RESUMO
BACKGROUND/OBJECTIVE: Iron deficiency (ID) is the most common nutrient deficiency, affecting two billion people worldwide, including about 30% of pregnant women. During gestation, the brain is particularly vulnerable to environmental insults, which can irrevocably impair critical developmental processes. Consequently, detrimental consequences of early-life ID for offspring brain structure and function have been described. Although early life ID has been associated with an increased long-term risk for several neuropsychiatric disorders, the effect on depressive disorders has remained unresolved. MATERIALS AND METHODS: A mouse model of moderate foetal and neonatal ID was established by keeping pregnant dams on an iron-deficient diet throughout gestation until postnatal day 10. The ensuing significant decrease of iron content in the offspring brain, as well as the impact on maternal behaviour and offspring vocalization was determined in the first postnatal week. The consequences of early-life ID for depression- and anxiety-like behaviour in adulthood were revealed employing dedicated behavioural assays. miRNA sequencing of hippocampal tissue of offspring revealed specific miRNAs signatures accompanying the behavioural deficits of foetal and neonatal ID in the adult brain. RESULTS: Mothers receiving iron-deficient food during pregnancy and lactation exhibited significantly less licking and grooming behaviour, while active pup retrieval and pup ultrasonic vocalizations were unaltered. Adult offspring with a history of foetal and neonatal ID showed an increase in depression- and anxiety-like behaviour, paralleled by a deranged miRNA expression profile in the hippocampus, specifically levels of miR200a and miR200b. CONCLUSION: ID during the foetal and neonatal periods has life-long consequences for affective behaviour in mice and leaves a specific and persistent mark on the expression of miRNAs in the brain. Foetal and neonatal ID needs to be further considered as risk factor for the development of depression and anxiety disorders later in life.Key MessagesMarginal reduction of gestational alimentary iron intake decreases brain iron content of the juvenile offspring.Early-life ID is associated with increased depression- and anxiety-like behaviour in adulthood.Reduction of maternal alimentary iron intake during pregnancy is reflected in an alteration of miRNA signatures in the adult offspring brain.
Assuntos
Deficiências de Ferro , MicroRNAs , Efeitos Tardios da Exposição Pré-Natal , Animais , Camundongos , Feminino , Gravidez , Humanos , Ferro , Hipocampo/metabolismo , Encéfalo , MicroRNAs/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/psicologiaRESUMO
The ability to care for the young is innate and readily displayed by postpartum females after delivery to ensure offspring survival. Upon pup exposure, rodent virgin (nulliparous) females also develop parental behavior that over time becomes displayed at levels equivalent to parenting mothers. Although maternal behavior in postpartum females and the associated neurocircuits are well characterized, the neural mechanisms underlying the acquisition of maternal behavior without prior experience remain poorly understood. Here, we show that the development of maternal care behavior in response to first-time pup exposure in virgin females is initiated by the activation of the anterior cingulate cortex (ACC). ACC activity is dependent on feedback excitation by Vglut2+ /Galanin+ neurons of the centrolateral nucleus of the thalamus (CL), with their activity sufficient to display parenting behaviors. Accordingly, acute bidirectional chemogenetic manipulation of neuronal activity in the ACC facilitates or impairs the attainment of maternal behavior, exclusively in virgin females. These results reveal an ACC-CL neurocircuit as an accessory loop in virgin females for the initiation of maternal care upon first-time exposure to pups.
Assuntos
Comportamento Materno , Período Pós-Parto , Humanos , Animais , Camundongos , Feminino , Período Pós-Parto/fisiologia , Neurônios/fisiologia , Tálamo , Córtex Pré-Frontal , Comportamento AnimalRESUMO
Experimental investigation of early postnatal brain development in infant mice (Assuntos
Encéfalo
, Imageamento Tridimensional
, Animais
, Cabeça
, Humanos
, Camundongos
, Impressão Tridimensional
, Software
RESUMO
The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology.
