RESUMEN
The neural cell adhesion molecule (NCAM) is a key regulator of brain plasticity. Substantial evidence indicates that NCAM is down-regulated by exposure to sustained stress and chronic stress seems to lead to increased aggression. In addition, constitutional NCAM deletion in mice has been shown to lead to increased intermale aggression and altered emotionality Forebrain-specific postnatal NCAM knockout was previously shown to impair cognitive function, particularly when animals were exposed to subchronic stress, but the effects on emotional and social behavior remain unclear. In this study, we investigated the potential interplay of a forebrain-specific postnatal NCAM deletion and exposure to different lengths of repeated stress (i.e. subchronic: 14 days; chronic: 29 days) on aggressive and emotional behavior. Our results show that postnatal deletion of NCAM in the forebrain leads to increased aggression and altered emotionality depending on the duration of stress, whereas conditional NCAM knockout has no basal impact on these behaviors. These findings support the involvement of NCAM in the regulation of emotional and aggressive behaviors, suggesting that diminished NCAM expression might be a critical vulnerability factor for the development of these behavioral alterations under repeated exposure to stress.
Asunto(s)
Agresión/fisiología , Moléculas de Adhesión de Célula Nerviosa/fisiología , Prosencéfalo/metabolismo , Estrés Psicológico/fisiopatología , Animales , Ansiedad/metabolismo , Conducta Exploratoria/fisiología , Masculino , Ratones , Ratones Noqueados , Moléculas de Adhesión de Célula Nerviosa/deficienciaRESUMEN
MuRF1 is a member of the TRIM/RBCC superfamily, a gene family that encompasses a large variety of proteins, all sharing the conserved TRIM (Tripartite Motive) sequential array of RING, B-box, and coiled-coil domains. Within this family, MuRF1(also named TRIM63) is a specialized member that contributes to the development of muscle atrophy and sarcopenia. Here we studied MuRF1's role in muscle atrophy during muscle unloading induced by hindlimb suspension. Consistent with previous studies, we found that MuRF1 inactivation leads to an attenuated muscle atrophy response. The amount of protection was higher as compared to the denervation model, and within the 10 day-suspension period the soleus muscle was spared from atrophy in MuRF1-KO mice. Contractility studies on hindlimb suspended muscle tissues suggested that MuRF1's functions extend beyond muscle trophicity and implicate MuRF1 in muscle fatigue and MLC phosphorylation control: soleus muscle from MuRF1-KO mice fatigued significantly faster and in addition showed a reduced posttetanic twitch potentiation. Thus the present work further established the role of MuRF1 in muscle atrophy and for the first time shows that MuRF1 plays a role in muscle fatigue and twitch potentiation.
Asunto(s)
Suspensión Trasera , Fatiga Muscular/fisiología , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatología , Cadenas Ligeras de Miosina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Electroforesis en Gel de Poliacrilamida , Ratones , Ratones Noqueados , Contracción Muscular/fisiología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Proteínas Musculares/deficiencia , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Tamaño de los Órganos , Fosforilación , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/deficienciaRESUMEN
