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Every day we make decisions critical for adaptation and survival. We repeat actions with known consequences. But we also draw on loosely related events to infer and imagine the outcome of entirely novel choices. These inferential decisions are thought to engage a number of brain regions; however, the underlying neuronal computation remains unknown. Here, we use a multi-day cross-species approach in humans and mice to report the functional anatomy and neuronal computation underlying inferential decisions. We show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally structured learned associations. Moreover, during resting behavior, coactivation of hippocampal cells in sharp-wave/ripples represent inferred relationships that include reward, thereby "joining-the-dots" between events that have not been observed together but lead to profitable outcomes. Computing mnemonic links in this manner may provide an important mechanism to build a cognitive map that stretches beyond direct experience, thus supporting flexible behavior.
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Toma de Decisiones/fisiología , Red Nerviosa/fisiología , Pensamiento/fisiología , Animales , Encéfalo/fisiología , Femenino , Hipocampo/metabolismo , Hipocampo/fisiología , Humanos , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Neuronas/metabolismo , Neuronas/fisiología , Estudios Prospectivos , Adulto JovenRESUMEN
Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2 mgkg-1 (±)-DOI. We then demonstrate lasting effects of (±)-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2 mgkg-1 (±)-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, (±)-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that (±)-DOI's effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. (±)-DOI's facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.
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Anfetaminas , Cognición , Alucinógenos , Plasticidad Neuronal , Aprendizaje Inverso , Animales , Alucinógenos/farmacología , Ratones , Anfetaminas/farmacología , Cognición/efectos de los fármacos , Masculino , Plasticidad Neuronal/efectos de los fármacos , Aprendizaje Inverso/efectos de los fármacos , Encéfalo/efectos de los fármacos , Imagen por Resonancia Magnética/métodos , Ratones Endogámicos C57BL , RecompensaRESUMEN
Oligodendrocytes continue to differentiate from their precursor cells even in adulthood, a process that can be modulated by neuronal activity and experience. Previous work has indicated that conditional ablation of oligodendrogenesis in adult mice leads to learning and memory deficits in a range of behavioral tasks. The current study replicated and re-evaluated evidence for a role of oligodendrogenesis in motor learning, using a complex running wheel task. Further, we found that ablating oligodendrogenesis alters brain microstructure (ex vivo MRI) and brain activity (in vivo EEG) independent of experience with the task. This suggests a role for adult oligodendrocyte formation in the maintenance of brain function and indicates that task-independent changes due to oligodendrogenesis ablation need to be considered when interpreting learning and memory deficits in this model.
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Encéfalo , Oligodendroglía , Animales , Oligodendroglía/fisiología , Oligodendroglía/patología , Encéfalo/patología , Ratones , Masculino , Ratones Transgénicos , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Imagen por Resonancia Magnética , ElectroencefalografíaRESUMEN
Involvement of the glutamate system, particularly N-methyl-D-aspartate (NMDA) receptor hypofunction, has long been postulated to be part of the pathophysiology of schizophrenia. An important development is provided by recent data that strongly implicate GRIN2A, the gene encoding the NR2A (GluN2A) NMDA receptor subunit, in the aetiology of the disorder. Rare variants and common variants are both robustly associated with genetic risk for schizophrenia. Some of the rare variants are point mutations likely affecting channel function, but most are predicted to cause protein truncation and thence result, like the common variants, in reduced gene expression. We review the genomic evidence, and the findings from Grin2a mutant mice and other models which give clues as to the likely phenotypic impacts of GRIN2A genetic variation. We suggest that one consequence of NR2A dysfunction is impairment in a form of hippocampal synaptic plasticity, producing deficits in short-term habituation and thence elevated and dysregulated levels of attention, a phenotype of relevance to schizophrenia and its cognitive aspects.
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Receptores de N-Metil-D-Aspartato , Esquizofrenia , Animales , Ratones , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Fenotipo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/genética , HumanosRESUMEN
Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the etiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1-/- mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1-/- mice. Furthermore, dopamine signals were initially similar in Gria1-/- mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1-/- mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.