Assuntos
Núcleo Dorsal da Rafe , Redes Reguladoras de Genes , Transtornos Mentais , Fator de Transcrição STAT3 , Animais , Núcleo Dorsal da Rafe/metabolismo , Camundongos , Fosforilação , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized by striatonigral degeneration and olivopontocerebellar atrophy. The main hallmark of MSA is the aggregation of alpha-synuclein in oligodendrocytes, which contributes to the dysfunction and death of the oligodendrocytes, followed by neurodegeneration. Studies suggested that oxidative-excitatory pathway is associated with the progression of the disease. The aim of the current study was to test this concept by overexpression of excitatory amino acid transporter 2, glutamate dehydrogenase and nuclear factor (erythroid-derived 2)-related factor 2 genes in the striatum of two established mouse models of MSA. To induce the first model, we injected the mitochondrial neurotoxin, 3-nitropropionic acid (3-NP), unilaterally into the right striatum in 2-month-old C57BL/6 male mice. We demonstrate a significant improvement in two drug-induced rotational behavior tests, following unilateral injection the three genes. For the second model, we used transgenic mice expressing the alpha-synuclein gene under the proteolipid protein, in the age of 7 months, boosted with 3-NP to enhance the motor deficits and neurodegeneration. We show that the overexpression of the three genes attenuated the motor-related deficit in the elevated bridge and pole tests. Thus, our study indicates that glutamate excito-oxidative toxicity plays a major role in this MSA model and our gene therapy approach might suggest a novel strategy for MSA treatment.
Assuntos
Comportamento Animal/fisiologia , Modelos Animais de Doenças , Terapia Genética , Atrofia de Múltiplos Sistemas/fisiopatologia , Atrofia de Múltiplos Sistemas/terapia , Animais , Convulsivantes/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Transportador 2 de Aminoácido Excitatório/genética , Glutamato Desidrogenase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/genética , Nitrocompostos/administração & dosagem , Propionatos/administração & dosagemRESUMO
The characteristics of the cycles of activity and rest stand out among the most intensively investigated aspects of circadian rhythmicity in humans and experimental animals. Alterations in the circadian patterns of activity and rest are strongly linked to cognitive and emotional dysfunctions in severe mental illnesses such as Alzheimer's disease (AD) and major depression (MDD). The proinflammatory cytokine interleukin 6 (IL-6) has been prominently associated with the pathogenesis of AD and MDD. However, the potential involvement of IL-6 in the modulation of the diurnal rhythms of activity and rest has not been investigated. Here, we set out to study the role of IL-6 in circadian rhythmicity through the characterization of patterns of behavioral locomotor activity in IL-6 knockout (IL-6 KO) mice and wild-type littermate controls. Deletion of IL-6 did not alter the length of the circadian period or the amount of locomotor activity under either light-entrained or free-running conditions. IL-6 KO mice also presented a normal phase shift in response to light exposure at night. However, the temporal architecture of the behavioral rhythmicity throughout the day, as characterized by the quantity of ultradian activity bouts, was significantly impaired under light-entrained and free-running conditions in IL-6 KO. Moreover, the assessment of clock gene expression in the hippocampus, a brain region involved in AD and depression, revealed altered levels of cry1, dec2, and rev-erb-beta in IL-6 KO mice. These data propose that IL-6 participates in the regulation of ultradian activity/rest rhythmicity and clock gene expression in the mammalian brain. Furthermore, we propose IL-6-dependent circadian misalignment as a common pathogenetic principle in some neurodegenerative and neuropsychiatric disorders.
