RESUMEN
Sleep, circadian rhythms, and mental health are reciprocally interlinked. Disruption to the quality, continuity, and timing of sleep can precipitate or exacerbate psychiatric symptoms in susceptible individuals, while treatments that target sleep-circadian disturbances can alleviate psychopathology. Conversely, psychiatric symptoms can reciprocally exacerbate poor sleep and disrupt clock-controlled processes. Despite progress in elucidating underlying mechanisms, a cohesive approach that integrates the dynamic interactions between psychiatric disorder with both sleep and circadian processes is lacking. This review synthesizes recent evidence for sleep-circadian dysfunction as a transdiagnostic contributor to a range of psychiatric disorders, with an emphasis on biological mechanisms. We highlight observations from adolescent and young adults, who are at greatest risk of developing mental disorders, and for whom early detection and intervention promise the greatest benefit. In particular, we aim to a) integrate sleep and circadian factors implicated in the pathophysiology and treatment of mood, anxiety, and psychosis spectrum disorders, with a transdiagnostic perspective; b) highlight the need to reframe existing knowledge and adopt an integrated approach which recognizes the interaction between sleep and circadian factors; and c) identify important gaps and opportunities for further research.
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Trastornos Mentales , Trastornos del Sueño-Vigilia , Adulto Joven , Adolescente , Humanos , Trastornos Mentales/etiología , Trastornos Mentales/terapia , Sueño/fisiología , Ritmo Circadiano/fisiología , Salud Mental , Trastornos del HumorRESUMEN
Genetic variation in CACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of mutations of one copy of Cacna1c on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbour marked impairments in learning to disregard non-salient stimuli, a behavioural change previously associated with psychosis. This behavioural deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+ signalling in dendritic spines and decreased signalling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small-molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioural and synaptic plasticity deficits in Cacna1c+/- rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signalling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signalling pathways with BDNF mimetic drugs as a genetically informed therapeutic approach for rescuing behavioural abnormalities in psychiatric disorder.
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Trastorno Bipolar , Esquizofrenia , Animales , Canales de Calcio Tipo L/genética , Cognición , Humanos , Factores de Crecimiento Nervioso , RatasRESUMEN
Hippocampal sharp-wave ripples (SWRs) support the reactivation of memory representations, relaying information to neocortex during "offline" and sleep-dependent memory consolidation. While blockade of NMDA receptors (NMDAR) is known to affect both learning and subsequent consolidation, the specific contributions of NMDAR activation to SWR-associated activity remain unclear. Here, we combine biophysical modeling with in vivo local field potential (LFP) and unit recording to quantify changes in SWR dynamics following inactivation of NMDAR. In a biophysical model of CA3-CA1 SWR activity, we find that NMDAR removal leads to reduced SWR density, but spares SWR properties such as duration, cell recruitment and ripple frequency. These predictions are confirmed by experiments in which NMDAR-mediated transmission in rats was inhibited using three different NMDAR antagonists, while recording dorsal CA1 LFP. In the model, loss of NMDAR-mediated conductances also induced a reduction in the proportion of cell pairs that co-activate significantly above chance across multiple events. Again, this prediction is corroborated by dorsal CA1 single-unit recordings, where the NMDAR blocker ketamine disrupted correlated spiking during SWR. Our results are consistent with a framework in which NMDA receptors both promote activation of SWR events and organize SWR-associated spiking content. This suggests that, while SWR are short-lived events emerging in fast excitatory-inhibitory networks, slower network components including NMDAR-mediated currents contribute to ripple density and promote consistency in the spiking content across ripples, underpinning mechanisms for fine-tuning of memory consolidation processes.
