RESUMEN

Modifying established behavior in novel situations is essential, and patients with neuropsychiatric disorders often lack this flexibility. Understanding how novelty affects behavioral flexibility therefore has therapeutic potential. Here, novelty differentially impacts connectivity within the ventral tegmental-hippocampal-medial prefrontal (VTA-HPC-mPFC) circuit, thereby enhancing the ability of mice to overcome established behavioral bias and adapt to new rules. Circuit connectivity was measured by local field potential (LFP) coherence. As mice exposed to novelty learned to overcome previously established spatial bias, the ventral HPC (vHPC) strengthens its coherence with the VTA and mPFC in theta frequency (4-8 Hz). Novelty or learning did not affect circuits involving the dorsal HPC (dHPC). Without novelty, however, mice continued following established spatial bias and connectivity strength remained stable in the VTA-HPC-mPFC circuit. Pharmacologically blocking dopamine D1-receptors (D1Rs) in the vHPC abolished the behavioral and physiological impacts of novelty. Thus, novelty promotes behavioral adaptation by permitting learning-associated plasticity in the vHPC-mPFC and VTA-vHPC circuit, a process mediated by D1Rs in the vHPC.

RESUMEN

Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.

Asunto(s)

Neuronas GABAérgicas/fisiología , Núcleo Accumbens/fisiología , Estrés Fisiológico/fisiología , Área Tegmental Ventral/fisiología , Ácido gamma-Aminobutírico/metabolismo , Potenciales de Acción/fisiología , Animales , Anticipación Psicológica/fisiología , Conducta Animal , Relojes Biológicos/fisiología , Dopamina/metabolismo , Neuronas Dopaminérgicas/fisiología , Neuronas Dopaminérgicas/efectos de la radiación , Femenino , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de la radiación , Inmunohistoquímica , Sistema Límbico/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/efectos de la radiación , Optogenética , Restricción Física/fisiología , Restricción Física/psicología , Recompensa , Área Tegmental Ventral/efectos de la radiación

RESUMEN

The ability to rapidly adapt to novel situations is essential for survival, and this flexibility is impaired in many neuropsychiatric disorders1. Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Exposure to novelty recruits the hippocampus and medial prefrontal cortex (mPFC)2 and may prime hippocampal-prefrontal circuitry for subsequent learning-associated plasticity. Here we show that novelty resets the neural circuits that link the ventral hippocampus (vHPC) and the mPFC, facilitating the ability to overcome an established strategy. Exposing mice to novelty disrupted a previously encoded strategy by reorganizing vHPC activity to local theta (4-12 Hz) oscillations and weakening existing vHPC-mPFC connectivity. As mice subsequently adapted to a new task, vHPC neurons developed new task-associated activity, vHPC-mPFC connectivity was strengthened, and mPFC neurons updated to encode the new rules. Without novelty, however, mice adhered to their established strategy. Blocking dopamine D1 receptors (D1Rs) or inhibiting novelty-tagged cells that express D1Rs in the vHPC prevented these behavioural and physiological effects of novelty. Furthermore, activation of D1Rs mimicked the effects of novelty. These results suggest that novelty promotes adaptive learning by D1R-mediated resetting of vHPC-mPFC circuitry, thereby enabling subsequent learning-associated circuit plasticity.

Asunto(s)

Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Vías Nerviosas/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Animales , Femenino , Hipocampo/citología , Potenciación a Largo Plazo , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/citología

RESUMEN

Activity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, translin knockout (KO) mice, which lack translin/trax, exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome (fragile X mental retardation protein-FMRP-KO mice). Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic protein kinase A (PKA) activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression (mGluR-LTD), a hallmark of the FMRP KO mice. On the contrary, translin KO mice exhibited deficits in N-methyl-D-aspartate receptor (NMDAR) dependent LTD, a phenotype not observed in the FMRP knockouts. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling and suggest that translin/trax and FMRP play distinct roles in hippocampal synaptic plasticity.