RESUMO
Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with increased neurodegeneration and vascular impairments. Vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, has recently been shown to play a crucial role in the nervous system. The objective of this research is to examine the role of VEGF in mediating the apoE4-driven pathologies. We show that hippocampal VEGF levels are lower in apoE4 targeted replacement mice compared to the corresponding apoE3 mice. This effect was accompanied by a specific decrease in both VEGF receptor-2 and HIF1-α. We next set to examine whether upregulation of VEGF can reverse apoE4-driven pathologies, namely the accumulation of hyperphosphorylated tau (AT8) and Aß42, and reduced levels of the pre-synaptic marker, VGluT1, and of the ApoE receptor, ApoER2. This was first performed utilizing intra-hippocampal injection of VEGF-expressing-lentivirus (LV-VEGF). This revealed that LV-VEGF treatment reversed the apoE4-driven cognitive deficits and synaptic pathologies. The levels of Aß42 and AT8, however, were increased in apoE3 mice, masking any potential effects of this treatment on the apoE4 mice. Follow-up experiments utilizing VEGF-expressing adeno-associated-virus (AAV-VEGF), which expresses VEGF specifically under the GFAP astrocytic promoter, prevented this effects on apoE3 mice, and reversed the apoE4-related increase in Aß42 and AT8. Taken together, these results suggest that apoE4-driven pathologies are mediated by a VEGF-dependent pathway, resulting in cognitive impairments and brain pathology. These animal model findings suggest that the VEGF system is a promising target for the treatment of apoE4 carriers in AD.
Assuntos
Apolipoproteína E4/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Dependovirus/genética , Modelos Animais de Doenças , Vetores Genéticos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Lentivirus/genética , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Sinapses/metabolismo , Sinapses/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteínas tau/metabolismoRESUMO
Multiple System Atrophy (MSA) is a sporadic neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and dysautonomia, in various combinations. In MSA with parkinsonism (MSA-P), the degeneration is mainly restricted to the substantia nigra pars compacta and putamen. Studies have identified alterations in DJ-1 (PARK7), a key component of the anti-oxidative stress response, in Parkinson's disease (PD) and MSA patients. Previously we have shown that a short DJ-1-based peptide named ND-13, protected cultured cells against neurotoxic insults and improved behavioral outcome in animal models of Parkinson's disease (PD). In this study, we used the 3-Nitropropionic acid (3-NP)-induced mouse model of MSA and treated the animals with ND-13 in order to evaluate its therapeutic effects. Our results show that ND-13 protects cultured cells against oxidative stress generated by the mitochondrial inhibitor, 3-NP. Moreover, we show that ND-13 attenuates nigrostriatal degeneration and improves performance in motor-related behavioral tasks in 3-NP-treated mice. Our findings suggest a rationale for using ND-13 as a promising therapeutic approach for treatment of MSA.
Assuntos
Proteínas Associadas aos Microtúbulos/química , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Peptídeos/química , Peptídeos/uso terapêutico , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Atrofia de Múltiplos Sistemas/induzido quimicamente , Fármacos Neuroprotetores/química , Nitrocompostos/farmacologia , Células PC12 , Propionatos/farmacologia , RatosRESUMO
Sciatic nerve damage is a common medical problem. The main causes include direct trauma, prolonged external nerve compression, and pressure from disk herniation. Possible complications include leg numbness and the loss of motor control. In mild cases, conservative treatment is feasible. However, following severe injury, recovery may not be possible. Neuronal regeneration, survival, and maintenance can be achieved by neurotrophic factors (NTFs). In this study, we examined the potency of combining brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) on the recovery of motor neuron function after crush injury of the sciatic nerve. We show that combined NTF application increases the survival of motor neurons exposed to a hypoxic environment. The ectopic expression of NTFs in the injured muscle improves the recovery of the sciatic nerve after crush injury. A significantly faster recovery of compound muscle action potential (CMAP) amplitude and conduction velocity is observed after muscle injections of viral vectors expressing a mixture of the four NTF genes. Our findings suggest a rationale for using genetic treatment with a combination of NTF-expressing vectors, as a potential therapeutic approach for severe peripheral nerve injury.