RESUMEN
BACKGROUND: Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced DA activity. On the other hand, psychostimulant drugs that increase DA signalling suppress food intake. This poses the questions of how endogenous DA neuronal activity regulates feeding, and whether enhancing DA neuronal activity would either promote or reduce food intake. METHODS: Here, we used designer receptors exclusively activated by designer drugs (DREADD) technology to determine the effects of enhancing DA neuronal activity on feeding behaviour. We chemogenetically activated selective midbrain DA neuronal subpopulations and assessed the effects on feeding microstructure in rats. RESULTS: Treatment with the psychostimulant drug amphetamine or the selective DA reuptake inhibitor GBR 12909 significantly suppressed food intake. Selective chemogenetic activation of DA neurons in the ventral tegmental area (VTA) was found to reduce meal size, but had less impact on total food intake. Targeting distinct VTA neuronal pathways revealed that specific activation of the mesolimbic pathway towards nucleus accumbens (NAc) resulted in smaller and shorter meals. In addition, the meal frequency was increased, rendering total food intake unaffected. The disrupted feeding patterns following activation of VTA DA neurons or VTA to NAc projection neurons were accompanied by locomotor hyperactivity. Activation of VTA neurons projecting towards prefrontal cortex or amygdala, or of DA neurons in the substantia nigra, did not affect feeding behaviour. CONCLUSIONS: Chemogenetic activation of VTA DA neurons or VTA to NAc pathway disrupts feeding patterns. Increased activity of mesolimbic DA neurons appears to both promote and reduce food intake, by facilitating both the initiation and cessation of feeding behaviour.
Asunto(s)
Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/fisiología , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Mesencéfalo/citología , Mesencéfalo/fisiología , Anfetamina/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Piperazinas/farmacología , Ratas , RecompensaRESUMEN
Febrile seizures (FS) are the most common seizure type in children and recurrent FS are a risk factor for developing temporal lobe epilepsy. Although the mechanisms underlying FS are largely unknown, recent family, twin and animal studies indicate that genetics are important in FS susceptibility. Here, a forward genetic strategy was used employing mouse chromosome substitution strains (CSS) to identify novel FS susceptibility quantitative trait loci (QTLs). FS were induced by exposure to warm air at postnatal day 14. Video electroencephalogram monitoring identified tonic-clonic convulsion onset, defined as febrile seizure latency (FSL), as a reliable phenotypic parameter to determine FS susceptibility. FSL was determined in both sexes of the host strain (C57BL/6J), the donor strain (A/J) and CSS. C57BL/6J mice were more susceptible to FS than A/J mice. Phenotypic screening of the CSS panel identified six strains(CSS1, -2, -6 -10, -13 and -X) carrying QTLs for FS susceptibility. CSS1, -10 and -13 were less susceptible (protective QTLs), whereas CSS2, -6 and -X were more susceptible (susceptibility QTLs) to FS than the C57BL/6J strain. Our data show that mouse FS susceptibility is determined by complex genetics, which is distinct from that for chemically induced seizures. This is the first dataset using CSS to screen for a seizure trait in mouse pups. It provides evidence for common FS susceptibility QTLs that serve as starting points to fine map FS susceptibility QTLs and to identify FS susceptibility genes. This will increase our understanding of human FS, working toward the identification of new therapeutic targets.