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Dopamina , Habituación Psicofisiológica , Ratones , Animales , Ratones Noqueados , Memoria a Corto Plazo , FenotipoRESUMEN
Light provides the primary signal for entraining circadian rhythms to the day/night cycle. In addition to rods and cones, the retina contains a small population of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4). Concerns have been raised that exposure to dim artificial lighting in the evening (DLE) may perturb circadian rhythms and sleep patterns, and OPN4 is presumed to mediate these effects. Here, we examine the effects of 4-h, 20-lux DLE on circadian physiology and behavior in mice and the role of OPN4 in these responses. We show that 2 wk of DLE induces a phase delay of â¼2 to 3 h in mice, comparable to that reported in humans. DLE-induced phase shifts are unaffected in Opn4-/- mice, indicating that rods and cones are capable of driving these responses in the absence of melanopsin. DLE delays molecular clock rhythms in the heart, liver, adrenal gland, and dorsal hippocampus. It also reverses short-term recognition memory performance, which is associated with changes in preceding sleep history. In addition, DLE modifies patterns of hypothalamic and cortical cFos signals, a molecular correlate of recent neuronal activity. Together, our data show that DLE causes coordinated realignment of circadian rhythms, sleep patterns, and short-term memory process in mice. These effects are particularly relevant as DLE conditions-due to artificial light exposure-are experienced by the majority of the populace on a daily basis.
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Ritmo Circadiano , Luz , Memoria a Corto Plazo/fisiología , Células Ganglionares de la Retina/fisiología , Opsinas de Bastones/fisiología , Sueño/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Ganglionares de la Retina/citologíaRESUMEN
BACKGROUND: Homeostatic regulation of sleep is reflected in the maintenance of a daily balance between sleep and wakefulness. Although numerous internal and external factors can influence sleep, it is unclear whether and to what extent the process that keeps track of time spent awake is determined by the content of the waking experience. We hypothesised that alterations in environmental conditions may elicit different types of wakefulness, which will in turn influence both the capacity to sustain continuous wakefulness as well as the rates of accumulating sleep pressure. To address this, we compared the effects of repetitive behaviours such as voluntary wheel running or performing a simple touchscreen task, with wakefulness dominated by novel object exploration, on sleep timing and EEG slow-wave activity (SWA) during subsequent NREM sleep. RESULTS: We find that voluntary wheel running is associated with higher wake EEG theta-frequency activity and results in longer wake episodes, as compared with exploratory behaviour; yet, it does not lead to higher levels of EEG SWA during subsequent NREM sleep in either the frontal or occipital derivation. Furthermore, engagement in a touchscreen task, motivated by food reward, results in lower SWA during subsequent NREM sleep in both derivations, as compared to exploratory wakefulness, even though the total duration of wakefulness is similar. CONCLUSION: Overall, our study suggests that sleep-wake behaviour is highly flexible within an individual and that the homeostatic processes that keep track of time spent awake are sensitive to the nature of the waking experience. We therefore conclude that sleep dynamics are determined, to a large degree, by the interaction between the organism and the environment.
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Conducta Exploratoria , Ratones/fisiología , Actividad Motora , Carrera , Sueño/fisiología , Vigilia , Animales , Masculino , Ratones Endogámicos C57BL , Sueño de Onda Lenta/fisiologíaRESUMEN
Following publication of this article, the authors noticed an error in the abstract, where they incorrectly stated that: "Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-/--dependent fashion". This has now been corrected to: "Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion". The authors would like to apologise for this error. This has been corrected in both the PDF and HTML versions of the article.
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Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1ß replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1ß synthesis. Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1ß but direct hippocampal action of IL-1ß causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.
