RESUMEN
Leptin receptor (LepRb) signaling in the hindbrain is required for energy balance control. Yet the specific hindbrain neurons and the behavioral processes mediating energy balance control by hindbrain leptin signaling are unknown. Studies here employ genetic [adeno-associated virally mediated RNA interference (AAV-RNAi)] and pharmacological methodologies to specify the neurons and the mechanisms through which hindbrain LepRb signaling contributes to the control of food intake. Results show that AAV-RNAi-mediated LepRb knockdown targeting a region encompassing the mNTS and area postrema (AP) (mNTS/AP LepRbKD) increases overall cumulative food intake by increasing the size of spontaneous meals. Other results show that pharmacological hindbrain leptin delivery and RNAi-mediated mNTS/AP LepRb knockdown increased and decreased the intake-suppressive effects of intraduodenal nutrient infusion, respectively. These meal size and intestinally derived signal amplification effects are likely mediated by LepRb signaling in the mNTS and not the AP, since 4th icv and mNTS parenchymal leptin (0.5 µg) administration reduced food intake, whereas this dose did not influence food intake when injected into the AP. Overall, these findings deepen the understanding of the distributed neuronal systems and behavioral mechanisms that mediate the effects of leptin receptor signaling on the control of food intake.
Asunto(s)
Ingestión de Alimentos/fisiología , Intestinos/fisiología , Receptores de Leptina/fisiología , Saciedad/fisiología , Transducción de Señal/fisiología , Núcleo Solitario/fisiología , Animales , Área Postrema/efectos de los fármacos , Área Postrema/fisiología , Ingestión de Alimentos/efectos de los fármacos , Intestinos/efectos de los fármacos , Leptina/farmacología , Masculino , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Receptores de Leptina/genética , Saciedad/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Núcleo Solitario/efectos de los fármacosRESUMEN
Recent evidence has emerged demonstrating that metabolic hormones such as ghrelin and leptin can act on ventral tegmental area (VTA) midbrain dopamine neurons to influence feeding. The VTA is the origin of mesolimbic dopamine neurons that project to the nucleus accumbens (NAc) to influence behavior. While blockade of dopamine via systemic antagonists or targeted gene delete can impair food intake, local NAc dopamine manipulations have little effect on food intake. Notably, non-dopaminergic manipulations in the VTA and NAc produce more consistent effects on feeding and food choice. More recent genetic evidence supports a role for the substantia nigra-striatal dopamine pathways in food intake, while the VTA-NAc circuit is more likely involved in higher-order aspects of food acquisition, such as motivation and cue associations. This rich and complex literature should be considered in models of how peripheral hormones influence feeding behavior via action on the midbrain circuits.
Asunto(s)
Dopamina/fisiología , Ingestión de Alimentos/fisiología , Hormonas Peptídicas/fisiología , Animales , Cuerpo Estriado/fisiología , Ghrelina/fisiología , Humanos , Leptina/fisiología , Neuronas/fisiología , Núcleo Accumbens/fisiología , Transducción de Señal , Sustancia Negra/fisiología , Área Tegmental Ventral/fisiologíaRESUMEN
The ad hoc genetic correlation between ethanol sensitivity and learning mechanisms in Drosophila could overemphasize a common process supporting both behaviors. To challenge directly the hypothesis that these mechanisms are singular, we examined the learning phenotypes of 10 new strains. Five of these have increased ethanol sensitivity, and the other 5 do not. We tested place and olfactory memory in each of these lines and found two new learning mutations. In one case, altering the tribbles gene, flies have a significantly reduced place memory, elevated olfactory memory, and normal ethanol response. In the second case, mutation of a gene we name ethanol sensitive with low memory (elm), place memory was not altered, olfactory memory was sharply reduced, and sensitivity to ethanol was increased. In sum, however, we found no overall correlation between ethanol sensitivity and place memory in the 10 lines tested. Furthermore, there was a weak but nonsignificant correlation between ethanol sensitivity and olfactory learning. Thus, mutations that alter learning and sensitivity to ethanol can occur independently of each other and this implies that the set of genes important for both ethanol sensitivity and learning is likely a subset of the genes important for either process.