Asunto(s)
Cromosomas de los Mamíferos/genética , Sitios de Carácter Cuantitativo/genética , Convulsiones Febriles/genética , Animales , Conducta Animal/fisiología , Temperatura Corporal/genética , Temperatura Corporal/fisiología , Interpretación Estadística de Datos , Electroencefalografía , Femenino , Ligamiento Genético/genética , Masculino , Ratones , Ratones Endogámicos A , Ratones Endogámicos C57BL , Fenotipo , Convulsiones Febriles/psicologíaRESUMEN
Febrile seizures (FS) are the most prevalent seizures in children. Although FS are largely benign, complex FS increase the risk to develop temporal lobe epilepsy (TLE). Studies in rat models for FS have provided information about functional changes in the hippocampus after complex FS. However, our knowledge about the genes and pathways involved in the causes and consequences of FS is still limited. To enable molecular, genetic and knockout studies, we developed and characterized an FS model in mice and used it as a phenotypic screen to analyze FS susceptibility. Hyperthermia was induced by warm air in 10- to 14-day-old mice and induced FS in all animals. Under the conditions used, seizure-induced behavior in mice and rats was similar. In adulthood, treated mice showed increased hippocampal Ih current and seizure susceptibility, characteristics also seen after FS in rats. Of the seven genetically diverse mouse strains screened for FS susceptibility, C57BL/6J mice were among the most susceptible, whereas A/J mice were among the most resistant. Strains genetically similar to C57BL/6J also showed a susceptible phenotype. Our phenotypic data suggest that complex genetics underlie FS susceptibility and show that the C57BL/6J strain is highly susceptible to FS. As this strain has been described as resistant to convulsants, our data indicate that susceptibility genes for FS and convulsants are distinct. Insight into the mechanisms underlying seizure susceptibility and FS may help to identify markers for the early diagnosis of children at risk for complex FS and TLE and may provide new leads for treatment.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Ratones Endogámicos C57BL/genética , Convulsiones Febriles/genética , Convulsiones Febriles/fisiopatología , Animales , Conducta Animal , Convulsivantes/farmacología , Electrofisiología , Fiebre/genética , Fiebre/fisiopatología , Hipocampo/fisiopatología , Masculino , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos DBA , Pentilenotetrazol/farmacología , Fenotipo , Ratas , Ratas Sprague-Dawley , Convulsiones Febriles/inducido químicamente , Especificidad de la EspecieRESUMEN
The sexual activity of 40 male Wistar rats was tested weekly in a bilevel test chamber to evaluate the involvement of endogenous opioids in the appetitive and consummatory aspects of sexual behavior. It has been suggested that the increase of the anticipatory level-changing behavior over repeated testing, displayed before the introduction of a receptive female, is sexually motivated. Two doses of the opioid antagonist naloxone, 1 and 10 mg/kg, prevented the increase of the anticipatory level-changing over four repeated tests of sexually experienced rats without prior experience in the bilevel test chamber and decreased the number of level changes of rats displaying a high number of level changes. Analysis of the pattern of inhibition suggested that the lower dose of naloxone may reduce sexual reward and that, in addition, the higher dose may block the expression of motivation. In contrast, naloxone treatment facilitated the efficiency of the sexual performance, with less mounts and intromissions preceding ejaculation and a shorter ejaculation latency, implying an inhibitory role of endogenous opioids in the neural control of some aspects of sexual performance (e.g., ejaculatory threshold). These results suggest that endogenous opioids may increase sexual appetite and diminish sexual performance.
Asunto(s)
Endorfinas/fisiología , Naloxona/farmacología , Conducta Sexual Animal/fisiología , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Análisis Multivariante , Ratas , Ratas Wistar , Valores de Referencia , Conducta Sexual Animal/efectos de los fármacosRESUMEN
Joint inflammations were induced in mice by cloned MT4+ Lyt-2- T cells specific for methylated bovine serum albumin. This was done either by intra-articular or by i.v. administration of the cloned T cells, together with local injection of the antigen. Local rechallenge with methylated bovine serum albumin several weeks after waning of the joint inflammation caused a flare-up reaction. The inflammations were quantified by a 99mTc-uptake method and examined histologically. The arthritis induced by the cloned T cells showed aspects of a delayed type hypersensitivity reaction characterized by an intense infiltrate which resembles the inflammation in the human rheumatoid joint. The data presented show that joint inflammations can be induced by T cells only and that, after waning, reexposition to the original antigen can induce a flare-up reaction. The data suggest a central role of T cells in the induction and the exacerbations observed in rheumatoid arthritis.