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Lesiones Encefálicas/inmunología , Disfunción Cognitiva/inmunología , Interleucina-1/metabolismo , Animales , Encéfalo/metabolismo , Cognición/fisiología , Trastornos del Conocimiento/inmunología , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Citocinas/metabolismo , Demencia/inmunología , Femenino , Hipocampo/metabolismo , Inflamación/complicaciones , Inflamación/metabolismo , Interleucina-1/inmunología , Lipopolisacáridos/farmacología , Trastornos de la Memoria/inmunología , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismoRESUMEN
Fear learning is highly adaptive if utilized in appropriate situations but can lead to generalized anxiety if applied too widely. A role of predictive cues in inhibiting fear generalization has been suggested by stress and fear learning studies, but the effects of partially predictive cues (ambiguous cues) and the neuronal populations responsible for linking the predictive ability of cues and generalization of fear responses are unknown. Here, we show that inhibition of adult neurogenesis in the mouse dentate gyrus decreases hippocampal network activation and reduces defensive behavior to ambiguous threat cues but has neither of these effects if the same negative experience is reliably predicted. Additionally, we find that this ambiguity related to negative events determines their effect on fear generalization, that is, how the events affect future behavior under novel conditions. Both new neurons and glucocorticoid hormones are required for the enhancement of fear generalization following an unpredictably cued threat. Thus, adult neurogenesis plays a central role in the adaptive changes resulting from experience involving unpredictable or ambiguous threat cues, optimizing behavior in novel and uncertain situations.
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Giro Dentado/citología , Reacción Cataléptica de Congelación , Generalización de la Respuesta , Hipocampo/fisiología , Neurogénesis , Neuronas/citología , Células Piramidales/citología , Animales , Ansiedad/etiología , Ansiedad/patología , Ansiedad/fisiopatología , Condicionamiento Psicológico , Cruzamientos Genéticos , Señales (Psicología) , Giro Dentado/patología , Giro Dentado/fisiología , Giro Dentado/fisiopatología , Depresión/etiología , Depresión/patología , Depresión/fisiopatología , Conducta Exploratoria , Glucocorticoides/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Masculino , Ratones , Ratones Transgénicos , Neuronas/patología , Neuronas/fisiología , Células Piramidales/patología , Células Piramidales/fisiología , Distribución AleatoriaRESUMEN
Recent studies using transgenic mice lacking NMDA receptors in the hippocampus challenge the long-standing hypothesis that hippocampal long-term potentiation-like mechanisms underlie the encoding and storage of associative long-term spatial memories. However, it may not be the synaptic plasticity-dependent memory hypothesis that is wrong; instead, it may be the role of the hippocampus that needs to be re-examined. We present an account of hippocampal function that explains its role in both memory and anxiety.
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Ansiedad/fisiopatología , Hipocampo/fisiología , Memoria/fisiología , Plasticidad Neuronal/fisiología , Percepción Espacial/fisiología , Sinapsis/fisiología , Animales , Conducta Animal/fisiología , Hipocampo/fisiopatología , Ratones , Ratones Noqueados , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/fisiologíaRESUMEN
Light plays a critical role in the regulation of numerous aspects of physiology and behaviour, including the entrainment of circadian rhythms and the regulation of sleep. These responses involve melanopsin (OPN4)-expressing photosensitive retinal ganglion cells (pRGCs) in addition to rods and cones. Nocturnal light exposure in rodents has been shown to result in rapid sleep induction, in which melanopsin plays a key role. However, studies have also shown that light exposure can result in elevated corticosterone, a response that is not compatible with sleep. To investigate these contradictory findings and to dissect the relative contribution of pRGCs and rods/cones, we assessed the effects of light of different wavelengths on behaviourally defined sleep. Here, we show that blue light (470 nm) causes behavioural arousal, elevating corticosterone and delaying sleep onset. By contrast, green light (530 nm) produces rapid sleep induction. Compared to wildtype mice, these responses are altered in melanopsin-deficient mice (Opn4-/-), resulting in enhanced sleep in response to blue light but delayed sleep induction in response to green or white light. We go on to show that blue light evokes higher Fos induction in the SCN compared to the sleep-promoting ventrolateral preoptic area (VLPO), whereas green light produced greater responses in the VLPO. Collectively, our data demonstrates that nocturnal light exposure can have either an arousal- or sleep-promoting effect, and that these responses are melanopsin-mediated via different neural pathways with different spectral sensitivities. These findings raise important questions relating to how artificial light may alter behaviour in both the work and domestic setting.