The microsomal triglyceride transfer protein (MTTP) is a key regulator in the assembly and secretion of chylomicrons and very low density lipoprotein (VLDL) in the intestine and in liver. Associations between MTTP variants and traits of the metabolic syndrome are carried out in relatively small cohorts and are not consistent. We analysed MTTP polymorphisms in 7582 participants of the KORA study cohort. Seven htSNPs covering a 52kb region of the MTTP locus and two cSNPs (I128T, H297Q) were selected. A MTTP haplotype containing the minor allele of H297Q showed a significant decrease of -0.636 (95% CI: -1.226, -0.046; p=0.035) BMI units in females but not in males. In comparison to homozygous H-carriers for the major allele of the MTTP H297Q polymorphism, homozygous Q297Q carriers showed a significant decrease in BMI of -0.425B MI units (95% CI: -0.74, -0.12; p=0.007), in waist circumference of -0.990 cm (95% CI: 1.74, -0.24; p=0.01) and in total cholesterol of -0.039 mmol/l (95% CI: -0.07, 0; p=0.03). Heterozygous Q-carriers displayed a reduction in BMI of -0.183 BMI unit (95% CI: -0.33, -0.04; p=0.012), in waist circumference of -0.45 cm (95% CI: 0.8, -0.1; p=0.01) and in total cholesterol of -0.103 mmol/l (95% CI: -0.18, -0.03; p=0.01). Gender stratified statistics revealed a significant reduction of -0.657 BMI units (95% CI: -1.14, -0.18; p=0.007), -1.437 cm waist circumference (95% CI: -2.55, -0.32; p=0.01) and -0.052 mmol/l total cholesterol (95% CI: -0.1, -0.01; p=0.03) for females homozygous for the Q297Q polymorphism. Females carrying the Q-allele showed a decrease of -0.259 BMI unit (95% CI: -0.48, -0.04; p=0.023), -0.662 cm waist circumference (95% CI: -1.18, -0.14; p=0.01) and -0.111 mmol/l total cholesterol (95% CI: -0.21, -0.01; p=0.03). Our association analysis in a large population based study cohort provides evidence that the minor allele of the MTTP H297Q polymorphism is associated with lower BMI, waist circumference and total cholesterol in females but not in males.
Asunto(s)
Índice de Masa Corporal , Proteínas Portadoras/genética , Colesterol/sangre , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/fisiopatología , Circunferencia de la Cintura , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Corea (Geográfico) , Masculino , Enfermedades Metabólicas/sangre , Persona de Mediana Edad , Polimorfismo Genético , Especificidad de la EspecieRESUMEN
Early-life stress is a key risk factor for the development of neuropsychiatric disorders later in life. Neuronal cell adhesion molecules have been strongly implicated in the pathophysiology of psychiatric disorders and in modulating social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic synapses, and is involved in synaptic stabilization and maturation. Alterations in neuroligin-2 expression have previously been associated with changes in social behavior linked to psychiatric disorders, including schizophrenia and autism. In this study, we show that early-life stress, induced by limited nesting and bedding material, leads to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of hippocampal neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood mimics early-life stress-induced alterations in social behavior and social cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus attenuates the early-life stress-induced behavioral changes. Our results highlight the importance of neuroligin-2 in mediating early-life stress effects on social behavior and social cognition and its promising role as a novel therapeutic target for neuropsychiatric disorders.
Asunto(s)
Agresión/fisiología , Conducta Animal , Moléculas de Adhesión Celular Neuronal/genética , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/genética , ARN Mensajero/metabolismo , Conducta Social , Percepción Social , Estrés Psicológico/genética , Agresión/psicología , Animales , Moléculas de Adhesión Celular Neuronal/metabolismo , Técnicas de Silenciamiento del Gen , Ratones , Proteínas del Tejido Nervioso/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/psicologíaRESUMEN
Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 knockout (KO) mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, whereas overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.