Asunto(s)
Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Etanol/farmacología , Memoria/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Elementos Transponibles de ADN/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Cabeza , Memoria/fisiología , Mutagénesis Insercional/efectos de los fármacos , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Novel therapeutic interventions for obesity and comorbid conditions require knowledge of the molecular elements playing a role in the development of obesity. Chronic low-grade inflammation has been consistently reported in obese individuals. In this study, we first determined whether key molecular modulators of inflammation, microRNA-155 (miR-155) and microRNA-146a (miR-146a), are regulated by an obesogenic diet within brain regions associated with reward, metabolism and energy balance. C57BL/6J mice were chronically exposed to a high-fat diet (HFD) or a standard chow (CTL). Significant reductions in the levels of miR-155 (82%) and miR-146a (41%) levels were observed within the nucleus accumbens of HFD mice compared to CTL. Further analysis of miR-155 regulation showed no significant changes in levels across peripheral tissue (white adipose, spleen, kidney or liver) between HFD and CTL mice. The effect of lower miR-155 on the development of obesity was determined by exposing wild-type (WT) and miR-155 knockout mice (miR-155 KO) to HFD. Male miR-155 KO gained significantly more weight than WT littermates. Metabolic analyses revealed that miR-155 KO significantly ate more HFD compared to WT, without differing in other metabolic measures including energy expenditure. Together, these data show that miR-155 is physiologically down-regulated after intake of an obesogenic diet, and that loss of miR-155 increases intake of an obesogenic diet. Moreover, these findings shed light on a potential miRNA-based mechanism contributing to the development of diet-induced obesity.
Asunto(s)
Encéfalo/metabolismo , MicroARNs/metabolismo , Obesidad/metabolismo , Tejido Adiposo Blanco/metabolismo , Adiposidad/genética , Animales , Peso Corporal/genética , Dieta Alta en Grasa , Regulación hacia Abajo , Ingestión de Alimentos/genética , Metabolismo Energético/genética , Riñón/metabolismo , Hígado/metabolismo , Ratones , Ratones Noqueados , MicroARNs/genética , Obesidad/genética , Bazo/metabolismoRESUMEN
Increasing rates of obesity have alarmed health officials and prompted much public dialogue. While the factors leading to obesity are numerous, an inability to control intake of freely available food is central to the problem. In order to understand this, we need to better define the mechanisms by which the brain regulates food intake, and why it is often difficult to control consumption. From this point of view, it seems valuable to consider the commonalities between food intake and drug abuse. While research in the two fields has historically emphasized different neural substrates, recent data have increased interest in better defining elements that may underlie both drug addiction and obesity. Here we discuss some of these shared elements with an emphasis on emerging areas of research that better define common mechanisms leading to overconsumption.
Asunto(s)
Conducta Adictiva/fisiopatología , Obesidad/fisiopatología , Trastornos Relacionados con Sustancias/fisiopatología , Animales , Conducta Adictiva/psicología , Encéfalo/fisiopatología , Humanos , Obesidad/psicología , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
In several animal species including humans, the acute administration of low doses of alcohol increases motor activity. Different theories have postulated that alcohol-induced hyperactivity is causally related to alcoholism. Moreover, a common biological mechanism in the mesolimbic dopamine system has been proposed to mediate the stimulant and motivational effects of alcohol. Numerous studies have examined whether alcohol-induced hyperactivity is related to alcoholism using a great variety of animal models and several animal species. However, there is no review that has summarized this extensive literature. In this article, we present the various experimental models that have been used to study the relationship between the stimulant and motivational effects of alcohol in rodents and primates. Furthermore, we discuss whether the theories hypothesizing a causal link between alcohol-induced hyperactivity and alcoholism are supported by published results. The reviewed findings indicate that animal species that are stimulated by alcohol also exhibit alcohol preference. Additionally, the role of dopamine in alcohol-induced hyperactivity is well established since blocking dopaminergic activity suppresses the stimulant effects of alcohol. However, dopamine transmission plays a much more complex function in the motivational properties of alcohol and the neuronal mechanisms involved in alcohol stimulation and reward are distinct. Overall, the current review provides mixed support for theories suggesting that the stimulant effects of alcohol are related to alcoholism and highlights the importance of animal models as a way to gain insight into alcoholism.