Asunto(s)
Albúmina Sérica Bovina/inmunología , Linfocitos T/inmunología , Animales , Antígenos/inmunología , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Células Clonales/inmunología , Células Clonales/trasplante , Modelos Animales de Enfermedad , Hipersensibilidad Tardía/inmunología , Hipersensibilidad Tardía/patología , Inmunización Pasiva , Inflamación , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Desnudos , Linfocitos T/trasplanteRESUMEN
Delayed-type hypersensitivity (DTH) reactions to allogeneic histocompatibility antigens in mice could be systemically suppressed by a single exposure to UV-B irradiation. The extent of suppression reached its maximum 4 days after irradiation, gradually waned thereafter, and disappeared at Day 21. Re-exposure of these mice to UV-B after waning reinduced the state of suppression. The suppression could be transferred to naive mice by means of splenic T lymphocytes. The suppressor T (Ts) cells suppressed the proliferative activity in the lymph nodes draining the site of immunization, but not the activity of already activated DTH-reactive T cells. Phenotypical analysis of these Ts cells revealed that two subpopulations of T cells are involved: one with the Lyt-1+, 2- phenotype, the other with the Lyt-1-, 2+ phenotype.
Asunto(s)
Antígenos de Histocompatibilidad/inmunología , Hipersensibilidad Tardía/inmunología , Tolerancia Inmunológica/efectos de la radiación , Rayos Ultravioleta , Animales , Antígenos de Superficie/análisis , Femenino , Cinética , Ratones , Ratones Endogámicos , Bazo/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Delayed-type hypersensitivity (DTH) reactions were induced in mice by cloned helper T cells directed against methylated bovine serum albumin (mBSA). The DTH reactions were induced either by local injection of the helper T cells together with the antigen in the hind feet or by intravenous (iv) administration of the cloned T cells and local injection of the antigen. Local or systemic (oral or iv) administration of mBSA after waning of the DTH induced by the cloned helper T cells caused a flare-up reaction. This indicates that functional helper T cells persist at the inflammation site. The inflammations were quantified in a foot swelling assay and were examined histologically. The inflammation measured in the flare-up reaction was generally lower than in the acute reaction. Histologically the acute inflammation showed edema and a large proportion of granulocytes, whereas the flare-up reaction appeared more histiocytic and showed less edema.
Asunto(s)
Hipersensibilidad Tardía/patología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Bovinos , Células Clonales/inmunología , Células Clonales/trasplante , Edema/etiología , Edema/patología , Eritema/etiología , Eritema/patología , Femenino , Hipersensibilidad Tardía/etiología , Hipersensibilidad Tardía/inmunología , Inmunización Pasiva , Inflamación , Ratones , Albúmina Sérica/inmunología , Linfocitos T Colaboradores-Inductores/trasplanteRESUMEN
Cytogenetic investigations were performed on 25 individuals belonging to six melanoma-prone families with multiple melanocytic lesions (the dysplastic nevus syndrome, DNS). Patients having DNS with or without a history of melanoma were compared with clinically normal relatives and unrelated normal controls. The results indicate normal frequencies of hyperdiploidy and spontaneous sister chromatid exchanges in the fibroblasts of all individuals studied. Karyotypic analyses were carried out on the members of one family. The patients with DNS had a normal constitutional karyotype. In lymphocytes or fibroblasts from five patients, however, increased frequencies of cells with random chromosomal rearrangements were observed. These abnormalities, mainly translocations and inversions, were not found in two of the patients' spouses and in six clinically normal relatives. In the fibroblast cultures considerable clonal selection of cytogenetically abnormal cells occurred.
Asunto(s)
Aberraciones Cromosómicas , Síndrome del Nevo Displásico/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Diploidia , Susceptibilidad a Enfermedades , Femenino , Fibroblastos/ultraestructura , Humanos , Cariotipificación , Linfocitos/ultraestructura , Masculino , Linaje , Intercambio de Cromátides HermanasRESUMEN
Joint inflammation was induced in mice by cloned helper T cells specific for methylated bovine serum albumin (mBSA). This occurred after local injection of the helper T cells together with mBSA into the knee joint, but also when the helper T cells were intravenously injected and the antigen directly into the joint. Local injection of mBSA several weeks after waning of a joint inflammation induced by cloned helper T cells caused a flare-up reaction, indicating that the helper T cells persisted in the joint after the primary inflammation.