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/uso terapêutico , Fator Neurotrófico Derivado de Linhagem de Célula Glial/uso terapêutico , Músculo Esquelético/metabolismo , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Potenciais de Ação , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Linhagem Celular , Terapia Genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Crescimento Insulin-Like I/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/fisiologia , Regeneração Nervosa/efeitos dos fármacos , Recuperação de Função Fisiológica , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/fisiologia , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Glial fibrillary acidic protein (GFAP) has been shown to be increased in the cerebrospinal fluid (CSF) of patients suffering from neurological diseases involving the activation of astrocytes, but has not been studied in amyotrophic lateral sclerosis (ALS) patients to our knowledge. CSF samples of patients with definite ALS and of those with other neurological diseases were evaluated for their GFAP concentrations. CSF-GFAP concentrations of patients with ALS were significantly elevated by 53% compared to patients with other neurologic diseases. GFAP might serve as a biomarker in ALS. Our findings support the concept that astrocytes play a role in ALS pathogenesis.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Astrócitos/metabolismo , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Adulto , Idoso , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Tau dysfunction is believed to be the primary cause of neurodegenerative disorders referred to as tauopathies, including Alzheimer's disease, Pick's disease, frontotemporal dementia and Parkinsonism. The role of microglial cells in the pathogenesis of tauopathies is still unclear. The activation of microglial cells has been correlated with neuroprotective effects through the release of neurotrophic factors and through clearance of cell debris and phagocytosis of cells with intracellular inclusions. In contrast, microglial activation has also been linked with chronic neuroinflammation contributing to the development of neurodegenerative diseases such as tauopathies. Microglial activation has been recently reported to precede tangle formation and the attenuation of tau pathology occurs after immunosuppression of transgenic mice. METHODS: Here we report the specific inhibition of microglial cells in rTg4510 tau-mutant mice by using fibrin γ377-395 peptide conjugated to iron oxide (γ-Fe2O3) nanoparticles of 21 ± 3.5 nm diameter. RESULTS: Stabilization of the peptide by its covalent conjugation to the γ-Fe2O3 nanoparticles significantly decreased the number of the microglial cells compared to the same concentration of the free peptide. The specific microglial inhibition induces different effects on tau pathology in an age dependent manner. The reduction of activation of microglial cells at an early age increases the number of neurons with hyperphosphorylated tau in transgenic mice. In contrast, reduction of activation of microglial cells reduced the severity of the tau pathology in older mice. The number of neurons with hyperphosphorylated tau and the number of neurons with tangles are reduced than those in animals not receiving the fibrin γ377-395 peptide-nanoparticle conjugate. CONCLUSIONS: These results demonstrate a differential effect of microglial activity on tau pathology using the fibrin γ377-395 peptide-nanoparticle conjugate, depending on age and/or stage of the neuropathological accumulation and aggregation.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Compostos Férricos/química , Microglia/efeitos dos fármacos , Nanopartículas/química , Peptídeos/farmacologia , Fatores Etários , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Células , Fibrina/química , Humanos , Proteínas Imobilizadas , Injeções Intraventriculares , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Tamanho da Partícula , Peptídeos/síntese química , Fosforilação/efeitos dos fármacos , Índice de Gravidade de Doença , Fatores de Tempo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Alzheimer's disease (AD) is a progressive neurological disorder characterized by the aggregation of two proteins, amyloid-ß and hyperphosphorylated tau, and by neuronal and synaptic loss. Although some drugs have been shown to slow the progression of the disease, at present no treatment has been developed that can stop or reverse the progression of the pathology. Recently, new therapeutic strategies have been proposed for the treatment of the disease. Among these, the development of stem cells and gene-modified cells is an especially promising therapeutic approach for AD. In this review we highlight the experimental and preclinical studies that have been focused on stem cell-based and gene-modified cell-based uses as potential therapies for AD. The potential clinical applications are also discussed.