Asunto(s)
Alcoholismo/psicología , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Motivación/efectos de los fármacos , Recompensa , Consumo de Bebidas Alcohólicas/patología , Consumo de Bebidas Alcohólicas/psicología , Alcoholismo/patología , Animales , Estimulantes del Sistema Nervioso Central/administración & dosificación , Relación Dosis-Respuesta a Droga , Humanos , Motivación/fisiología , Primates , Especificidad de la EspecieRESUMEN
The orexin/hypocretin system interacts with many of the same circuitries contributing to stress-associated disorders like depression and anxiety. These include potentially reciprocal connections with corticotropin releasing factor (CRF) neurons which drive the hypothalamic-pituitary-adrenal (HPA) endocrine response in addition to having an anxiogenic effect in the central amygdala (CeA). Antagonism of the orexin type 1 receptor (Orx1) in the hypothalamus has also been shown to block panic attacks. However, few studies have investigated the effect of orexinergic signaling in the basolateral amygdala (BLA) which is responsible for contextual fear, and modulates the activity of the CeA. To this end, we chronically stressed c57bl/6 mice with social defeat and examined the gene expression of the orexin receptors in the BLA. We found that the transcripts for the Orx1 and Orx2 receptors diverged in the BLA with Orx1 increasing and Orx2 decreasing in animals that were susceptible to the chronic defeat. These changes were not seen in the prelimbic cortex (PrL) which sends efferents to the BLA. We then tried to recapitulate these expression patterns in the BLA using short hairpin interfering sequences delivered by adeno-associated viruses to knock down the orexin receptors. While the Orx1 knockdown did reduce locomotor activity, it did not decrease depressive or anxious behaviors. Knocking down the Orx2 receptors in the BLA increased anxious behavior as measured by reduced social preference and reduced time spent in the center of an open field. Due to the divergent expression patterns of the two receptors in response to chronic stress, orexinergic activity in the BLA may be responsible for bidirectional modulation of anxious behavior. Furthermore, these data raise the possibility that an Orx2 agonist may serve as an effective means to treat anxiety disorders.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Ansiolíticos , Ansiedad/genética , Ansiedad/metabolismo , Receptores de Orexina/genética , Amígdala del Cerebelo/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Ansiolíticos/metabolismo , Conducta Animal/efectos de los fármacos , Dominación-Subordinación , Miedo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Antagonistas de los Receptores de Orexina , Receptores de Orexina/metabolismo , ARN Interferente Pequeño/farmacología , Resiliencia Psicológica/efectos de los fármacosRESUMEN
Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake.
