RESUMO
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.
Assuntos
Ritmo Circadiano , Luz , Memória de Curto Prazo/fisiologia , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/fisiologia , Sono/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Ganglionares da Retina/citologiaRESUMO
Optogenetic strategies to restore vision in patients who are blind from end-stage retinal degenerations aim to render remaining retinal cells light sensitive once photoreceptors are lost. Here, we assessed long-term functional outcomes following subretinal delivery of the human melanopsin gene (OPN4) in the rd1 mouse model of retinal degeneration using an adeno-associated viral vector. Ectopic expression of OPN4 using a ubiquitous promoter resulted in cellular depolarization and ganglion cell action potential firing. Restoration of the pupil light reflex, behavioral light avoidance, and the ability to perform a task requiring basic image recognition were restored up to 13 mo following injection. These data suggest that melanopsin gene therapy via a subretinal route may be a viable and stable therapeutic option for the treatment of end-stage retinal degeneration in humans.
Assuntos
Terapia Genética/métodos , Degeneração Retiniana/terapia , Opsinas de Bastonetes/genética , Animais , Dependovirus , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos C3H , Visão OcularRESUMO
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.
Assuntos
Nível de Alerta/efeitos da radiação , Luz , Opsinas de Bastonetes/metabolismo , Sono/efeitos da radiação , Animais , Nível de Alerta/fisiologia , Corticosterona/sangue , Corticosterona/metabolismo , Expressão Gênica/efeitos da radiação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Proteínas Circadianas Period/genética , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/efeitos da radiação , Área Pré-Óptica/metabolismo , Área Pré-Óptica/efeitos da radiação , Proteínas Proto-Oncogênicas c-fos/genética , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/efeitos da radiação , Opsinas de Bastonetes/genética , Sono/fisiologia , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/efeitos da radiação , Fatores de TempoRESUMO
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).
Assuntos
Ritmo Circadiano/fisiologia , Percepção de Forma/fisiologia , Memória/fisiologia , Mascaramento Perceptivo/fisiologia , Reconhecimento Psicológico/fisiologia , Olfato/fisiologia , Navegação Espacial/fisiologia , Animais , Sincronização Cortical/fisiologia , Masculino , Rememoração Mental/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Reconhecimento Visual de Modelos/fisiologia , Estimulação Luminosa/métodos , Análise e Desempenho de TarefasRESUMO
Acute light exposure exerts various effects on physiology and behaviour. Although the effects of light on brain network activity in humans are well demonstrated, the effects of light on cognitive performance are inconclusive, with the size, as well as direction, of the effect depending on the nature of the task. Similarly, in nocturnal rodents, bright light can either facilitate or disrupt performance depending on the type of task employed. Crucially, it is unclear whether the effects of light on behavioural performance are mediated via the classical image-forming rods and cones or the melanopsin-expressing photosensitive retinal ganglion cells. Here, we investigate the modulatory effects of light on memory performance in mice using the spontaneous object recognition task. Importantly, we examine which photoreceptors are required to mediate the effects of light on memory performance. By using a cross-over design, we show that object recognition memory is disrupted when the test phase is conducted under a bright light (350 lux), regardless of the light level in the sample phase (10 or 350 lux), demonstrating that exposure to a bright light at the time of test, rather than at the time of encoding, impairs performance. Strikingly, the modulatory effect of light on memory performance is completely abolished in both melanopsin-deficient and rodless-coneless mice. Our findings provide direct evidence that melanopsin-driven and rod/cone-driven photoresponses are integrated in order to mediate the effect of light on memory performance.
Assuntos
Luz , Reconhecimento Psicológico , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Opsinas de Bastonetes/química , Animais , Estudos Cross-Over , CamundongosRESUMO
Behavioral findings suggest that the dorsal hippocampus (DHPC) plays a role in timing of appetitive conditioned responding. The present article explored the relationship between the extent of DHPC damage and timing ability, in a pooled analysis of three published studies from our laboratory. Initial analyses of variance confirmed our previous reports that DHPC damage reduced peak time (a measure of timing accuracy). However, the spread (a measure of timing precision) was unchanged, such that the coefficient of variation (spread/peak time) was significantly larger in DHPC-lesioned animals. This implies that, in addition to the well-established effect of DHPC lesions on timing accuracy, DHPC damage produced a deficit in precision of timing. To complement this analysis, different generalized linear mixed-effects models (GLMMs) were performed on the combined dataset, to examine which combinations of the different behavioral measures of timing were the best predictors of the degree of hippocampal damage. The results from the GLMM analysis suggested that the greater the DHPC damage, the greater the absolute difference between the observed peak time and reinforced duration. Nevertheless, this systematic relationship between damage and performance was not specific to the temporal domain: paradoxically the greater the damage the greater the magnitude of peak responding. We discuss these lesion effects in terms of scalar timing theory.