Asunto(s)
Proteínas Portadoras/metabolismo , Trastorno Depresivo/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Resiliencia Psicológica , Estrés Psicológico/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas Portadoras/genética , Enfermedad Crónica , Modelos Animales de Enfermedad , Dominación-Subordinación , Agonismo Inverso de Drogas , Antagonistas de Aminoácidos Excitadores/farmacología , Proteínas de Andamiaje Homer , Imidazoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Isoformas de Proteínas , Piridinas/farmacología , ARN Mensajero/metabolismo , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Resiliencia Psicológica/efectos de los fármacosRESUMEN
Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse CRH receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported genes × environment interactions of early trauma and CRHR1 in humans. We identified 2 main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, because Crhr1 mRNA expression and CRHR1 binding were enhanced in risk haplotype carriers. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep sequencing of the Crhr1 locus in CD1 mice revealed a large number of linked single-nucleotide polymorphisms with some located in important regulatory regions, similar to the location of human CRHR1 variants implicated in modulating gene × stress exposure interactions. Our data support that the described gene × stress exposure interaction in this animal model is based on naturally occurring genetic variations in the Crhr1 gene associated with enhanced CRHR1-mediated signaling. Our results suggest that patients with a specific genetic predisposition in the CRHR1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Receptores de Hormona Liberadora de Corticotropina/genética , Estrés Psicológico/genética , Animales , Conducta Animal/efectos de los fármacos , Unión Competitiva , Corticosterona/sangre , Femenino , Expresión Génica , Frecuencia de los Genes , Interacción Gen-Ambiente , Genotipo , Haplotipos , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Hibridación in Situ , Masculino , Ratones , Hipófisis/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Pirazoles/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos/genética , Transducción de Señal/genética , Triazinas/farmacologíaRESUMEN
Disturbances of the excitation/inhibition (E/I) balance in the brain were recently suggested as potential factors underlying disorders like autism and schizophrenia resulting in associated behavioral alterations including changes in social and emotional behavior as well as abnormal aggression. Neuronal cell adhesion molecules (nCAMs) and mutations in these genes were found to be strongly implicated in the pathophysiology of these disorders. Neuroligin2 (nlgn2) is a postsynaptic cell adhesion molecule, which is predominantly expressed at inhibitory synapses and required for synapse specification and stabilization. Changes in the expression of nlgn2 were shown to result in alterations of social behavior as well as altered inhibitory synaptic transmission, hence modifying the E/I balance. In our study, we focused on the role of nlgn2 in the dorsal hippocampus in the regulation of emotional and social behaviors. To this purpose, we injected an AAV construct overexpressing nlgn2 in the hippocampus of rats and investigated the effects on behavior and on markers for the E/I ratio. We could show an increase in GAD65, a GABA-synthesizing protein in neuronal terminals, and furthermore, reduced exploration of novel stimuli and less offensive behavior. Our data suggest nlgn2 in the hippocampus to be strongly implicated in maintaining the E/I balance in the brain and thereby modulating social and emotional behavior.
Asunto(s)
Agresión/fisiología , Conducta Animal/fisiología , Moléculas de Adhesión Celular Neuronal/metabolismo , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Moléculas de Adhesión Celular Neuronal/genética , Masculino , Proteínas del Tejido Nervioso/genética , Ratas , Ratas WistarRESUMEN
BACKGROUND: The aim of the study was to examine the association between the need for psychosocial support, the patients' desire for support and the actually received psychosocial interventions in cancer patients. METHODS: The need for psychosocial support was assessed with the Hornheider Screening Instrument (HSI ³ 4) in 455 cancer patients. The subjective desire for psychosocial support was assessed with a single question. In addition, the actually received psychosocial interventions were retrieved from the hospital documentation system of the psycho-oncology service. RESULTS: Overall, 41.8 % of the participants received a positive screening result indicative for the need for psychosocial support, 19.8 % reported a desire for support, and 41.5 % actually received at least one psychosocial intervention. The agreement between objective need and subjective desire for psychosocial support was low (k = 0.352). Received psychosocial interventions were significantly associated with the subjective desire but not with the objective need for support as assessed with the HSI. CONCLUSIONS: The low associations between need and desire for psychosocial support as well as between need and actually received psychosocial interventions suggest that the decision for psychosocial support should be based on the objective as well as the self-reported need for help.