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Región CA1 Hipocampal/fisiología , Modelos Neurológicos , Células Piramidales/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Electrodos Implantados , Antagonistas de Aminoácidos Excitadores/farmacología , Células Piramidales/efectos de los fármacos , Ratas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
The locus coeruleus (LC) in the pons is the major source of noradrenaline (NA) in the brain. Two modes of LC firing have been associated with distinct cognitive states: changes in tonic rates of firing are correlated with global levels of arousal and behavioural flexibility, whilst phasic LC responses are evoked by salient stimuli. Here, we unify these two modes of firing by modelling the response of the LC as a correlate of a prediction error when inferring states for action planning under Active Inference (AI). We simulate a classic Go/No-go reward learning task and a three-arm 'explore/exploit' task and show that, if LC activity is considered to reflect the magnitude of high level 'state-action' prediction errors, then both tonic and phasic modes of firing are emergent features of belief updating. We also demonstrate that when contingencies change, AI agents can update their internal models more quickly by feeding back this state-action prediction error-reflected in LC firing and noradrenaline release-to optimise learning rate, enabling large adjustments over short timescales. We propose that such prediction errors are mediated by cortico-LC connections, whilst ascending input from LC to cortex modulates belief updating in anterior cingulate cortex (ACC). In short, we characterise the LC/ NA system within a general theory of brain function. In doing so, we show that contrasting, behaviour-dependent firing patterns are an emergent property of the LC that translates state-action prediction errors into an optimal balance between plasticity and stability.
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Aprendizaje/fisiología , Locus Coeruleus/fisiología , Recompensa , Animales , Cognición/fisiología , Biología Computacional , Modelos Neurológicos , Norepinefrina/metabolismoAsunto(s)
Incendios , Incendios Forestales , Brasil , Conservación de los Recursos Naturales , BosquesRESUMEN
The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. SIGNIFICANCE STATEMENT: Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.
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Región CA1 Hipocampal/patología , Potenciales Postsinápticos Excitadores/fisiología , Red Nerviosa/fisiopatología , Células Piramidales/fisiología , Tauopatías/patología , Animales , Región CA1 Hipocampal/fisiopatología , Modelos Animales de Enfermedad , Potenciales Evocados/genética , Potenciales Evocados/fisiología , Potenciales Postsinápticos Excitadores/genética , Análisis de Fourier , Humanos , Aprendizaje por Laberinto/fisiología , Potenciales de la Membrana/genética , Potenciales de la Membrana/fisiología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/genética , Ratones , Ratones Transgénicos , Modelos Neurológicos , Técnicas de Placa-Clamp , Simbiosis/genética , Transmisión Sináptica/genética , Tauopatías/complicaciones , Tauopatías/genética , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
KEY POINTS: High frequency (100-250 Hz) neuronal oscillations in the hippocampus, known as sharp-wave ripples (SWRs), synchronise the firing behaviour of groups of neurons and play a key role in memory consolidation. Learning and memory are severely compromised in dementias such as Alzheimer's disease; however, the effects of dementia-related pathology on SWRs are unknown. The frequency and temporal structure of SWRs was disrupted in a transgenic mouse model of tauopathy (one of the major hallmarks of several dementias). Excitatory pyramidal neurons were more likely to fire action potentials in a phase-locked manner during SWRs in the mouse model of tauopathy; conversely, inhibitory interneurons were less likely to fire phase-locked spikes during SWRs. These findings indicate there is reduced inhibitory control of hippocampal network events and point to a novel mechanism which may underlie the cognitive impairments in this model of dementia. ABSTRACT: Neurons within the CA1 region of the hippocampus are co-activated during high frequency (100-250 Hz) sharp-wave ripple (SWR) activity in a manner that probably drives synaptic plasticity and promotes memory consolidation. In this study we have used a transgenic mouse model of dementia (rTg4510 mice), which overexpresses a mutant form of tau protein, to examine the effects of tauopathy on hippocampal SWRs and associated neuronal firing. Tetrodes were used to record simultaneous extracellular action potentials and local field potentials from the dorsal CA1 pyramidal cell layer of 7- to 8-month-old wild-type and rTg4510 mice at rest in their home cage. At this age point these mice exhibit neurofibrillary tangles, neurodegeneration and cognitive deficits. Epochs of sleep or quiet restfulness were characterised by minimal locomotor activity and a low theta/delta ratio in the local field potential power spectrum. SWRs detected off-line were significantly lower in amplitude and had an altered temporal structure in rTg4510 mice. Nevertheless, the average frequency profile and duration of the SWRs were relatively unaltered. Putative interneurons displayed significantly less temporal and phase locking to SWRs in rTg4510 mice, whilst putative pyramidal neurons showed increased temporal and phase locking to SWRs. These findings indicate there is reduced inhibitory control of hippocampal network events and point to a novel mechanism which may contribute to impairments in memory consolidation in this model of dementia.
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Región CA1 Hipocampal/fisiología , Demencia/fisiopatología , Potenciales de Acción , Animales , Modelos Animales de Enfermedad , Masculino , Ratones Transgénicos , Células Piramidales/fisiología , Proteínas tau/genéticaRESUMEN
Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders.