Asunto(s)

Proteínas de Unión al ADN/metabolismo , Hipocampo/fisiología , Plasticidad Neuronal , Proteínas de Unión al ARN/metabolismo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Potenciación a Largo Plazo/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo

RESUMEN

Decreased hippocampal-prefrontal synchrony may mediate cognitive deficits in schizophrenia, but it remains unclear which cells orchestrate this long-range synchrony. Parvalbumin (PV)- and somatostatin (SOM)-expressing interneurons show histological abnormalities in individuals with schizophrenia and are hypothesized to regulate oscillatory synchrony within the prefrontal cortex. To examine the relationship between interneuron function, long-range hippocampal-prefrontal synchrony, and cognition, we optogenetically inhibited SOM and PV neurons in the medial prefrontal cortex (mPFC) of mice performing a spatial working memory task while simultaneously recording neural activity in the mPFC and the hippocampus (HPC). We found that inhibiting SOM, but not PV, interneurons during the encoding phase of the task impaired working memory accuracy. This behavioral impairment was associated with decreased hippocampal-prefrontal synchrony and impaired spatial encoding in mPFC neurons. These findings suggest that interneuron dysfunction may contribute to cognitive deficits associated with schizophrenia by disrupting long-range synchrony between the HPC and PFC.

Asunto(s)

Hipocampo/metabolismo , Interneuronas/metabolismo , Corteza Prefrontal/metabolismo , Somatostatina/biosíntesis , Animales , Hipocampo/química , Interneuronas/química , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Vías Nerviosas/química , Vías Nerviosas/metabolismo , Optogenética/métodos , Parvalbúminas/análisis , Parvalbúminas/biosíntesis , Corteza Prefrontal/química , Somatostatina/análisis

RESUMEN

Long-lasting forms of synaptic plasticity and memory require de novo protein synthesis. Yet, how learning triggers this process to form memory is unclear. Translin/trax is a candidate to drive this learning-induced memory mechanism by suppressing microRNA-mediated translational silencing at activated synapses. We find that mice lacking translin/trax display defects in synaptic tagging, which requires protein synthesis at activated synapses, and long-term memory. Hippocampal samples harvested from these mice following learning show increases in several disease-related microRNAs targeting the activin A receptor type 1C (ACVR1C), a component of the transforming growth factor-ß receptor superfamily. Furthermore, the absence of translin/trax abolishes synaptic upregulation of ACVR1C protein after learning. Finally, synaptic tagging and long-term memory deficits in mice lacking translin/trax are mimicked by ACVR1C inhibition. Thus, we define a new memory mechanism by which learning reverses microRNA-mediated silencing of the novel plasticity protein ACVR1C via translin/trax.

Asunto(s)

Receptores de Activinas Tipo I/metabolismo , Proteínas de Unión al ADN/metabolismo , Expresión Génica , Aprendizaje , Memoria , Proteínas de Unión al ARN/metabolismo , Ribonucleasas/metabolismo , Animales , Hipocampo/fisiología , Ratones , Plasticidad Neuronal

RESUMEN

OBJECTIVE: Breast reconstruction is associated with multiple psychological benefits. However, few studies have identified clinical and psychological factors associated with improved satisfaction and quality of life. This study examined factors, which predict satisfaction with breast appearance, outcome satisfaction and quality of life following post-mastectomy breast reconstruction. METHODS: Women who underwent post-mastectomy breast reconstruction between 2010 and 2016 received a postal questionnaire consisting of The BREAST-Q Patient Reported Outcomes Instrument, The European Organisation for Research and Treatment of Cancer QLQ-30 Questionnaire, The Patient and Observer Scar Assessment Scale, and a series of Visual-Analogue Scales. One hundredforty-eight women completed the questionnaire, a 56% response rate. RESULTS: Hierarchical multiple regression analyses revealed psychosocial factors accounted for 75% of the variance in breast satisfaction, 68% for outcome satisfaction, and 46% forquality of life. Psychosocial well-being emerged as a significant predictor of satisfaction with breast appearance (ß = .322) and outcome satisfaction (ß = .406). Deep inferior epigastric perforator flap patients reported greater satisfaction with breast appearance (ß = .120) and outcome satisfaction (ß = .167). CONCLUSIONS: This study extends beyond the limited research by distinguishing between satisfaction with breast appearance and outcome satisfaction. The study provides evidence for the role of psychosocial factors predicting key patient reported outcomes and demonstrates the importance of psychosocial well-being and reconstruction type. The findings also highlight the need for healthcare providers to consider the psychosocial well-being of patients both preoperatively and post operatively and provide preliminary evidence for the use of deep inferior epigastric perforator reconstructions over other types of reconstructive procedures.

Asunto(s)

Neoplasias de la Mama/psicología , Mamoplastia/métodos , Mamoplastia/psicología , Mastectomía/psicología , Satisfacción Personal , Calidad de Vida/psicología , Adulto , Anciano , Neoplasias de la Mama/cirugía , Femenino , Humanos , Persona de Mediana Edad , Encuestas y Cuestionarios , Resultado del Tratamiento

RESUMEN

Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease.

