RESUMO
The activity-regulated cytoskeleton-associated protein (Arc) gene is a neural immediate early gene that is involved in synaptic downscaling and is robustly induced by prolonged wakefulness in rodent brains. Converging evidence has led to the hypothesis that wakefulness potentiates, and sleep reduces, synaptic strengthening. This suggests a potential role for Arc in these and other sleep-related processes. However, the role of Arc in sleep remains unknown. Here, we demonstrated that Arc is important for the induction of multiple behavioral and molecular responses associated with sleep homeostasis. Arc knockout (KO) mice displayed increased time spent in rapid eye movement (REM) sleep under baseline conditions and marked attenuation of sleep rebound to both 4 h of total sleep deprivation (SD) and selective REM deprivation. At the molecular level, the following homeostatic sleep responses to 4-h SD were all blunted in Arc KO mice: increase of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 and its phosphorylation in synaptoneurosomes; induction of a subset of SD-response genes; and suppression of the GluA1 messenger RNA in the cortex. In wild-type brains, SD increased Arc protein expression in multiple subcellular locations, including the nucleus, cytoplasm, and synapse, which is reversed in part by recovery sleep. Arc is critical for these behavioral and multiple molecular responses to SD, thus providing a multifunctional role for Arc in the maintenance of sleep homeostasis, which may be attributed by the sleep/wake-associated changes in subcellular location of Arc.
Assuntos
Proteínas do Citoesqueleto/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sono/fisiologia , Animais , Encéfalo/fisiologia , Núcleo Celular/metabolismo , Córtex Cerebral/fisiologia , Citoplasma/metabolismo , Proteínas do Citoesqueleto/genética , Eletroencefalografia/métodos , Homeostase/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Receptores de AMPA/metabolismo , Sono/genética , Privação do Sono/fisiopatologia , Sono REM/fisiologia , Vigília/genética , Vigília/fisiologiaRESUMO
The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH+) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH+ neurons project more profusely than ventral tegmental area TH+ neurons to the hippocampus, optogenetic activation of locus coeruleus TH+ neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH+ photoactivation are sensitive to hippocampal D1/D5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, locus coeruleus TH+ neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus.
Assuntos
Dopamina/metabolismo , Locus Cerúleo/fisiologia , Consolidação da Memória/fisiologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiologia , Técnicas In Vitro , Locus Cerúleo/citologia , Locus Cerúleo/efeitos da radiação , Masculino , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/efeitos da radiação , Optogenética , Receptores Adrenérgicos/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/antagonistas & inibidores , Receptores de Dopamina D5/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/fisiologiaRESUMO
Patients with sleeping sickness, caused by the parasite Trypanosoma brucei, have disruptions in both sleep timing and sleep architecture. However, the underlying cause of these sleep disturbances is not well understood. Here, we assessed the sleep architecture of male mice infected with T. brucei and found that infected mice had drastically altered sleep patterns. Interestingly, T. brucei-infected mice also had a reduced homeostatic sleep response to sleep deprivation, a response modulated by the adenosine system. We found that infected mice had a reduced electrophysiological response to an adenosine receptor antagonist and increased adenosine receptor gene expression. Although the mechanism by which T. brucei infection causes these changes remains to be determined, our findings suggest that the symptoms of sleeping sickness may be because of alterations in homeostatic adenosine signaling.SIGNIFICANCE STATEMENT Sleeping sickness is a fatal disease that disrupts the circadian clock, causes disordered temperature regulation, and induces sleep disturbance. To examine the neurologic effects of infection in the absence of other symptoms, in this study, we used a mouse model of sleeping sickness in which the acute infection was treated but brain infection remained. Using this model, we evaluated the effects of the sleeping sickness parasite, Trypanosoma brucei, on sleep patterns in mice, under both normal and sleep-deprived conditions. Our findings suggest that signaling of adenosine, a neuromodulator involved in mediating homeostatic sleep drive, may be reduced in infected mice.