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Modelos Animales de Enfermedad , Proteínas de la Membrana/genética , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Sueño/fisiología , Investigación Biomédica Traslacional/métodos , Animales , Humanos , Proteínas de Membrana de los Lisosomas , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/fisiopatología , OvinosRESUMEN
BACKGROUND: Schizophrenia is a complex, polygenic disorder for which over 100 genetic variants have been identified that correlate with diagnosis. However, the biological mechanisms underpinning the different symptom clusters remain undefined. The rs1344706 single nucleotide polymorphism within ZNF804A was among the first genetic variants found to be associated with schizophrenia. Previously, neuroimaging and cognitive studies have revealed several associations between rs1344706 and brain structure and function. The aim of this study is to use a recall-by-genotype (RBG) design to investigate the biological basis for the association of ZNF804A variants with schizophrenia. A RBG study, implemented in a population cohort, will be used to evaluate the impact of genetic variation at rs1344706 on sleep neurophysiology and procedural memory consolidation in healthy participants. METHODS/DESIGN: Participants will be recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) on the basis of genotype at rs1344706 (n = 24). Each participant will be asked to take part in two nights of in-depth sleep monitoring (polysomnography) allowing collection of neurophysiological sleep data in a manner not amenable to large-scale study. Sleep questionnaires will be used to assess general sleep quality and subjective sleep experience after each in-house recording. A motor sequencing task (MST) will be performed before and after the second night of polysomnography. In order to gather additional data about habitual sleep behaviour participants will be asked to wear a wrist worn activity monitor (actiwatch) and complete a sleep diary for two weeks. DISCUSSION: This study will explore the biological function of ZNF804A genotype (rs1344706) in healthy volunteers by examining detailed features of sleep architecture and physiology in relation to motor learning. Using a RBG approach will enable us to collect precise and detailed phenotypic data whilst achieving an informative biological gradient. It would not be feasible to collect such data in the large sample sizes that would be required under a random sampling scheme. By dissecting the role of individual variants associated with schizophrenia in this way, we can begin to unravel the complex genetic mechanisms of psychiatric disorders and pave the way for future development of novel therapeutic approaches.
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Factores de Transcripción de Tipo Kruppel/genética , Consolidación de la Memoria/fisiología , Actividad Motora/fisiología , Polimorfismo de Nucleótido Simple , Sueño/fisiología , Adulto , Encéfalo/fisiología , Voluntarios Sanos/psicología , Humanos , Estudios Longitudinales , Masculino , Proyectos Piloto , Polisomnografía/métodos , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
The 8-15 Hz thalamocortical oscillations known as sleep spindles are a universal feature of mammalian non-REM sleep, during which they are presumed to shape activity-dependent plasticity in neocortical networks. The cortex is hypothesized to contribute to initiation and termination of spindles, but the mechanisms by which it implements these roles are unknown. We used dual-site local field potential and multiple single-unit recordings in the thalamic reticular nucleus (TRN) and medial prefrontal cortex (mPFC) of freely behaving rats at rest to investigate thalamocortical network dynamics during natural sleep spindles. During each spindle epoch, oscillatory activity in mPFC and TRN increased in frequency from onset to offset, accompanied by a consistent phase precession of TRN spike times relative to the cortical oscillation. In mPFC, the firing probability of putative pyramidal cells was highest at spindle initiation and termination times. We thus identified "early" and "late" cell subpopulations and found that they had distinct properties: early cells generally fired in synchrony with TRN spikes, whereas late cells fired in antiphase to TRN activity and also had higher firing rates than early cells. The accelerating and highly structured temporal pattern of thalamocortical network activity over the course of spindles therefore reflects the engagement of distinct subnetworks at specific times across spindle epochs. We propose that early cortical cells serve a synchronizing role in the initiation and propagation of spindle activity, whereas the subsequent recruitment of late cells actively antagonizes the thalamic spindle generator by providing asynchronous feedback.