Asunto(s)
Ingestión de Alimentos/fisiología , Neuronas/metabolismo , Corteza Prefrontal/citología , Receptores de Dopamina D1/metabolismo , Amígdala del Cerebelo/metabolismo , Análisis de Varianza , Animales , Biofisica , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Channelrhodopsins , Ingestión de Alimentos/genética , Estimulación Eléctrica , Femenino , Privación de Alimentos/fisiología , Lateralidad Funcional , Regulación de la Expresión Génica/genética , Técnicas In Vitro , Proteínas Luminiscentes/genética , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibición Neural/genética , Inhibición Neural/efectos de la radiación , Vías Nerviosas/fisiología , Optogenética , Técnicas de Placa-Clamp , Estimulación Luminosa/efectos adversos , Receptores de Dopamina D1/genética , Factores de TiempoRESUMEN
BACKGROUND: Food restriction is known to enhance learning and motivation. The neural mechanisms underlying these responses likely involve alterations in gene expression in brain regions mediating the motivation to feed. METHODS: Analysis of gene expression profiles in male C57BL/6J mice using whole-genome microarrays was completed in the medial prefrontal cortex, nucleus accumbens, ventral tegmental area, and the hypothalamus following a 5-day food restriction. Quantitative polymerase chain reaction was used to validate these findings and determine the time course of expression changes. Plasma levels of the stress hormone corticosterone (CORT) were measured by enzyme-linked immunosorbent assay. Expression changes were measured in adrenalectomized animals that underwent food restriction, as well as in animals receiving daily injections of CORT. Progressive ratio responding for food, a measure of motivated behavior, was assessed after CORT treatment in restricted and fed animals. RESULTS: Brief food restriction results in an upregulation of peripheral stress responsive genes in the mammalian brain. Time-course analysis demonstrated rapid and persistent expression changes in all four brain regions under study. Administration of CORT to nonrestricted animals was sufficient to induce a subset of the genes, and alterations in gene expression after food restriction were dependent on intact adrenal glands. CORT can increase the motivation to work for food only in the restricted state. CONCLUSIONS: These data demonstrate a central role for CORT in mediating both molecular and behavioral responses to food restriction. The stress hormone-induced alterations in gene expression described here may be relevant for both adaptive and pathological responses to stress.
Asunto(s)
Corticosterona , Perfilación de la Expresión Génica , Aprendizaje/efectos de los fármacos , Motivación/efectos de los fármacos , Inanición , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/cirugía , Adrenalectomía/psicología , Hormona Adrenocorticotrópica/antagonistas & inhibidores , Hormona Adrenocorticotrópica/metabolismo , Animales , Conducta Animal , Encéfalo/metabolismo , Corticosterona/administración & dosificación , Corticosterona/metabolismo , Ensayo de Inmunoadsorción Enzimática , Estudio de Asociación del Genoma Completo , Glucocorticoides/administración & dosificación , Glucocorticoides/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/genética , Inanición/genética , Inanición/metabolismo , Inanición/psicologíaRESUMEN
The genetic mechanisms that influence memory formation and sensitivity to the effects of ethanol on behavior in Drosophila have some common elements. So far, these have centered on the cAMP/PKA signaling pathway, synapsin and fas2-dependent processes, pumilio-dependent regulators of translation, and a few other genes. However, there are several genes that are important for one or the other behaviors, suggesting that there is an incomplete overlap in the mechanisms that support memory and ethanol sensitive behaviors. The basis for this overlap is far from understood. We therefore examined memory in arouser (aru) mutant flies, which have recently been identified as having ethanol sensitivity deficits. The aru mutant flies showed memory deficits in both short-term place memory and olfactory memory tests. Flies with a revertant aru allele had wild-type levels of memory performance, arguing that the aru gene, encoding an EPS8L3 product, has a role in Drosophila memory formation. Furthermore, and interestingly, flies with the aru(8-128) insertion allele had deficits in only one of two genetic backgrounds in place and olfactory memory tests. Flies with an aru imprecise excision allele had deficits in tests of olfactory memory. Quantitative measurements of aru EPS8L3 mRNA expression levels correlate decreased expression with deficits in olfactory memory while over expression is correlated with place memory deficits. Thus, mutations of the aru EPS8L3 gene interact with the alleles of a particular genetic background to regulate arouser expression and reveals a role of this gene in memory.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Arabidopsis/genética , Drosophila melanogaster/genética , Drosophila melanogaster/fisiología , Genes de Insecto/genética , Memoria/fisiología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Alelos , Animales , Proteínas de Arabidopsis/metabolismo , Conducta Animal , Proteínas de Drosophila , Regulación de la Expresión Génica , Trastornos de la Memoria/genética , Trastornos de la Memoria/fisiopatología , Mutación/genética , Bulbo Olfatorio/metabolismo , FenotipoRESUMEN
A reduced sensitivity to the sedating effects of alcohol is a characteristic associated with alcohol use disorders (AUDs). A genetic screen for ethanol sedation mutants in Drosophila identified arouser (aru), which functions in developing neurons to reduce ethanol sensitivity. Genetic evidence suggests that aru regulates ethanol sensitivity through its activation by Egfr/Erk signaling and its inhibition by PI3K/Akt signaling. The aru mutant also has an increased number of synaptic terminals in the larva and adult fly. Both the increased ethanol sensitivity and synapse number of the aru mutant are restored upon adult social isolation, suggesting a causal relationship between synapse number and ethanol sensitivity. We thus show that a developmental abnormality affecting synapse number and ethanol sensitivity is not permanent and can be reversed by manipulating the environment of the adult fly.