Assuntos
Adenosina/fisiologia , Sono , Tripanossomíase Africana/fisiopatologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Eletroencefalografia , Eletromiografia , Fenômenos Eletrofisiológicos , Expressão Gênica , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/metabolismo , Privação do Sono , Trypanosoma brucei bruceiRESUMO
Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices. Neuronal knock-out of AdK did not influence homeostatic sleep need. Together, these findings implicate a glial-neuronal circuit mediated by intercellular Ado, controlling expression of homeostatic sleep drive. Because AdK is tightly regulated by glial metabolic state, our findings suggest a functional link between cellular metabolism and sleep homeostasis. SIGNIFICANCE STATEMENT: The work presented here provides evidence for an adenosine-mediated regulation of sleep in response to waking (i.e., homeostatic sleep need), requiring activation of neuronal adenosine A1 receptors and controlled by glial adenosine kinase. Adenosine kinase acts as a highly sensitive and important metabolic sensor of the glial ATP/ADP and AMP ratio directly controlling intracellular adenosine concentration. Glial equilibrative adenosine transporters reflect the intracellular concentration to the extracellular milieu to activate neuronal adenosine receptors. Thus, adenosine mediates a glial-neuronal circuit linking glial metabolic state to neural-expressed sleep homeostasis. This indicates a metabolically related function(s) for this glial-neuronal circuit in the buildup and resolution of our need to sleep and suggests potential therapeutic targets more directly related to sleep function.
Assuntos
Adenosina/metabolismo , Homeostase/fisiologia , Rede Nervosa/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologia , Sono/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Adenosina Quinase/genética , Adenosina Quinase/imunologia , Adenosina Quinase/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Antagonistas de Estrogênios/farmacologia , Hipocampo/citologia , Hipocampo/fisiologia , Homeostase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Receptor A1 de Adenosina/genética , Receptor A1 de Adenosina/metabolismo , Sono/genética , Tamoxifeno/farmacologia , Fatores de TempoRESUMO
Sleep is regulated by homeostatic mechanisms, and the low-frequency power in the electroencephalogram (delta power) during non-rapid eye movement sleep reflects homeostatic sleep need. Additionally, sleep is limited by circadian and environmentally influenced arousal. Little is known, however, about the underlying neural substrates for sleep homeostasis and arousal and about the potential link between them. Here, we subjected C57BL/6 mice to 6 h of sleep deprivation using two different methods: gentle handling and continual cage change. Both groups were deprived of sleep to a similar extent (>99%), and, as expected, the delta power increase during recovery sleep was quantitatively similar in both groups. However, in a multiple sleep latency test, the cage change group showed significantly longer sleep latencies than the gentle handling group, indicating that the cage change group had a higher level of arousal despite the similar sleep loss. To investigate the possible biochemical correlates of these behavioral changes, we screened for arousal-related and sleep need-related phosphoprotein markers from the diencephalon. We found that the abundance of highly phosphorylated forms of dynamin 1, a presynaptic neuronal protein, was associated with sleep latency in the multiple sleep latency test. In contrast, the abundance of highly phosphorylated forms of N-myc downstream regulated gene 2, a glial protein, was increased in parallel with delta power. The changes of these protein species disappeared after 2 h of recovery sleep. These results suggest that homeostatic sleep need and arousal can be dissociated behaviorally and biochemically and that phosphorylated N-myc downstream regulated gene 2 and dynamin 1 may serve as markers of homeostatic sleep need and arousal, respectively.