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Potenciales de Acción/fisiología , Ritmo beta/fisiología , Dinámicas no Lineales , Corteza Prefrontal/fisiología , Sueño/fisiología , Núcleos Talámicos/fisiología , Algoritmos , Ritmo alfa/fisiología , Animales , Electroencefalografía , Masculino , Neuronas/fisiología , Corteza Prefrontal/citología , Ratas , Ratas Sprague-Dawley , Análisis Espectral , Núcleos Talámicos/citología , Factores de TiempoRESUMEN
The neurophysiology of non-rapid eye movement sleep is characterized by the occurrence of neural network oscillations with distinct origins and frequencies, which act in concert to support sleep-dependent information processing. Thalamocortical circuits generate slow (0.25-4 Hz) oscillations reflecting synchronized temporal windows of cortical activity, whereas concurrent waxing and waning spindle oscillations (8-15 Hz) act to facilitate cortical plasticity. Meanwhile, fast (140-200 Hz) and brief (< 200 ms) hippocampal ripple oscillations are associated with the reactivation of neural assemblies recruited during prior wakefulness. The extent of the forebrain areas engaged by these oscillations, and the variety of cellular and synaptic mechanisms involved, make them sensitive assays of distributed network function. Each of these three oscillations makes crucial contributions to the offline memory consolidation processes supported by non-rapid eye movement sleep. Slow, spindle and ripple oscillations are therefore potential surrogates of cognitive function and may be used as diagnostic measures in a range of brain diseases. We review the evidence for disrupted slow, spindle and ripple oscillations in schizophrenia, linking pathophysiological mechanisms to the functional impact of these neurophysiological changes and drawing links with the cognitive symptoms that accompany this condition. Finally, we discuss potential therapies that may normalize the coordinated activity of these three oscillations in order to restore healthy cognitive function.
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Ondas Encefálicas , Esquizofrenia/fisiopatología , Sueño REM , Animales , Cognición , Hipocampo/fisiopatología , Humanos , Transmisión SinápticaRESUMEN
Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/-) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/- rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/- rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.
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Proteínas Adaptadoras Transductoras de Señales , Haploinsuficiencia , Corteza Prefrontal , Esquizofrenia , Animales , Ratas , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Masculino , Proteínas Adaptadoras Transductoras de Señales/genética , Corteza Prefrontal/fisiopatología , Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Región CA1 Hipocampal/fisiopatología , Modelos Animales de Enfermedad , Red Nerviosa/fisiopatología , Conducta Animal/fisiología , Cuerpo Estriado/fisiopatología , Estriado Ventral/fisiopatologíaRESUMEN
INTRODUCTION: Federally Qualified Community Health Centers (FQHCs) are on the frontline of efforts to improve healthcare equity and reduce disparities exacerbated by the COVID-19 pandemic. This study assesses the provision and equity of preventive care and chronic disease management by FQHCs before, during, and after the pandemic. METHODS: Using electronic health record data from 210 FQHCs nationwide and employing segmented regression in an interrupted time series design, preventive screening and chronic disease management were assessed for 939,053 patients from 2019 to 2022. Care measures included cancer screenings, blood pressure control, diabetes control, and childhood immunizations; patient-level factors including race and ethnicity, language preference, and multimorbidity status were analyzed for equitable care provision. Analyses were conducted in 2023-2024. RESULTS: Cancer screening rates and blood pressure control initially declined after the onset of the pandemic but later rebounded, while diabetes control showed a slight increase, later stabilizing. Racial and ethnic disparities persisted, with Asian individuals having a higher prevalence of screenings and blood pressure control, and Black/African American individuals facing a lower prevalence for most screenings but a higher prevalence for cervical cancer screening. Hispanic/Latino individuals had a higher prevalence of various screenings and diabetes control. Disparities persisted for Native Hawaiian/Other Pacific Islander and American Indian/Alaska Native individuals and were observed based on language and multimorbidity status. CONCLUSIONS: While preventive screening and chronic disease management in FQHCs have largely rebounded to pre-pandemic levels following an initial decline, persistent disparities highlight the need for targeted interventions to support FQHCs in addressing healthcare inequities.