Asunto(s)
Conducta Animal/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Proteínas de Drosophila/genética , Etanol/farmacología , Mutación/genética , Sinapsis/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Animales Modificados Genéticamente , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Conducta Animal/fisiología , Encéfalo/citología , Encéfalo/metabolismo , Drosophila , Proteínas de Drosophila/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Larva , Unión Neuromuscular/genética , Unión Neuromuscular/crecimiento & desarrollo , Unión Neuromuscular/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Interferencia de ARN/fisiología , Receptores de Péptidos de Invertebrados/genética , Receptores de Péptidos de Invertebrados/metabolismo , Reflejo/efectos de los fármacos , Reflejo/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Aislamiento Social , Sinapsis/efectos de los fármacosRESUMEN
The relationship between alcohol consumption, sensitivity, and tolerance is an important question that has been addressed in humans and rodent models. Studies have shown that alcohol consumption and risk of abuse may correlate with (1) increased sensitivity to the stimulant effects of alcohol, (2) decreased sensitivity to the depressant effects of alcohol, and (3) increased alcohol tolerance. However, many conflicting results have been observed. To complement these studies, we utilized a different organism and approach to analyze the relationship between ethanol consumption and other ethanol responses. Using a set of 20 Drosophila melanogaster mutants that were isolated for altered ethanol sensitivity, we measured ethanol-induced hyperactivity, ethanol sedation, sedation tolerance, and ethanol consumption preference. Ethanol preference showed a strong positive correlation with ethanol tolerance, consistent with some rodent and human studies, but not with ethanol hyperactivity or sedation. No pairwise correlations were observed between ethanol hyperactivity, sedation, and tolerance. The evolutionary conservation of the relationship between tolerance and ethanol consumption in flies, rodents, and humans indicates that there are fundamental biological mechanisms linking specific ethanol responses.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Intoxicación Alcohólica/genética , Depresores del Sistema Nervioso Central/farmacología , Drosophila melanogaster/genética , Etanol/farmacología , Animales , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/metabolismo , Preferencias Alimentarias , Hipercinesia/inducido químicamente , Masculino , Factores de Transcripción/metabolismoRESUMEN
Leptin acts on the ventral tegmental area (VTA) to modulate neuronal function and feeding behavior in rats and mice. To identify the intracellular effectors of the leptin receptor (Lepr), downstream signal transduction events were assessed for regulation by direct leptin infusion. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and phosphorylated extracellular signal-regulated kinase-1 and -2 (pERK1/2) were increased in the VTA while phospho-AKT (pAKT) was unaffected. Pretreatment of brain slices with the mitogen-activated protein kinase kinase -1 and -2 (MEK1/2) inhibitor U0126 blocked the leptin-mediated decrease in firing frequency of VTA dopamine neurons. The anorexigenic effects of VTA-administered leptin were also blocked by pretreatment with U0126, which effectively blocked phosphorylation of ERK1/2 but not STAT3. These data demonstrate that pERK1/2 may have a critical role in mediating both the electrophysiogical and behavioral effects of leptin receptor signaling in the VTA.