Assuntos
Nível de Alerta/fisiologia , Homeostase/fisiologia , Fases do Sono/fisiologia , Vigília/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Comportamento Animal/fisiologia , Biomarcadores/metabolismo , Ritmo Delta , Diencéfalo/metabolismo , Dinaminas/genética , Dinaminas/metabolismo , Eletroencefalografia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Restrição Física , Privação do Sono/fisiopatologia , Estresse Psicológico/fisiopatologia , Eletroforese em Gel Diferencial BidimensionalRESUMO
CA1 hippocampal N-methyl-d-aspartate-receptors (NMDARs) are necessary for contextually related learning and memory processes. Extinction, a form of learning, has been shown to require intact hippocampal NMDAR signalling. Renewal of fear expression can occur after fear extinction training, when the extinguished fear stimulus is presented in an environmental context different from the training context and thus, renewal is dependent on contextual memory. In this study, we show that a Grin1 knock-out (loss of the essential NR1 subunit for the NMDAR) restricted to the bilateral CA1 subfield of the dorsal hippocampus does not affect acquisition of learned fear, but does attenuate extinction of a cued fear response even when presented in the extinction-training context. We propose that failure to remember the (safe) extinction context is responsible for the abnormal fear response and suggest it is a dysfunctional renewal. The results highlight the difference in outcome of extinguished fear memory resulting from a partial rather than complete loss of function of the hippocampus and suggest a potential mechanism for abnormally increased fear expression in PTSD.
Assuntos
Comportamento Animal/fisiologia , Região CA1 Hipocampal/fisiopatologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Sinais (Psicologia) , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Transtornos de Estresse Pós-Traumáticos/fisiopatologiaRESUMO
A1 adenosine receptor activation ameliorates ischemic AKI through the induction of renal proximal tubular sphingosine kinase-1. However, systemic adverse effects may limit A1 adenosine receptor-based therapy for ischemic AKI, indicating a need to identify alternative therapeutic targets within this pathway. Here, we evaluated the function of renal proximal tubular IL-11, a clinically approved hematopoietic cytokine, in A1 adenosine receptor-mediated induction of sphingosine kinase-1 and renal protection. Treatment of human proximal tubule epithelial (HK-2) cells with a selective A1 adenosine receptor agonist, chloro-N(6)-cyclopentyladenosine (CCPA), induced the expression of IL-11 mRNA and protein in an extracellular signal-regulated kinase-dependent manner, and administration of CCPA in mice induced renal synthesis of IL-11. Pretreatment with CCPA protected against renal ischemia-reperfusion injury in wild-type mice, but not in IL-11 receptor-deficient mice. Administration of an IL-11-neutralizing antibody abolished the renal protection provided by CCPA. Similarly, CCPA did not induce renal IL-11 expression or protect against renal ischemia-reperfusion injury in mice lacking the renal proximal tubular A1 adenosine receptor. Finally, treatment with CCPA induced sphingosine kinase-1 in HK-2 cells and wild-type mice, but not in IL-11 receptor-deficient or renal proximal tubule A1 adenosine receptor-deficient mice. Taken together, these results suggest that induction of renal proximal tubule IL-11 is a critical intermediary in A1 adenosine receptor-mediated renal protection that warrants investigation as a novel therapeutic target for the treatment of ischemic AKI.
Assuntos
Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Interleucina-11/fisiologia , Receptor A1 de Adenosina/fisiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/uso terapêutico , Agonistas do Receptor A1 de Adenosina/farmacologia , Agonistas do Receptor A1 de Adenosina/uso terapêutico , Animais , Linhagem Celular , Humanos , Interleucina-11/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor A1 de Adenosina/genéticaRESUMO
The neuromodulator orexin has been identified as a key factor for motivated arousal including recent evidence that sleep deprivation-induced enhancement of reward behavior is modulated by orexin. While orexin is not necessary for either reward or arousal behavior, orexin neurons' broad projections, ability to sense the internal state of the animal, and high plasticity of signaling in response to natural rewards and drugs of abuse may underlie heightened drug seeking, particularly in a subset of highly motivated reward seekers. As such, orexin receptor antagonists have gained deserved attention for putative use in addiction treatments. Ongoing and future clinical trials are expected to identify individuals most likely to benefit from orexin receptor antagonist treatment to promote abstinence, such as those with concurrent sleep disorders or high craving, while attention to methodological considerations will aid interpretation of the numerous preclinical studies investigating disparate aspects of the role of orexin in reward and arousal.