RESUMEN
Benzodiazepines and 'Z-drugs' (including zolpidem and zopiclone) are GABAA receptor (GABAAR) positive modulators commonly prescribed as hypnotics to treat insomnia and/or anxiety. However, alongside sedation, augmenting GABAAR function may also alter coordinated neuronal activity during sleep, thereby influencing sleep-dependent processes including memory consolidation. We used simultaneous recordings of neural population activity from the medial prelimbic cortex (PrL) and CA1 of the dorsal hippocampus (dCA1) of naturally sleeping rats to detail the effects of zolpidem on network activity during the cardinal oscillations of non-REM sleep. For comparison, we also characterized the effects of diazepam and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP/gaboxadol), which acts predominantly at extra-synaptic GABAARs. Zolpidem and THIP significantly increased the amplitudes of slow-waves, which were attenuated by diazepam. Zolpidem increased hippocampal ripple density whereas diazepam decreased both ripple density and intrinsic frequency. While none of the drugs affected thalamocortical spindles in isolation, zolpidem augmented the temporal coordination between slow-waves and spindles. At the cellular level, analyses of spiking activity from 523 PrL and 579 dCA1 neurons revealed that zolpidem significantly enhanced synchronized pauses in cortical firing during slow-wave down states, while increasing correlated activity within and between dCA1 and PrL populations. Of the drugs compared here, zolpidem was unique in augmenting coordinated activity within and between hippocampus and neocortex during non-REM sleep. Zolpidem's enhancement of hippocampal-prefrontal coupling may reflect the cellular basis of its potential to modulate offline memory processing.
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Hipocampo , Receptores de GABA-A , Sueño , Zolpidem , Animales , Ratas , Diazepam/farmacología , Electroencefalografía , Ácido gamma-Aminobutírico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Receptores de GABA-A/metabolismo , Zolpidem/farmacologíaRESUMEN
Anthropogenic emissions of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) have made significant contributions to global warming since the pre-industrial period and are therefore targeted in international climate policy. There is substantial interest in tracking and apportioning national contributions to climate change and informing equitable commitments to decarbonisation. Here, we introduce a new dataset of national contributions to global warming caused by historical emissions of carbon dioxide, methane, and nitrous oxide during the years 1851-2021, which are consistent with the latest findings of the IPCC. We calculate the global mean surface temperature response to historical emissions of the three gases, including recent refinements which account for the short atmospheric lifetime of CH4. We report national contributions to global warming resulting from emissions of each gas, including a disaggregation to fossil and land use sectors. This dataset will be updated annually as national emissions datasets are updated.
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Cambio Climático , Dióxido de Carbono/análisis , Metano , Óxido Nitroso/análisisRESUMEN
Coordinated activity spanning anatomically distributed neuronal networks underpins cognition and mediates limbic-cortical interactions during learning, memory, and decision-making. We used CP55940, a potent agonist of brain cannabinoid receptors known to disrupt coordinated activity in hippocampus, to investigate the roles of network oscillations during hippocampal and medial prefrontal cortical (mPFC) interactions in rats. During quiet wakefulness and rest, CP55940 dose-dependently reduced 0.1-30 Hz local field potential power in CA1 of the hippocampus while concurrently decreasing 30-100 Hz power in mPFC; these contrasting population-level effects were paralleled by differential effects on underlying single-unit activity in the two structures. During decision-making phases of a spatial working memory task, CP5540-induced deficits in hippocampal theta and prefrontal gamma oscillations were observed alongside disrupted theta-frequency coherence between the two structures. These changes in coordinated limbic-cortical network activities correlated with (1) reduced accuracy of task performance, (2) impaired phase-locking of prefrontal single-unit spiking to the local gamma and hippocampal theta rhythms, and (3) impaired task-dependent activity in a subset of mPFC units. In addition to highlighting the importance of CA1-mPFC network oscillations for cognition, these results implicate disrupted theta-frequency coordination of CA1-mPFC activity in the cognitive deficits caused by exogenous activation of brain cannabinoid receptors.
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Ondas Encefálicas/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Receptores de Cannabinoides/metabolismo , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Relojes Biológicos/efectos de los fármacos , Relojes Biológicos/fisiología , Ondas Encefálicas/efectos de los fármacos , Agonistas de Receptores de Cannabinoides , Antagonistas de Receptores de Cannabinoides , Intervalos de Confianza , Ciclohexanoles/farmacología , Dronabinol/farmacología , Estimulación Eléctrica/métodos , Potenciales Evocados/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Inmunosupresores/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Trastornos Mentales/inducido químicamente , Trastornos Mentales/patología , Red Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Long-Evans , Tiempo de Reacción/efectos de los fármacos , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
Establishing novel episodic memories and stable spatial representations depends on an exquisitely choreographed, multistage process involving the online encoding and offline consolidation of sensory information, a process that is largely dependent on the hippocampus. Each step is influenced by distinct neural network states that influence the pattern of activation across cellular assemblies. In recent years, the occurrence of hippocampal sharp wave ripple (SWR) oscillations has emerged as a potentially vital network phenomenon mediating the steps between encoding and consolidation, both at a cellular and network level by promoting the rapid replay and reactivation of recent activity patterns. Such events facilitate memory formation by optimising the conditions for synaptic plasticity to occur between contingent neural elements. In this paper, we explore the ways in which SWRs and other network events can bridge the gap between spatiomnemonic processing at cellular/synaptic and network levels in the hippocampus.