Asunto(s)

Prolina Oxidasa/genética , Prolina/deficiencia , Esquizofrenia/genética , Ácido gamma-Aminobutírico/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Citosol/metabolismo , Modelos Animales de Enfermedad , Ritmo Gamma , Predisposición Genética a la Enfermedad , Glutamato Descarboxilasa/antagonistas & inhibidores , Humanos , Ratones , Prolina/genética , Prolina Oxidasa/deficiencia , Esquizofrenia/metabolismo , Esquizofrenia/patología , Vigabatrin/administración & dosificación

RESUMEN

UNLABELLED: Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. SIGNIFICANCE STATEMENT: Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The phosphodiesterase 4 (PDE4) family coordinates the degradation of cAMP, leading to the local attenuation of cAMP-dependent signaling pathways. Sleep deprivation leads to increased hippocampal expression of the PDE4A5 isoform. Here, we explored whether PDE4A5 overexpression mimics behavioral and synaptic plasticity phenotypes associated with sleep deprivation. Viral expression of PDE4A5 in hippocampal neurons impairs long-term potentiation and attenuates the formation of hippocampus-dependent long-term memories. Our findings suggest that PDE4A5 is a molecular constraint on cognitive processes and may contribute to the development of novel therapeutic approaches to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling.

Asunto(s)

Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Hipocampo/citología , Hipocampo/fisiología , Memoria a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Análisis de Varianza , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Células Cultivadas , Colforsina/farmacología , Condicionamiento Clásico/fisiología , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Estimulación Eléctrica , Ensayo de Inmunoadsorción Enzimática , Miedo , Transferencia Resonante de Energía de Fluorescencia , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratas , Reconocimiento en Psicología/fisiología , Transducción de Señal/genética , Transducción Genética , Vasodilatadores/farmacología

RESUMEN

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density.

Asunto(s)

Región CA1 Hipocampal/fisiología , Trastornos de la Memoria , Neuronas/fisiología , Privación de Sueño/complicaciones , Factores Despolimerizantes de la Actina/metabolismo , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Espinas Dendríticas/fisiología , Ratones , Neuronas/citología

RESUMEN

Sleep deprivation is a public health epidemic that causes wide-ranging deleterious consequences, including impaired memory and cognition. Protein synthesis in hippocampal neurons promotes memory and cognition. The kinase complex mammalian target of rapamycin complex 1 (mTORC1) stimulates protein synthesis by phosphorylating and inhibiting the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2). We investigated the involvement of the mTORC1-4EBP2 axis in the molecular mechanisms mediating the cognitive deficits caused by sleep deprivation in mice. Using an in vivo protein translation assay, we found that loss of sleep impaired protein synthesis in the hippocampus. Five hours of sleep loss attenuated both mTORC1-mediated phosphorylation of 4EBP2 and the interaction between eukaryotic initiation factor 4E (eIF4E) and eIF4G in the hippocampi of sleep-deprived mice. Increasing the abundance of 4EBP2 in hippocampal excitatory neurons before sleep deprivation increased the abundance of phosphorylated 4EBP2, restored the amount of eIF4E-eIF4G interaction and hippocampal protein synthesis to that seen in mice that were not sleep-deprived, and prevented the hippocampus-dependent memory deficits associated with sleep loss. These findings collectively demonstrate that 4EBP2-regulated protein synthesis is a critical mediator of the memory deficits caused by sleep deprivation.

Asunto(s)

Factores Eucarióticos de Iniciación/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Trastornos de la Memoria/metabolismo , Biosíntesis de Proteínas , Privación de Sueño/metabolismo , Animales , Western Blotting , Cognición , Proteínas del Citoesqueleto/metabolismo , Chaperón BiP del Retículo Endoplásmico , Ensayo de Inmunoadsorción Enzimática , Factor 4E Eucariótico de Iniciación/metabolismo , Factor 4G Eucariótico de Iniciación/metabolismo , Proteínas de Choque Térmico/metabolismo , Hipocampo/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Fosforilación , Puromicina/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Estadísticas no Paramétricas

RESUMEN

Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a month after training, sleep-deprived and control aged animals performed similarly, primarily due to remote memory decay in the control aged animals. Gene expression analysis supported the finding that SD has similar effects on the hippocampus in young and aged mice.