Assuntos
Nível de Alerta , Neuropeptídeos , Receptores de Orexina , Orexinas , Recompensa , Orexinas/metabolismo , Humanos , Animais , Nível de Alerta/fisiologia , Neuropeptídeos/metabolismo , Receptores de Orexina/metabolismo , Antagonistas dos Receptores de Orexina/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Motivação/fisiologia , Neurônios/metabolismoRESUMO
The presynaptic source of dopamine in the CA1 field of dorsal hippocampus is uncertain due to an anatomical mismatch between dopaminergic terminals and receptors. We show, in an in vitro slice preparation from C57BL/6 male mice, that a dopamine (DA) D1 receptor (D1R)-mediated enhancement in glutamate synaptic transmission occurs following release of endogenous DA with amphetamine exposure. It is assumed DA is released from terminals innervating from the ventral tegmental area (VTA) even though DA transporter (DAT)-positive fibers are absent in hippocampus, a region with abundant D1Rs. It has been suggested this results from a lack of DAT expression on VTA terminals rather than a lack of these terminals per se. Neither a knockdown of tyrosine hydroxylase (TH) expression in the VTA by THsiRNA, delivered locally, by adeno-associated viral vector, nor localized pharmacological blockade of DAT to prevent amphetamine uptake into DA terminals, has any effect on the D1R synaptic, enhancement response to amphetamine. However, either a decrease in TH expression in the locus ceruleus (LC) or a blockade of the norepinephrine (NE) transporter prevents the DA-mediated response, indicating LC terminals can release both NE and DA. These findings suggest noradrenergic fibers may be the primary source of DA release in hippocampus and corresponding DA-mediated increase in synaptic transmission. Accordingly, these data imply the LC may have a role in DA transmission in the CNS in response to drugs of abuse, and potentially, under physiological conditions.
Assuntos
Neurônios Adrenérgicos/fisiologia , Dopamina/metabolismo , Hipocampo/fisiologia , Locus Cerúleo/fisiologia , Neurotransmissores/fisiologia , Receptores Dopaminérgicos/metabolismo , Transmissão Sináptica/fisiologia , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologiaRESUMO
Brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB, regulate a wide range of cellular processes, including dendritic spine formation and functional synapse plasticity. However, the signaling mechanisms that link BDNF-activated TrkB to F-actin remodeling enzymes and dendritic spine morphological plasticity remain poorly understood. We report here that BDNF/TrkB signaling in neurons activates the Vav family of Rac/RhoA guanine nucleotide exchange factors through a novel TrkB-dependent mechanism. We find that Vav is required for BDNF-stimulated Rac-GTP production in cortical and hippocampal neurons. Vav is partially enriched at excitatory synapses in the postnatal hippocampus but does not appear to be required for normal dendritic spine density. Rather, we observe significant reductions in both BDNF-induced, rapid, dendritic spine head growth and in CA3-CA1 theta burst-stimulated long-term potentiation in Vav-deficient mouse hippocampal slices, suggesting that Vav-dependent regulation of dendritic spine morphological plasticity facilitates normal functional synapse plasticity.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/citologia , Proteínas Proto-Oncogênicas c-vav/metabolismo , Sinapses/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/citologia , Estimulação Elétrica , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas de Fluorescência Verde , Hipocampo/citologia , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Camundongos , Neurônios/ultraestrutura , Técnicas de Cultura de Órgãos , Ratos , Sinapses/fisiologia , Sinaptossomos/efeitos dos fármacos , Transfecção/métodosRESUMO
Acute cocaine disturbs sleep on a dose-dependent basis; however, the consequences of chronic cocaine remain unclear. While the arousal promotion following cocaine has been well-established, effects of cocaine on sleep after termination of chronic cocaine exposure appear variable in human subjects with few studies in non-human subjects. Here, a within-subjects design (outcomes normalized to baseline, undisturbed behavior) and between-subjects design (repeated experimenter-administered cocaine vs. experimenter-administered saline) was used to investigate sleep homeostasis and sleep/waking under repeated cocaine/saline exposure and prolonged forced abstinence conditions in mice. Overall, during the forced abstinence period increases in arousal, as determined by sleep latency and gamma energy, persisted for 2 weeks. However, the sleep response to externally enforced sleep deprivation was unchanged suggesting that sleep disruptions during the forced abstinence period were driven by enhancement of arousal in the absence of changes in sleep homeostatic responses.