Asunto(s)
Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Receptores de Leptina/metabolismo , Transducción de Señal , Área Tegmental Ventral/metabolismo , Animales , Western Blotting , Butadienos/farmacología , Neuronas Dopaminérgicas/metabolismo , Electrofisiología , Inhibidores Enzimáticos/farmacología , Leptina/metabolismo , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/antagonistas & inhibidores , MAP Quinasa Quinasa 2/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Nitrilos/farmacología , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Área Tegmental Ventral/citologíaRESUMEN
Orexin (or hypocretin) has been implicated in mediating drug addiction and reward. Here, we investigated orexin's contribution to morphine-induced behavioral sensitization and place preference. Orexin-/- (OKO) mice and littermate wild-type (WT) controls (n=56) and C57BL/6J mice (n=67) were tested for chronic morphine-induced locomotor sensitization or for conditioned place preference (CPP) for a morphine- or a cocaine-paired environment. C57BL/6J mice received the orexin receptor 1 (Ox1r) antagonist, SB-334867, prior to test sessions. OKO mice did not significantly differ from WT controls in locomotor activity following acute- or chronic-morphine treatments. Similarly, mice treated with the Ox1r antagonist did not differ from vehicle controls in locomotor activity following acute- or chronic-morphine treatments. In contrast, while OKO mice did not differ from WT controls in preference for a morphine-paired environment, the Ox1r antagonist significantly attenuated place preference for a morphine-, but not a cocaine-paired, environment. These data suggest that orexin action is not required for locomotor responses to acute and chronic morphine, but Ox1r signaling can influence morphine-seeking in WT animals.
Asunto(s)
Condicionamiento Clásico/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Narcóticos/farmacología , Neuropéptidos/metabolismo , Percepción Espacial/efectos de los fármacos , Animales , Benzoxazoles/administración & dosificación , Benzoxazoles/farmacología , Fármacos del Sistema Nervioso Central/administración & dosificación , Fármacos del Sistema Nervioso Central/farmacología , Cocaína/administración & dosificación , Cocaína/farmacología , Condicionamiento Clásico/fisiología , Inhibidores de Captación de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/farmacología , Femenino , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morfina/administración & dosificación , Actividad Motora/fisiología , Mutación , Naftiridinas , Narcóticos/administración & dosificación , Neuropéptidos/deficiencia , Neuropéptidos/genética , Receptores de Orexina , Orexinas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores de Neuropéptido/metabolismo , Percepción Espacial/fisiología , Factores de Tiempo , Urea/administración & dosificación , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
BACKGROUND: Orexin (hypocretin) signaling is implicated in drug addiction and reward, but its role in feeding and food-motivated behavior remains unclear. METHODS: We investigated orexin's contribution to food-reinforced instrumental responding using an orexin 1 receptor (Ox1r) antagonist, orexin -/- (OKO) and littermate wildtype (WT) mice, and RNAi-mediated knockdown of orexin. C57BL/6J (n = 76) and OKO (n = 39) mice were trained to nose poke for food under a variable ratio schedule of reinforcement. After responding stabilized, a progressive ratio schedule was initiated to evaluate motivation to obtain food reinforcement. RESULTS: Blockade of Ox1r in C57BL/6J mice impaired performance under both the variable ratio and progressive ratio schedules of reinforcement, indicating impaired motivational processes. In contrast, OKO mice initially demonstrated a delay in acquisition but eventually achieved levels of responding similar to those observed in WT animals. Moreover, OKO mice did not differ from WT mice under a progressive ratio schedule, indicating delayed learning processes but no motivational impairments. Considering the differences between pharmacologic blockade of Ox1r and the OKO mice, animals with RNAi mediated knockdown of orexin were then generated and analyzed to eliminate possible developmental effects of missing orexin. Orexin gene knockdown in the lateral hypothalamus in C57BL/6J mice resulted in blunted performance under both the variable ratio and progressive ratio schedules, resembling data obtained following Ox1r antagonism. CONCLUSIONS: The behavior seen in OKO mice likely reflects developmental compensation often seen in mutant animals. These data suggest that activation of the Ox1r is a necessary component of food-reinforced responding, motivation, or both in normal mice.