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Nivel de Alerta/efectos de la radiación , Luz , Opsinas de Bastones/metabolismo , Sueño/efectos de la radiación , Animales , Nivel de Alerta/fisiología , Corticosterona/sangre , Corticosterona/metabolismo , Expresión Génica/efectos de la radiación , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Proteínas Circadianas Period/genética , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/efectos de la radiación , Área Preóptica/metabolismo , Área Preóptica/efectos de la radiación , Proteínas Proto-Oncogénicas c-fos/genética , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/efectos de la radiación , Opsinas de Bastones/genética , Sueño/fisiología , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/efectos de la radiación , Factores de TiempoRESUMEN
Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-ß aggregation, deposition of amyloid-ß plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-ß aggregation correlates with an unexpected shift in soluble amyloid-ß 40/42 ratio. This alteration in amyloid-ß isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-ß. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.
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Síndrome de Down/genética , Síndrome de Down/patología , Placa Amiloide/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/fisiología , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , TrisomíaRESUMEN
The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Therefore, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (≤1 Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed that this effect was mediated by glutamate and not 5-HT because it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10-20 Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT because they were blocked by antagonists of 5-HT2A and 5-HT1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often coexisted in the same neuron. Interestingly, fast-spiking and non-fast-spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons, but inhibited these cells directly via activation of 5-HT1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell-type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output.SIGNIFICANCE STATEMENT The modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders. Therefore, it is essential to determine the physiological mechanisms through which 5-HT neurons in the dorsal raphe nuclei modulate amygdala circuits. Here, we combined optogenetic, electrophysiological, and pharmacological approaches to study the effects of activation of 5-HT axons in the basal nucleus of the amygdala (BA). We found that 5-HT neurons co-release 5-HT and glutamate onto BA neurons in a cell-type-specific and frequency-dependent manner. Therefore, we suggest that theories on the contribution of 5-HT neurons to amygdala function should be revised to incorporate the concept of 5-HT/glutamate cotransmission.
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Amígdala del Cerebelo/citología , Ácido Glutámico/metabolismo , Red Nerviosa/fisiología , Neuronas/metabolismo , Serotonina/metabolismo , Animales , Animales Recién Nacidos , Channelrhodopsins , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Femenino , Antagonistas del GABA/farmacología , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/efectos de los fármacos , Piperazinas/farmacología , Piridinas/farmacología , Receptores de Serotonina/metabolismo , Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genéticaRESUMEN
Circadian rhythms optimize physiology and behavior to the varying demands of the 24 h day. The master circadian clock is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and it regulates circadian oscillators in tissues throughout the body to prevent internal desynchrony. Here, we demonstrate for the first time that, under standard 12 h:12 h light/dark (LD) cycles, object, visuospatial, and olfactory recognition performance in C57BL/6J mice is consistently better at midday relative to midnight. However, under repeated exposure to constant light (rLL), recognition performance becomes desynchronized, with object and visuospatial performance better at subjective midday and olfactory performance better at subjective midnight. This desynchrony in behavioral performance is mirrored by changes in expression of the canonical clock genes Period1 and Period2 (Per1 and Per2), as well as the immediate-early gene Fos in the SCN, dorsal hippocampus, and olfactory bulb. Under rLL, rhythmic Per1 and Fos expression is attenuated in the SCN. In contrast, hippocampal gene expression remains rhythmic, mirroring object and visuospatial performance. Strikingly, Per1 and Fos expression in the olfactory bulb is reversed, mirroring the inverted olfactory performance. Temporal desynchrony among these regions does not result in arrhythmicity because core body temperature and exploratory activity rhythms persist under rLL. Our data provide the first demonstration that abnormal lighting conditions can give rise to temporal desynchrony between autonomous circadian oscillators in different regions, with different consequences for performance across different sensory domains. Such a dispersed network of dissociable circadian oscillators may provide greater flexibility when faced with conflicting environmental signals.SIGNIFICANCE STATEMENT A master circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus regulates physiology and behavior across the 24 h day by synchronizing peripheral clocks throughout the brain and body. Without the SCN, these peripheral clocks rapidly become desynchronized. Here, we provide a unique demonstration that, under lighting conditions in which the central clock in the SCN is dampened, peripheral oscillators in the hippocampus and olfactory bulb become desynchronized, along with the behavioral processes mediated by these clocks. Multiple clocks that adopt different phase relationships may enable processes occurring in different brain regions to be optimized to specific phases of the 24 h day. Moreover, such a dispersed network of dissociable circadian clocks may provide greater flexibility when faced with conflicting environmental signals (e.g., seasonal changes in photoperiod).