RESUMO
Non-rapid eye movement (NREM) sleep is tightly homeostatically regulated and essential for survival. In the electroencephalogram (EEG), oscillations in the delta (0.5-4 Hz) range are prominent during NREM sleep. These delta oscillations are, to date, the best indicator for homeostatic sleep regulation; they are increased after prolonged waking and fade during NREM sleep. The precise mechanisms underlying sleep homeostasis and the generation of EEG delta oscillations are still being investigated. Activity-dependent neuronal calcium influx has been hypothesized to play an important role in generating delta oscillations and might be involved in downstream signaling that mediates sleep function. Dihydropyridine blockers of L-type voltage-gated calcium channels (VGCCs) are in wide clinical use to treat hypertension and other cardiovascular disorders and are readily blood-brain-barrier penetrant. We therefore, wanted to investigate their potential effects on EEG delta oscillation and homeostatic NREM sleep regulation in freely behaving mice. In vivo two-photon imaging of cortical neurons showed larger spontaneous calcium transients in NREM sleep compared to waking. Application of the dihydropyridine calcium blocker nicardipine significantly reduced cortical calcium transients without affecting the generation of delta oscillations. Nicardipine also did not affect EEG delta oscillations over 24 h following application. The time spent in NREM sleep and NREM episode duration was also not affected. Thus, acute block of calcium entry through L-type VGCCs does not interfere with EEG delta oscillations or their homeostatic regulation, despite prior evidence from calcium channel knockout mice.
RESUMO
The rodent dorsal hippocampus is essential for episodic memory consolidation, a process heavily modulated by dopamine D1-like receptor (D1/5R) activation. It was previously thought that the ventral tegmental area provided the only supply of dopamine release to dorsal hippocampus, but several recent studies have established the locus coeruleus (LC) as the major source for CA1. Here we show that selective blockade of the norepinephrine transporter (NET) prevents dopamine-dependent, late long-term synaptic potentiation (LTP) in dorsal CA1, a neural correlate of memory formation that relies on LC-mediated activation of D1/5Rs. Since dopamine activation of D1/5Rs by vesicular release is expected to be enhanced by NET antagonism, our data identify NET reversal as a plausible mechanism for LC-mediated DA release. We also show that genetic deletion of LC NMDA receptors (NMDARs) blocks D1R-mediated LTP, suggesting the requirement of both a functional NET and presynaptic NMDARs for this release. As LC activity is highly correlated with attentional processes and memory, these experiments provide insight into how selective attention influences memory formation at the synaptic and circuit levels.