Asunto(s)
Condicionamiento Operante/fisiología , Alimentos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Neuropéptidos/fisiología , Receptores de Neuropéptido/genética , Receptores de Neuropéptido/fisiología , Animales , Benzoxazoles/farmacología , Interpretación Estadística de Datos , Área Hipotalámica Lateral/fisiología , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Naftiridinas , Receptores de Orexina , Orexinas , Interferencia de ARN , Esquema de Refuerzo , Refuerzo en Psicología , Urea/análogos & derivados , Urea/farmacología , Virus/genéticaRESUMEN
Medial nucleus tractus solitarius (mNTS) neurons express leptin receptors (LepRs), and intra-mNTS delivery of leptin reduces food intake and body weight. Here, the contribution of endogenous LepR signaling in mNTS neurons to energy balance control was examined. Knockdown of LepR in mNTS and area postrema (AP) neurons of rats (LepRKD) via adeno-associated virus short hairpin RNA-interference (AAV-shRNAi) resulted in significant hyperphagia for chow, high-fat, and sucrose diets, yielding increased body weight and adiposity. The chronic hyperphagia of mNTS/AP LepRKD rats is likely mediated by a reduction in leptin potentiation of gastrointestinal satiation signaling, as LepRKD rats showed decreased sensitivity to the intake-reducing effects of cholecystokinin. LepRKD rats showed increased basal AMP-kinase activity in mNTS/AP micropunches, and pharmacological data suggest that this increase provides a likely mechanism for their chronic hyperphagia. Overall these findings demonstrate that LepRs in mNTS and AP neurons are required for normal energy balance control.
Asunto(s)
Área Postrema/metabolismo , Receptores de Leptina/metabolismo , Núcleo Solitario/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Peso Corporal , Ingestión de Alimentos , Metabolismo Energético , Técnicas de Silenciamiento del Gen , Masculino , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Leptina/genética , Transducción de SeñalRESUMEN
Elucidation of the molecular basis of disease depends upon continued progress in defining the mechanisms by which genomic information is encoded and expressed. Transcription factor-mediated regulation of mRNA is clearly a major source of regulatory control and has been well studied. The more recent discovery of small RNAs as key regulators of gene function has introduced a new level and mechanism of regulation. Mammalian genomes contain hundreds of microRNAs (miRNAs) that each can potentially downregulate many target genes. This suggests a new source for broad control over gene regulation and has inspired extensive interest in defining miRNAs and their functions. Here, the identification of miRNAs, their biogenesis, and some examples of miRNA effects on biology and disease are reviewed and discussed. Emphasis is placed on the possible role for miRNA in nervous system development, function, and disease.
Asunto(s)
MicroARNs/metabolismo , Enfermedades del Sistema Nervioso/genética , Sistema Nervioso/metabolismo , Animales , Regulación hacia Abajo/fisiología , Redes Reguladoras de Genes , Genoma/fisiología , HumanosAsunto(s)
Química Encefálica/genética , Metabolismo Energético/fisiología , Plasticidad Neuronal/genética , Transcripción Genética/fisiología , Animales , Química Encefálica/fisiología , Metabolismo Energético/genética , Humanos , Plasticidad Neuronal/fisiología , Estrés Oxidativo/genética , Estrés Oxidativo/fisiologíaRESUMEN
Dynamic modulation of the actin cytoskeleton is critical for synaptic plasticity, abnormalities of which are thought to contribute to mental illness and addiction. Here we report that mice lacking Eps8, a regulator of actin dynamics, are resistant to some acute intoxicating effects of ethanol and show increased ethanol consumption. In the brain, the N-methyl-D-aspartate (NMDA) receptor is a major target of ethanol. We show that Eps8 is localized to postsynaptic structures and is part of the NMDA receptor complex. Moreover, in Eps8 null mice, NMDA receptor currents and their sensitivity to inhibition by ethanol are abnormal. In addition, Eps8 null neurons are resistant to the actin-remodeling activities of NMDA and ethanol. We propose that proper regulation of the actin cytoskeleton is a key determinant of cellular and behavioral responses to ethanol.