Asunto(s)
Neoplasias , Apoyo Social , Humanos , MotivaciónRESUMEN
Monocytes are key players in inflammatory processes that are triggered by lipopolysaccharide (LPS), the major outer membrane component of Gram-negative bacteria. The present study in human monocytic THP-1 cells was designed in order to identify LPS-inducible genes that are down-regulated by the reduced form of coenzyme Q(10) (ubiquinol, Q(10)H(2)). For this purpose, THP-1 cells were incubated with 10 µM Q(10)H(2) for 24 hours. Subsequently, cells were stimulated for 4 hours with 1 µg/mL LPS, and the resulting gene expression levels were determined using microarrays. Fourteen LPS-inducible genes were identified to be significantly (P ≤ .05) down-regulated by Q(10)H(2) pretreatment between a factor of 1.32 and 1.65. The strongest effect of Q(10)H(2) incubation was found for the nuclear receptor coactivator 2 gene (NCOA2). Gene ontology terms revealed for the Q(10)H(2)-sensitive genes an involvement in, e.g., signal transduction processes (centaurin, delta 1; NCOA2; pleckstrin and Sec7 domain containing 3; protein phosphatase 2, regulatory subunit B [B56], γ isoform), transcriptional regulation (NCOA2; POU domain, class 2, transcription factor 1; ETS variant gene 3), and cell proliferation pathways (hypothetical protein FLJ36090, epidermal growth factor receptor pathway substrate 15). In conclusion, we provide evidence in THP-1 cells that Q(10)H(2) modulates LPS-induced gene expression.
Asunto(s)
Regulación hacia Abajo , Lipopolisacáridos/metabolismo , Coactivador 2 del Receptor Nuclear/genética , Ubiquinona/análogos & derivados , Línea Celular , Proliferación Celular , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Transducción de Señal , Ubiquinona/farmacologíaRESUMEN
BACKGROUND: Human paraoxonase 1 (PON1) is an HDL-associated enzyme with anti-oxidant/anti-inflammatory properties that has been suggested to play an important protective role against coronary heart diseases and underlying atherogenesis. The common PON1 Q192R polymorphism (rs662, A>G), a glutamine to arginine substitution at amino acid residue 192, has been analyzed in numerous association studies as a genetic marker for coronary heart diseases, however, with controversial results. FINDINGS: To get a better understanding about the pathophysiological function of PON1, we analyzed the relationships between the Q192R polymorphism, serum paraoxonase activity and serum biomarkers important for atherogenesis. Genotyping a cohort of 49 healthy German males for the Q192R polymorphism revealed an allele distribution of 0.74 and 0.26 for the Q and R allele, respectively, typical for Caucasian populations. Presence of the R192 allele was found to be associated with a significantly increased paraoxonase enzyme activity of 187.8 ± 11.4 U/l in comparison to the QQ192 genotype with 60.5 ± 4.9 U/l. No significant differences among the genotypes were found for blood pressure, asymmetric dimethylarginine, LDL, HDL, triglycerides, and cholesterol. As expected, MIP-2 alpha a cytokine rather not related to atherosclerosis is not affected by the PON1 polymorphism. In contrast to that, the pro-inflammatory cytokine TNF-alpha is enhanced in R192 carriers (163.8 ± 24.7 pg/ml vs 94.7 ± 3.2 pg/ml in QQ192 carriers). CONCLUSIONS: Our findings support the hypothesis that the common PON1 R192 allele may be a genetic risk factor for atherogenesis by inducing chronic low-grade inflammation.
RESUMEN
Spontaneous waves of activity that propagate across large structures during specific developmental stages play central roles in CNS development. To understand the genesis and functions of these waves, it is critical to understand the spatial and temporal patterns of their propagation. We recently reported that spontaneous waves in the neonatal cerebral cortex originate from a ventrolateral pacemaker region. We have now analyzed a large number of spontaneous waves using calcium imaging over the entire area of coronal slices from E18-P1 mouse brains. In all waves, the first cortical region active is this ventrolateral pacemaker. In half of the waves, however, the cortical pacemaker activity is itself triggered by preceding activity in the septal nuclei. Most waves are restricted to the septum and/or ventral cortex, with only some invading the dorsal cortex or the contralateral hemisphere. Waves fail to propagate at very stereotyped locations at the boundary between ventral and dorsal cortex and at the dorsal midline. Waves that cross these boundaries pause at these same locations. Waves at these stages are blocked by both picrotoxin and CNQX, indicating that both GABA(A) and AMPA receptors are involved in spontaneous activity.