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Ondas Encefálicas/fisiología , Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/fisiología , Memoria a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Acetilcolina/fisiología , Potenciales de Acción/fisiología , Animales , Carbacol/farmacología , Colinérgicos/farmacología , Humanos , Locomoción , Memoria Episódica , Memoria a Largo Plazo/efectos de los fármacos , Modelos Neurológicos , Red Nerviosa/fisiología , Ratas , Fases del Sueño/fisiología , Trastornos del Sueño-Vigilia/fisiopatología , Trastornos del Sueño-Vigilia/psicología , Conducta Espacial/fisiología , Sinapsis/fisiología , Vigilia/fisiologíaRESUMEN
The rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia and schizophrenia is, in turn, associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants. We recruited healthy adult males with no history of psychiatric disorder from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the schizophrenia-associated 'A' allele (N = 22) or the alternative 'C' allele (N = 18) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequence task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation. Average MST learning and sleep-dependent performance improvements were similar across genotype groups, albeit more variable in the AA group. During sleep after learning, CC participants showed increased slow-wave (SW) and spindle amplitudes, plus augmented coupling of SW activity across recording electrodes. SW and spindles in those with the AA genotype were insensitive to learning, whilst SW coherence decreased following MST training. Accordingly, NREM neurophysiology robustly predicted the degree of overnight motor memory consolidation in CC carriers, but not in AA carriers. We describe evidence that rs1344706 polymorphism in ZNF804A is associated with changes in the coordinated neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of schizophrenia-associated common genetic variants on neural circuit oscillations and function.
Asunto(s)
Consolidación de la Memoria , Esquizofrenia , Niño , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Estudios Longitudinales , Masculino , Consolidación de la Memoria/fisiología , Polisomnografía , Esquizofrenia/genética , Sueño/genética , Adulto JovenRESUMEN
Quantification of CO2 fluxes at the Earth's surface is required to evaluate the causes and drivers of observed increases in atmospheric CO2 concentrations. Atmospheric inversion models disaggregate observed variations in atmospheric CO2 concentration to variability in CO2 emissions and sinks. They require prior constraints fossil CO2 emissions. Here we describe GCP-GridFED (version 2019.1), a gridded fossil emissions dataset that is consistent with the national CO2 emissions reported by the Global Carbon Project (GCP). GCP-GridFEDv2019.1 provides monthly fossil CO2 emissions estimates for the period 1959-2018 at a spatial resolution of 0.1°. Estimates are provided separately for oil, coal and natural gas, for mixed international bunker fuels, and for the calcination of limestone during cement production. GCP-GridFED also includes gridded estimates of O2 uptake based on oxidative ratios for oil, coal and natural gas. It will be updated annually and made available for atmospheric inversions contributing to GCP global carbon budget assessments, thus aligning the prior constraints on top-down fossil CO2 emissions with the bottom-up estimates compiled by the GCP.
RESUMEN
Black carbon (BC) is a recalcitrant form of organic carbon (OC) produced by landscape fires. BC is an important component of the global carbon cycle because, compared to unburned biogenic OC, it is selectively conserved in terrestrial and oceanic pools. Here we show that the dissolved BC (DBC) content of dissolved OC (DOC) is twice greater in major (sub)tropical and high-latitude rivers than in major temperate rivers, with further significant differences between biomes. We estimate that rivers export 18 ± 4 Tg DBC year-1 globally and that, including particulate BC fluxes, total riverine export amounts to 43 ± 15 Tg BC year-1 (12 ± 5% of the OC flux). While rivers export ~1% of the OC sequestered by terrestrial vegetation, our estimates suggest that 34 ± 26% of the BC produced by landscape fires has an oceanic fate. Biogeochemical models require modification to account for the unique dynamics of BC and to predict the response of recalcitrant OC export to changing environmental conditions.