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Ritmo Circadiano/fisiología , Percepción de Forma/fisiología , Memoria/fisiología , Enmascaramiento Perceptual/fisiología , Reconocimiento en Psicología/fisiología , Olfato/fisiología , Navegación Espacial/fisiología , Animales , Sincronización Cortical/fisiología , Masculino , Recuerdo Mental/fisiología , Ratones , Ratones Endogámicos C57BL , Reconocimiento Visual de Modelos/fisiología , Estimulación Luminosa/métodos , Análisis y Desempeño de TareasRESUMEN
Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions. Aged (18-21 months) G2019S and R1441C mutant transgenic rats exhibit L-DOPA-responsive motor dysfunction, impaired striatal dopamine release as determined by fast-scan cyclic voltammetry, and cognitive deficits. In addition, in vivo recordings of identified substantia nigra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction in burst firing, which likely results in further reductions to striatal dopamine release. These alterations to dopamine circuit function occur in the absence of neurodegeneration or abnormal protein accumulation within the substantia nigra pars compacta, suggesting that nigrostriatal dopamine dysfunction precedes detectable protein aggregation and cell death in the development of Parkinson's disease. In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics.
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Envejecimiento/metabolismo , Antiparkinsonianos/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Levodopa/farmacología , Mutación , Enfermedad de Parkinson/genética , Potenciales de Acción , Envejecimiento/patología , Sustitución de Aminoácidos , Animales , Muerte Celular/genética , Cromosomas Artificiales Bacterianos/química , Cromosomas Artificiales Bacterianos/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Masculino , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Regiones Promotoras Genéticas , Dominios Proteicos , Ratas , Ratas Transgénicas , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1-/- mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1-/- mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.
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Compuestos Bicíclicos con Puentes/farmacología , Antagonistas de Dopamina/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Haloperidol/farmacología , Hipercinesia/metabolismo , Memoria a Corto Plazo/efectos de los fármacos , Receptores AMPA/genética , Animales , Compuestos Bicíclicos con Puentes/uso terapéutico , Antagonistas de Dopamina/uso terapéutico , Agonistas de Aminoácidos Excitadores/uso terapéutico , Femenino , Haloperidol/uso terapéutico , Hipercinesia/tratamiento farmacológico , Hipercinesia/fisiopatología , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/metabolismoRESUMEN
Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V-VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15-52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target.
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Autoanticuerpos/inmunología , Inmunoglobulina G/metabolismo , Proteínas de la Membrana/inmunología , Microglía/inmunología , Proteínas del Tejido Nervioso/inmunología , Proteínas/inmunología , Animales , Animales no Consanguíneos , Autoanticuerpos/administración & dosificación , Encéfalo/inmunología , Encéfalo/patología , Encefalitis/inmunología , Femenino , Ácido Glutámico/metabolismo , Células HEK293 , Humanos , Inmunoglobulina G/administración & dosificación , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones Noqueados , Microglía/patología , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Neuronas/inmunología , Neuronas/patología , Corteza Prefrontal/inmunología , Corteza Prefrontal/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Distribución Aleatoria , Conducta SocialRESUMEN
Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.
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Región CA3 Hipocampal/fisiología , Memoria/fisiología , Animales , Conducta Animal , Mapeo Encefálico , Dependovirus , Silenciador del Gen , Halorrodopsinas/metabolismo , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Células Piramidales/fisiología , Memoria Espacial , Sinapsis/fisiologíaRESUMEN
A common strategy when searching for cognitive-enhancing drugs has been to target the N-methyl-d-aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D-amino acid oxidase (DAO) degrades neutral D-amino acids such as D-serine, the primary endogenous co-agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long-term potentiation and facilitated water maze acquisition of ddY/Dao(-) mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao(-/-) ) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao(-/-) mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao(-/-) mice exhibited normal performance in two alternative assays of long-term spatial memory: the appetitive and aversive Y-maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long-term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted.