RESUMEN
Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone-modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K-acetyltransferase 2a (Kat2a)--a HAT that has not been studied for its role in memory function so far--shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long-term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation.
Asunto(s)
Regulación de la Expresión Génica , Redes Reguladoras de Genes , Histona Acetiltransferasas/metabolismo , Memoria , Animales , Región CA1 Hipocampal/enzimología , Perfilación de la Expresión Génica , Histona Acetiltransferasas/genética , Ratones , Ratones NoqueadosRESUMEN
Mammalian neuronal stem cells produce multiple neuron types in the course of an individual's development. Similarly, neuronal progenitors in the Drosophila brain generate different types of closely related neurons that are born at specific time points during development. We found that in the post-embryonic Drosophila brain, steroid hormones act as temporal cues that specify the cell fate of mushroom body (MB) neuroblast progeny. Chronological regulation of neurogenesis is subsequently mediated by the microRNA (miRNA) let-7, absence of which causes learning impairment due to morphological MB defects. The miRNA let-7 is required to regulate the timing of α'/ß' to α/ß neuronal identity transition by targeting the transcription factor Abrupt. At a cellular level, the ecdysone-let-7-Ab signalling pathway controls the expression levels of the cell adhesion molecule Fasciclin II in developing neurons that ultimately influences their differentiation. Our data propose a novel role for miRNAs as transducers between chronologically regulated developmental signalling and physical cell adhesion.
Asunto(s)
Diferenciación Celular/fisiología , Drosophila/crecimiento & desarrollo , Hormonas Esteroides Gonadales/metabolismo , MicroARNs/fisiología , Cuerpos Pedunculados/crecimiento & desarrollo , Células-Madre Neurales/fisiología , Neurogénesis/fisiología , Animales , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de Drosophila/metabolismo , Ecdisona/metabolismo , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/fisiología , Inmunohistoquímica , Hibridación in Situ , MicroARNs/metabolismo , Cuerpos Pedunculados/citología , Proteínas Nucleares/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Training can improve the ability to discriminate between similar, confusable stimuli, including odors. One possibility of enhancing behaviorally expressed discrimination (i.e., sensory acuity) relies on differential associative learning, during which animals are forced to detect the differences between similar stimuli. Drosophila represents a key model organism for analyzing neuronal mechanisms underlying both odor processing and olfactory learning. However, the ability of flies to enhance fine discrimination between similar odors through differential associative learning has not been analyzed in detail. We performed associative conditioning experiments using chemically similar odorants that we show to evoke overlapping neuronal activity in the fly's antennal lobes and highly correlated activity in mushroom body lobes. We compared the animals' performance in discriminating between these odors after subjecting them to one of two types of training: either absolute conditioning, in which only one odor is reinforced, or differential conditioning, in which one odor is reinforced and a second odor is explicitly not reinforced. First, we show that differential conditioning decreases behavioral generalization of similar odorants in a choice situation. Second, we demonstrate that this learned enhancement in olfactory acuity relies on both conditioned excitation and conditioned inhibition. Third, inhibitory local interneurons in the antennal lobes are shown to be required for behavioral fine discrimination between the two similar odors. Fourth, differential, but not absolute, training causes decorrelation of odor representations in the mushroom body. In conclusion, differential training with similar odors ultimately induces a behaviorally expressed contrast enhancement between the two similar stimuli that facilitates fine discrimination.
Asunto(s)
Aprendizaje por Asociación/fisiología , Discriminación en Psicología/fisiología , Movimiento/fisiología , Bulbo Olfatorio/fisiología , Vías Olfatorias/fisiología , Olfato/fisiología , Análisis de Varianza , Animales , Animales Modificados Genéticamente , Reacción de Prevención/fisiología , Calcio/metabolismo , Condicionamiento Clásico/fisiología , Proteínas de Drosophila/genética , Drosophila melanogaster , Femenino , Generalización Psicológica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Odorantes , Vías Olfatorias/citología , Análisis de Componente Principal , Células Receptoras Sensoriales/fisiología , Olfato/genética , Factores de TiempoRESUMEN
Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Our findings provide evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting.