Assuntos
Lesões Encefálicas/patologia , Condicionamento Operante , Hipocampo/fisiopatologia , Tempo de Reação/fisiologia , Estimulação Acústica , Análise de Variância , Animais , Sinais (Psicologia) , Modelos Lineares , Masculino , Estimulação Luminosa , RatosRESUMO
d-amino acid oxidase (DAO, DAAO) is an enzyme that degrades d-serine, the primary endogenous co-agonist of the synaptic N-methyl-d-aspartate receptor. Convergent evidence implicates DAO in the pathophysiology and potential treatment of schizophrenia. To better understand the functional role of DAO, we characterized the behaviour of the first genetically engineered Dao knockout (Dao(-/-) ) mouse. Our primary objective was to assess both spatial and non-spatial short-term memory performance. Relative to wildtype (Dao(+/+) ) littermate controls, Dao(-/-) mice demonstrated enhanced spatial recognition memory performance, improved odour recognition memory performance, and enhanced spontaneous alternation in the T-maze. In addition, Dao(-/-) mice displayed increased anxiety-like behaviour in five tests of approach/avoidance conflict: the open field test, elevated plus maze, successive alleys, light/dark box and novelty-suppressed feeding. Despite evidence of a reciprocal relationship between anxiety and sleep and circadian function in rodents, we found no evidence of sleep or circadian rhythm disruption in Dao(-/-) mice. Overall, our observations are consistent with, and extend, findings in the natural mutant ddY/Dao(-) line. These data add to a growing body of preclinical evidence linking the inhibition, inactivation or deletion of DAO with enhanced cognitive performance. Our results have implications for the development of DAO inhibitors as therapeutic agents.
Assuntos
Ansiedade/metabolismo , Ritmo Circadiano , D-Aminoácido Oxidase/metabolismo , Memória de Curto Prazo , Sono , Animais , Ansiedade/fisiopatologia , Aprendizagem da Esquiva , D-Aminoácido Oxidase/genética , Feminino , Deleção de Genes , Masculino , Aprendizagem em Labirinto , CamundongosRESUMO
Involvement of the dorsal hippocampus (DHPC) in conditioned-response timing and maintaining temporal information across time gaps was examined in an appetitive Pavlovian conditioning task, in which rats with sham and DHPC lesions were first conditioned to a 15-s visual cue. After acquisition, the subjects received a series of non-reinforced test trials, on which the visual cue was extended (45 s) and gaps of different duration, 0.5, 2.5, and 7.5 s, interrupted the early portion of the cue. Dorsal hippocampal-lesioned subjects underestimated the target duration of 15 s and showed broader response distributions than the control subjects on the no-gap trials in the first few blocks of test, but the accuracy and precision of their timing reached the level of that of the control subjects by the last block. On the gap trials, the DHPC-lesioned subjects showed greater rightward shifts in response distributions than the control subjects. We discussed these lesion effects in terms of temporal versus non-temporal processing (response inhibition, generalisation decrement, and inhibitory conditioning).
Assuntos
Condicionamento Operante/fisiologia , Hipocampo/fisiologia , Tempo de Reação/fisiologia , Animais , Masculino , RatosRESUMO
The dentate gyrus (DG) gates neocortical information flow to the hippocampus. Intriguingly, the DG also produces adult-born dentate granule cells (abDGCs) throughout the lifespan, but their contribution to downstream firing dynamics remains unclear. Here, we show that abDGCs promote sparser hippocampal population spiking during mnemonic processing of novel stimuli. By combining triple-(DG-CA3-CA1) ensemble recordings and optogenetic interventions in behaving mice, we show that abDGCs constitute a subset of high-firing-rate neurons with enhanced activity responses to novelty and strong modulation by theta oscillations. Selectively activating abDGCs in their 4-7-week post-birth period increases sparsity of hippocampal population patterns, whereas suppressing abDGCs reduces this sparsity, increases principal cell firing rates and impairs novel object recognition with reduced dimensionality of the network firing structure, without affecting single-neuron spatial representations. We propose that adult-born granule cells transiently support sparser hippocampal population activity structure for higher-dimensional responses relevant to effective mnemonic information processing.