Asunto(s)

Envejecimiento/fisiología , Trastornos de la Memoria/fisiopatología , Memoria a Largo Plazo/fisiología , Privación de Sueño/fisiopatología , Privación de Sueño/psicología , Animales , Expresión Génica , Masculino , Ratones Endogámicos C57BL , Pruebas Neuropsicológicas , Factores de Tiempo

RESUMEN

Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and memory because PKA also regulates presynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of synaptic vesicles is supported by biochemical assays showing that synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for presynaptically anchored PKA in pathway-specific synaptic tagging and long-term contextual fear memory. These results suggest that a presynaptically compartmentalized PKA is critical for synaptic plasticity and memory by regulating the readily releasable pool of synaptic vesicles.

Asunto(s)

Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Hipocampo/metabolismo , Memoria/fisiología , Plasticidad Neuronal/fisiología , Terminales Presinápticos/metabolismo , Sinapsis/metabolismo , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Miedo/fisiología , Proteínas de Unión al GTP/metabolismo , Hipocampo/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Memoria/efectos de los fármacos , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Proteínas/farmacología , Sinapsis/efectos de los fármacos , Proteína 25 Asociada a Sinaptosomas/metabolismo

RESUMEN

STUDY OBJECTIVES: Gentle handling is commonly used to perform brief sleep deprivation in rodents. It was recently reported that daily acclimation handling, which is often used before behavioral assays, causes alterations in sleep, stress, and levels of N-methyl-D-aspartate receptor subunits prior to the actual period of sleep deprivation. It was therefore suggested that acclimation handling could mediate some of the observed effects of subsequent sleep deprivation. Here, we examine whether acclimation handling, performed as in our sleep deprivation studies, alters sleep/wake behavior, stress, or forms of hippocampal synaptic plasticity that are impaired by sleep deprivation. DESIGN: Adult C57BL/6J mice were either handled daily for 6 days or were left undisturbed in their home cages. On the day after the 6(th) day of handling, long-term potentiation (LTP) was induced in hippocampal slices with spaced four-train stimulation, which we previously demonstrated to be impaired by brief sleep deprivation. Basal synaptic properties were also assessed. In three other sets of animals, activity monitoring, polysomnography, and stress hormone measurements were performed during the 6 days of handling. RESULTS: Daily gentle handling alone does not alter LTP, rest/activity patterns, or sleep/wake architecture. Handling initially induces a minimal stress response, but by the 6(th) day, stress hormone levels are unaltered by handling. CONCLUSION: It is possible to handle mice daily to accustom them to the researcher without causing alterations in sleep, stress, or synaptic plasticity in the hippocampus. Therefore, effects of acclimation handling cannot explain the impairments in signaling mechanisms, synaptic plasticity, and memory that result from brief sleep deprivation.

Asunto(s)

Aclimatación/fisiología , Manejo Psicológico , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Privación de Sueño , Sueño/fisiología , Análisis de Varianza , Animales , Conducta Animal/fisiología , Enfermedad Crónica , Corticosterona/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Polisomnografía/métodos

RESUMEN

A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D (phosphodiesterase 4D) to the ß2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including ß2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Furthermore, both hippocampal ß2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK in the CA1 region of the hippocampus are attenuated in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced ß2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, thereby organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage.

Asunto(s)

Proteínas de Anclaje a la Quinasa A/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Memoria/fisiología , Plasticidad Neuronal/fisiología , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal/fisiología , Animales , Western Blotting , Estimulación Eléctrica , Femenino , Hipocampo/fisiología , Inmunohistoquímica , Inmunoprecipitación , Hibridación in Situ , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

Sleep deprivation is a common problem of considerable health and economic impact in today's society. Sleep loss is associated with deleterious effects on cognitive functions such as memory and has a high comorbidity with many neurodegenerative and neuropsychiatric disorders. Therefore, it is crucial to understand the molecular basis of the effect of sleep deprivation in the brain. In this study, we combined genome-wide and traditional molecular biological approaches to determine the cellular and molecular impacts of sleep deprivation in the mouse hippocampus, a brain area crucial for many forms of memory. Microarray analysis examining the effects of 5 h of sleep deprivation on gene expression in the mouse hippocampus found 533 genes with altered expression. Bioinformatic analysis revealed that a prominent effect of sleep deprivation was to downregulate translation, potentially mediated through components of the insulin signaling pathway such as the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis. Consistent with this analysis, sleep deprivation reduced levels of total and phosphorylated mTOR, and levels returned to baseline after 2.5 h of recovery sleep. Our findings represent the first genome-wide analysis of the effects of sleep deprivation on the mouse hippocampus, and they suggest that the detrimental effects of sleep deprivation may be mediated by reductions in protein synthesis via downregulation of mTOR. Because protein synthesis and mTOR activation are required for long-term memory formation, our study improves our understanding of the molecular mechanisms underlying the memory impairments induced by sleep deprivation.