Assuntos
Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Sinapses/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Atenção/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Dopamina/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
Dopamine, orexin (hypocretin), and adenosine systems have dual roles in reward and sleep/arousal suggesting possible mechanisms whereby drugs of abuse may influence both reward and sleep/arousal. While considerable variability exists across studies, drugs of abuse such as cocaine induce an acute sleep loss followed by an immediate recovery pattern that is consistent with a normal response to loss of sleep. Under more chronic cocaine exposure conditions, an abnormal recovery pattern is expressed that includes a retention of sleep disturbance under withdrawal and into abstinence conditions. Conversely, experimentally induced sleep disturbance can increase cocaine seeking. Thus, complementary, sleep-related therapeutic approaches may deserve further consideration along with development of non-human models to better characterize sleep disturbance-reward seeking interactions across drug experience.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína/farmacologia , Transtornos do Sono-Vigília/psicologia , Sono/efeitos dos fármacos , Adenosina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Cocaína/efeitos adversos , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Condicionamento Operante/efeitos dos fármacos , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Feminino , Humanos , Masculino , Orexinas/metabolismo , Recompensa , Autoadministração , Transtornos do Sono-Vigília/metabolismoRESUMO
During sleep, the mammalian CNS undergoes widespread, synchronized slow-wave activity (SWA) that directly varies with previous waking duration (Borbély, 1982; Dijk et al., 1990). When sleep is restricted, an enhanced SWA response follows in the next sleep period. The enhancement of SWA is associated with improved cognitive performance (Huber et al., 2004), but it is unclear either how the SWA is enhanced or whether SWA is needed to maintain normal cognitive performance. A conditional, CNS knock-out of the adenosine receptor, AdoA(1)R gene, shows selective attenuation of the SWA rebound response to restricted sleep, but sleep duration is not affected. During sleep restriction, wild phenotype animals express a rebound SWA response and maintain cognitive performance in a working memory task. However, the knock-out animals not only show a reduced rebound SWA response but they also fail to maintain normal cognitive function, although this function is normal when sleep is not restricted. Thus, AdoA(1)R activation is needed for normal rebound SWA, and when the SWA rebound is reduced, there is a failure to maintain working memory function, suggesting a functional role for SWA homeostasis.
Assuntos
Homeostase/fisiologia , Receptor A1 de Adenosina/fisiologia , Sono/fisiologia , Animais , Deleção de Genes , Regulação da Expressão Gênica/fisiologia , Homeostase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor A1 de Adenosina/deficiência , Receptor A1 de Adenosina/genética , Sono/genética , Privação do Sono/genética , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Vigília/genética , Vigília/fisiologiaRESUMO
Converging evidence suggests that salience-associated modulation of behavior is mediated by the release of monoamines and that monoaminergic activation of D(1)/D(5) receptors is required for normal hippocampal-dependent learning and memory. However, it is not understood how D(1)/D(5) modulation of hippocampal circuits can affect salience-associated learning and memory. We have observed in CA1 pyramidal neurons that D(1)/D(5) receptor activation elicits a bidirectional long-term plasticity of NMDA receptor-mediated synaptic currents with the polarity of plasticity determined by NMDA receptor, NR2A/B subunit composition. This plasticity results in a decrease in the NR2A/NR2B ratio of subunit composition. Synaptic responses mediated by NMDA receptors that include NR2B subunits are potentiated by D(1)/D(5) receptor activation, whereas responses mediated by NMDA receptors that include NR2A subunits are depressed. Furthermore, these bidirectional, subunit-specific effects are mediated by distinctive intracellular signaling mechanisms. Because there is a predominance of NMDA receptors composed of NR2A subunits observed in entorhinal-CA1 inputs and a predominance of NMDA receptors composed of NR2B subunits in CA3-CA1 synapses, potentiation of synaptic NMDA currents predominates in the proximal CA3-CA1 synapses, whereas depression of synaptic NMDA currents predominates in the distal entorhinal-CA1 synapses. Finally, all of these effects are reproduced by the release of endogenous monoamines through activation of D(1)/D(5) receptors. Thus, endogenous D(1)/D(5) activation can (1) decrease the NR2A/NR2B ratio of NMDA receptor subunit composition at glutamatergic synapses, a rejuvenation to a composition similar to developmentally immature synapses, and, (2) in CA1, bias NMDA receptor responsiveness toward the more highly processed trisynaptic CA3-CA1 circuit and away from the direct entorhinal-CA1 input.