Asunto(s)
Endocitosis , Memoria , Receptores AMPA/fisiología , Sinapsis/fisiología , Sinaptotagminas/fisiología , Animales , Calcio/fisiología , Células Cultivadas , Femenino , Células HEK293 , Hipocampo/citología , Hipocampo/fisiología , Humanos , Inmunohistoquímica , Técnicas In Vitro , Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Noqueados , Neuronas/fisiología , Transporte de Proteínas , Ratas Wistar , Fracciones Subcelulares , Vesículas Sinápticas , Sinaptosomas , Sinaptotagminas/genética , TransfecciónRESUMEN
Animal behavior is, on the one hand, controlled by neuronal circuits that integrate external sensory stimuli and induce appropriate motor responses. On the other hand, stimulus-evoked or internally generated behavior can be influenced by motivational conditions, e.g., the metabolic state. Motivational states are determined by physiological parameters whose homeostatic imbalances are signaled to and processed within the brain, often mediated by modulatory peptides. Here, we investigate the regulation of appetitive and feeding behavior in the fruit fly, Drosophila melanogaster. We report that four neurons in the fly brain that release SIFamide are integral elements of a complex neuropeptide network that regulates feeding. We show that SIFamidergic cells integrate feeding stimulating (orexigenic) and feeding suppressant (anorexigenic) signals to appropriately sensitize sensory circuits, promote appetitive behavior, and enhance food intake. Our study advances the cellular dissection of evolutionarily conserved signaling pathways that convert peripheral metabolic signals into feeding-related behavior.
Asunto(s)
Proteínas de Drosophila/metabolismo , Neuropéptidos/metabolismo , Animales , Conducta Apetitiva/fisiología , Conducta Animal/fisiología , Drosophila melanogaster , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , Hambre/fisiología , Neuronas/metabolismoRESUMEN
Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's disease (AD). Effective therapies for these diseases are lacking. Here, we evaluated mouse models of age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity in the brain and peripheral organs. We determined that aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region as the result of epigenetic-dependent alterations in gene expression. In both amyloid and aging models, inflammation was associated with increased gene expression linked to a subset of transcription factors, while plasticity gene deregulation was differentially mediated. Amyloid pathology impaired histone acetylation and decreased expression of plasticity genes, while aging altered H4K12 acetylation-linked differential splicing at the intron-exon junction in neurons, but not nonneuronal cells. Furthermore, oral administration of the clinically approved histone deacetylase inhibitor vorinostat not only restored spatial memory, but also exerted antiinflammatory action and reinstated epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This study provides a systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and suggests that histone deacetylase inhibitors should be further explored as a cost-effective therapeutic strategy against age-associated cognitive decline.
Asunto(s)
Enfermedad de Alzheimer , Región CA1 Hipocampal , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Memoria/efectos de los fármacos , Transcriptoma , Acetilación/efectos de los fármacos , Envejecimiento , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Amiloide/genética , Amiloide/metabolismo , Animales , Región CA1 Hipocampal/enzimología , Región CA1 Hipocampal/patología , Modelos Animales de Enfermedad , Histonas/genética , Histonas/metabolismo , Humanos , Ratones , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , VorinostatRESUMEN
Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.
RESUMEN
The fruit fly Drosophila melanogaster represents a key model organism for analyzing how neuronal circuits regulate behavior. The mushroom body in the central brain is a particularly prominent brain region that has been intensely studied in several insect species and been implicated in a variety of behaviors, e.g., associative learning, locomotor activity, and sleep. Drosophila melanogaster offers the advantage that transgenes can be easily expressed in neuronal subpopulations, e.g., in intrinsic mushroom body neurons (Kenyon cells). A number of transgenes has been described and engineered to visualize the anatomy of neurons, to monitor physiological parameters of neuronal activity, and to manipulate neuronal function artificially. To target the expression of these transgenes selectively to specific neurons several sophisticated bi- or even multipartite transcription systems have been invented. However, the number of transgenes that can be combined in the genome of an individual fly is limited in practice. To facilitate the analysis of the mushroom body we provide a compilation of transgenic fruit flies that express transgenes under direct control of the Kenyon-cell specific promoter, mb247. The transgenes expressed are fluorescence reporters to analyze neuroanatomical aspects of the mushroom body, proteins to restrict ectopic gene expression to mushroom bodies, or fluorescent sensors to monitor physiological parameters of neuronal activity of Kenyon cells. Some of the transgenic animals compiled here have been published already, whereas others are novel and characterized here for the first time. Overall, the collection of transgenic flies expressing sensor and reporter genes in Kenyon cells facilitates combinations with binary transcription systems and might, ultimately, advance the physiological analysis of mushroom body function.