Asunto(s)

Genómica , Hipocampo/metabolismo , Análisis por Matrices de Proteínas/métodos , Privación de Sueño/genética , Animales , Biología Computacional/métodos , Regulación de la Expresión Génica , Insulina/metabolismo , Masculino , Memoria , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia por Matrices de Oligonucleótidos , Biosíntesis de Proteínas , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo

RESUMEN

The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring.

Asunto(s)

Adenilil Ciclasas/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Potenciación a Largo Plazo/fisiología , Células Piramidales/metabolismo , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Calcio/metabolismo , Colforsina/farmacología , Simulación por Computador , AMP Cíclico/metabolismo , Difusión , Dopamina/metabolismo , Ratones , Modelos Biológicos , Proteínas/farmacología , Células Piramidales/fisiología , Procesos Estocásticos , Especificidad por Sustrato , Potenciales Sinápticos/efectos de los fármacos

RESUMEN

BACKGROUND: There is some debate in the recent literature regarding the routine submission of mastectomy scars for histologic analysis when performing delayed breast reconstructions. The aim of this study was to review the relevant publications and evaluate the practice of routine histologic examination of mastectomy scars. METHODS: The authors conducted a retrospective review, across three regional plastic and reconstructive surgery units, of 433 patients who had 455 scars routinely sent for histologic examination following delayed breast reconstruction between January of 2000 and December of 2006. Patients with clinical evidence of recurrent carcinoma were excluded. RESULTS: Data from 433 patients revealed an average age at reconstruction of 49.9 years (range, 25 to 77 years). The mean interval from primary breast surgery to reconstruction was 3.9 years (range, 2 months to 32 years), and the average length of patient follow-up, from primary surgery, was 6.4 years (range, 1 to 40 years). The majority of the initial operations were carried out for invasive carcinoma (89 percent). Four mastectomy scars in three patients were positive for carcinoma recurrence. CONCLUSIONS: The publications related to the practice of routine histologic analysis of mastectomy scars provide conflicting conclusions. As a proportion of patients may benefit from the early detection and treatment of locoregional recurrence, the authors suggest that the routine submission of mastectomy scars will allow for the earlier detection of soft-tissue recurrences that may affect long-term outcome. In keeping with cancer surgery principles, the authors recommend routine histologic examination of mastectomy scars following delayed breast reconstruction.

Asunto(s)

Cicatriz/etiología , Cicatriz/patología , Mamoplastia , Mastectomía/efectos adversos , Adulto , Anciano , Neoplasias de la Mama/cirugía , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos

RESUMEN

The current provision of hypospadias correctional surgery lies across the specialities of paediatric surgery, general surgery, urology and plastic surgery. This study aimed to look at how this provision is structured within plastic surgery, what plastic surgeons are currently doing and how this impacts on training. All plastic surgery units within the UK were contacted via letter and telephone in order to ascertain their current practice with regard to hypospadias surgery. Specialist registrars in the West Midlands Deanery were also questioned on their training in this area. The results indicate that 42 plastic surgeons in the UK carry out hypospadias surgery. The majority of clinicians use the Bracka two-stage repair (88%), with Snodgrass (45%) and MAGPI (43%) widely used. Operations are being carried out across the age spectrum from birth, with 51% favouring intervention at 3 years or more. Approximately two-thirds of plastic surgeons treat less than 25 patients per year. One-third treat 26 to 50, with only two clinicians claiming to treat more than 50 patients per year. Of the specialist registrars questioned in the West Midlands Deanery the majority (74%) were confident with the assessment of new cases and in obtaining consent. One-quarter of registrars (28%) only wished to carry out hypospadias surgery once they were consultants, with only one feeling that they had the necessary training to achieve this now. Plastic surgeons represent about half (52%) of the consultants currently identified in the UK as carrying out hypospadias surgery. If this provision is to be maintained then a greater opportunity for development of skills and experience needs to be created within plastic surgery training. The authors advocate the formulation of a coordinated national framework for the provision of this service, promoting a regional focus for skills and governance.

Asunto(s)

Hipospadias/cirugía , Procedimientos de Cirugía Plástica/métodos , Encuestas de Atención de la Salud , Humanos , Masculino , Programas Nacionales de Salud/tendencias , Pautas de la Práctica en Medicina/tendencias , Procedimientos de Cirugía Plástica/tendencias , Encuestas y Cuestionarios , Reino Unido/epidemiología