologia , Degeneração Neural/patologia , Nervo Frênico/patologia , Nervo Frênico/fisiopatologia , Receptor IGF Tipo 1/metabolismo , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Sensação/fisiologiaRESUMO
Pro- and mature BDNF activate very different receptors and intracellular pathways, potentially leading to either neuronal death or survival. Here we examined the biochemistry of endogenous BDNF in mouse neurons using sensitive reagents and found that pro-BDNF is rapidly converted intracellularly to mature BDNF, the latter being stored and released by excitatory input.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/citologia , Neurônios/metabolismo , Precursores de Proteínas/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/deficiência , Células COS , Chlorocebus aethiops , Relação Dose-Resposta à Radiação , Estimulação Elétrica/métodos , Ensaio de Imunoadsorção Enzimática , Imunoprecipitação/métodos , Potenciação de Longa Duração/fisiologia , Potenciação de Longa Duração/efeitos da radiação , Metionina/metabolismo , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Transmissão Sináptica/fisiologia , Transmissão Sináptica/efeitos da radiação , Transfecção/métodos , Trítio/metabolismoRESUMO
OBJECTIVE: Alzheimer's disease (AD) is a growing challenge worldwide, which is why the search for early-onset predictors must be focused as soon as possible. Longitudinal studies that investigate courses of neuropsychological and other variables screen for such predictors correlated to mild cognitive impairment (MCI). However, one often neglected issue in analyses of such studies is measurement invariance (MI), which is often assumed but not tested for. This study uses the absence of MI (non-MI) and latent factor scores instead of composite variables to assess properties of cognitive domains, compensation mechanisms, and their predictability to establish a method for a more comprehensive understanding of pathological cognitive decline. METHODS: An exploratory factor analysis (EFA) and a set of increasingly restricted confirmatory factor analyses (CFAs) were conducted to find latent factors, compared them with the composite approach, and to test for longitudinal (partial-)MI in a neuropsychiatric test battery, consisting of 14 test variables. A total of 330 elderly (mean age: 73.78 ± 1.52 years at baseline) were analyzed two times (3 years apart). RESULTS: EFA revealed a four-factor model representing declarative memory, attention, working memory, and visual-spatial processing. Based on CFA, an accurate model was estimated across both measurement timepoints. Partial non-MI was found for parameters such as loadings, test- and latent factor intercepts as well as latent factor variances. The latent factor approach was preferable to the composite approach. CONCLUSION: The overall assessment of non-MI latent factors may pose a possible target for this field of research. Hence, the non-MI of variances indicated variables that are especially suited for the prediction of pathological cognitive decline, while non-MI of intercepts indicated general aging-related decline. As a result, the sole assessment of MI may help distinguish pathological from normative aging processes and additionally may reveal compensatory neuropsychological mechanisms.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Análise Fatorial , Humanos , Estudos Longitudinais , Testes NeuropsicológicosRESUMO
Risk factors such as dysregulation of Insulin-like growth factor (IGF) signaling have been linked to Alzheimer's disease. Here we show that Insulin-like Growth Factor Binding Protein 5 (Igfbp5), an inhibitory binding protein for insulin-like growth factor 1 (Igf-1) accumulates in hippocampal pyramidal neurons and in amyloid plaques in brains of Alzheimer patients. We investigated the pathogenic relevance of this finding with transgenic mice overexpressing Igfbp5 in pyramidal neurons of the brain. Neuronal overexpression of Igfbp5 prevents the training-induced increase of hippocampal and cortical Bdnf expression and reduces the effects of exercise on memory retention, but not on learning acquisition. Hence, elevated IGFBP5 expression could be responsible for some of the early cognitive deficits that occur during the course of Alzheimer's disease.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina , Animais , Humanos , Camundongos , Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Camundongos Transgênicos , Neurônios/metabolismo , Placa Amiloide/patologiaRESUMO
Although brain-derived neurotrophic factor (BDNF) is linked with an increasing number of conditions causing brain dysfunction, its role in the postnatal CNS has remained difficult to assess. This is because the bdnf-null mutation causes the death of the animals before BDNF levels have reached adult levels. In addition, the anterograde axonal transport of BDNF complicates the interpretation of area-specific gene deletion. The present study describes the generation of a new conditional mouse mutant essentially lacking BDNF throughout the CNS. It shows that BDNF is not essential for prolonged postnatal survival, but that the behavior of such mutant animals is markedly altered. It also reveals that BDNF is not a major survival factor for most CNS neurons and for myelination of their axons. However, it is required for the postnatal growth of the striatum, and single-cell analyses revealed a marked decreased in dendritic complexity and spine density. In contrast, BDNF is dispensable for the growth of the hippocampus and only minimal changes were observed in the dendrites of CA1 pyramidal neurons in mutant animals. Spine density remained unchanged, whereas the proportion of the mushroom-type spine was moderately decreased. In line with these in vivo observations, we found that BDNF markedly promotes the growth of cultured striatal neurons and of their dendrites, but not of those of hippocampal neurons, suggesting that the differential responsiveness to BDNF is part of a neuron-intrinsic program.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/crescimento & desenvolvimento , Neostriado/crescimento & desenvolvimento , Animais , Contagem de Células , Células Cultivadas , Dendritos/metabolismo , Dendritos/ultraestrutura , Feminino , Hipocampo/citologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Neostriado/ultraestrutura , Neurônios/citologia , Neurônios/ultraestrutura , Oligodendroglia/citologia , Oligodendroglia/ultraestrutura , Nervo Óptico/crescimento & desenvolvimento , Nervo Óptico/ultraestrutura , Proteínas tau/metabolismoRESUMO
Although brain-derived neurotrophic factor (BDNF) regulates numerous and complex biological processes including memory retention, its extremely low levels in the mature central nervous system have greatly complicated attempts to reliably localize it. Using rigorous specificity controls, we found that antibodies reacting either with BDNF or its pro-peptide both stained large dense core vesicles in excitatory presynaptic terminals of the adult mouse hippocampus. Both moieties were ~10-fold more abundant than pro-BDNF. The lack of postsynaptic localization was confirmed in Bassoon mutants, a seizure-prone mouse line exhibiting markedly elevated levels of BDNF. These findings challenge previous conclusions based on work with cultured neurons, which suggested activity-dependent dendritic synthesis and release of BDNF. They instead provide an ultrastructural basis for an anterograde mode of action of BDNF, contrasting with the long-established retrograde model derived from experiments with nerve growth factor in the peripheral nervous system.