Assuntos
Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D5/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
BACKGROUND: Our understanding of the mechanisms that protect the developing embryo from intrauterine stress is limited. Recently, adenosine has been demonstrated to play a critical role in protecting the embryo against hypoxia via adenosine A1 receptors (A1ARs), which are expressed in the heart, nervous system, and other sites during development. However, the sites of A1AR action that mediate embryo protection are not known. To determine if the heart is a key site of adenosine-mediated embryo protection, A1ARs were selectively deleted in the embryonic heart using a Cre-LoxP system in which the alpha-myosin heavy chain promoter drives Cre-recombinase expression and excision of the A1AR gene from cardiomyocytes. RESULTS: With increasing exposure of maternal hypoxia (10% O2) from 48-96 hours beginning at embryonic day (E) 8.5, embryo viability decreased in the cardiac-A1AR deleted embryos. 48 hours of hypoxia reduced embryonic viability by 49% in embryos exposed from E10.5-12.5 but no effect on viability was observed in younger embryos exposed to hypoxia from E8.5-10.5. After 72 hours of hypoxia, 57.8% of the cardiac-A1AR deleted embryos were either dead or re-absorbed compared to 13.7% of control littermates and after 96 hours 81.6% of cardiac-A1AR deleted embryos were dead or re-absorbed. After 72 hours of hypoxia, cardiac size was reduced significantly more in the cardiac-A1AR deleted hearts compared to controls. Gene expression analysis revealed clusters of genes that are regulated by both hypoxia and A1AR expression. CONCLUSIONS: These data identify the embryonic heart as the critical site where adenosine acts to protect the embryo against hypoxia. As such these studies identify a previously unrecognized mechanism of embryo protection.
Assuntos
Adenosina/metabolismo , Hipóxia Fetal/metabolismo , Coração/embriologia , Animais , Cruzamentos Genéticos , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Receptor A1 de Adenosina/genética , Receptor A1 de Adenosina/metabolismoRESUMO
Drug addiction and withdrawal are characterized by sleep disruption, but the effects of sleep disruption on these states are not well characterized. Sleep deprivation (SD) immediately before the cocaine conditioning trials enhanced cocaine conditioned place preference (CPP) in a dose-dependent manner (3, 8 mg/kg but not 15 mg/kg) in mice. SD immediately before the postconditioning test also enhanced cocaine CPP preference in a dose-dependent manner (8 mg/kg, but not 3, 15 mg/kg). Exposure to orexin-receptor antagonism (1 mg/kg SB 334867, an orexin 1 receptor antagonist; OX1R) just before cocaine-conditioning trials or the postconditioning test attenuated SD-enhanced preference. This suggests a potential therapeutic role for the manipulation of the orexin system to mitigate drug seeking, especially in the context of sleep loss before drug exposure.
Assuntos
Cocaína , Animais , Condicionamento Clássico , Camundongos , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina , Privação do SonoRESUMO
Cortical networks exhibit large shifts in spontaneous dynamics depending on the vigilance state. Waking and rapid eye movement (REM) sleep are characterized by ongoing irregular activity of cortical neurons while during slow wave sleep (SWS) these neurons show synchronous alterations between silent (OFF) and active (ON) periods. The network dynamics underlying these phenomena are not fully understood. Additional information about the state of cortical networks can be obtained by evaluating evoked cortical responses during the sleep-wake cycle. We measured local field potentials (LFP) and multi-unit activity (MUA) in the cortex in response to repeated brief optogenetic stimulation of thalamocortical afferents. Both LFP and MUA responses were considerably increased in sleep compared to waking, with larger responses during SWS than during REM sleep. The strongly increased cortical response in SWS is discussed within the context of SWS-associated neuro-modulatory tone that may reduce feedforward inhibition. Responses to stimuli were larger during SWS-OFF periods than during SWS-ON periods. SWS responses showed clear daily fluctuation correlated to light-dark cycle, but no reaction to increased sleep need following sleep deprivation. Potential homeostatic synaptic plasticity was either absent or masked by large vigilance-state effects.