Assuntos
Giro Denteado , Hipocampo , Animais , Camundongos , Giro Denteado/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Memória/fisiologiaRESUMO
Light is known to exert powerful effects on behavior and physiology, including upon the amount and distribution of activity across the day/night cycle. Here we use home cage activity monitoring to measure the effect of differences in home cage light spectrum and intensity on key circadian activity parameters in mice. Due to the relative positioning of any individually ventilated cage (IVC) with regard to the animal facility lighting, notable differences in light intensity occur across the IVC rack. Although all mice were found to be entrained, significant differences in the timing of activity onset and differences in activity levels were found between mice housed in standard versus red filtering cages. Furthermore, by calculating the effective irradiance based upon the known mouse photopigments, a significant relationship between light intensity and key circadian parameters are shown. Perhaps unsurprisingly given the important role of the circadian photopigment melanopsin in circadian entrainment, melanopic illuminance is shown to correlate more strongly with key circadian activity parameters than photopic lux. Collectively, our results suggest that differences in light intensity may reflect an uncharacterized source of variation in laboratory rodent research, with potential consequences for reproducibility. Room design and layout vary within and between facilities, and caging design and lighting location relative to cage position can be highly variable. We suggest that cage position should be factored into experimental design, and wherever possible, experimental lighting conditions should be characterized as a way of accounting for this source of variation.
RESUMO
Acute exposure to light exerts widespread effects on physiology, in addition to its key role in photoentrainment. Although the modulatory effect of light on physiological arousal is well demonstrated in mice, its effect on memory performance is inconclusive, as the direction of the effect depends on the nature of the behavioural task employed and/or the type of stimulus utilised. Moreover, in all rodent studies that reported significant effects of light on performance, brain activity was not assessed during the task and thus it is unclear how brain activity was modulated by light or the exact relationship between light-modulated brain activity and performance. Here we examine the modulatory effects of light of varying intensities on recognition memory performance and frontoparietal waking electroencephalography (EEG) in mice using the spontaneous recognition memory task. We report a light-intensity-dependent disruptive effect on recognition memory performance at the group level, but inspection of individual-level data indicates that light-intensity-dependent facilitation is observed in some cases. Using linear mixed-effects models, we then demonstrate that EEG fast theta (θ) activity at the time of encoding negatively predicts recognition memory performance, whereas slow gamma (γ) activity at the time of retrieval positively predicts performance. These relationships between θ/γ activity and performance are strengthened by increasing light intensity. Thus, light modulates θ and γ band activities involved in attentional and mnemonic processes, thereby affecting recognition memory performance. However, extraneous factors including the phase of the internal clock at which light is presented and homeostatic sleep pressure may determine how photic input is translated into behavioural performance.
Assuntos
Encéfalo/fisiologia , Ritmo Gama/fisiologia , Memória/fisiologia , Estimulação Luminosa/métodos , Reconhecimento Psicológico/fisiologia , Ritmo Teta/fisiologia , Animais , Eletroencefalografia/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Odorantes , Olfato/fisiologiaRESUMO
Dysfunction of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and circadian rhythm disruption. To investigate the role of GluA1 in circadian and sleep behaviour, we used wheel-running, passive-infrared, and video-based home-cage activity monitoring to assess daily rest-activity profiles of GluA1-knockout mice (Gria1-/-). We showed that these mice displayed various circadian abnormalities, including misaligned, fragmented, and more variable rest-activity patterns. In addition, they showed heightened, but transient, behavioural arousal to lightâdark and darkâlight transitions, as well as attenuated nocturnal-light-induced activity suppression (negative masking). In the hypothalamic suprachiasmatic nuclei (SCN), nocturnal-light-induced cFos signals (a molecular marker of neuronal activity in the preceding ~1-2 h) were attenuated, indicating reduced light sensitivity in the SCN. However, there was no change in the neuroanatomical distribution of expression levels of two neuropeptides-vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP)-differentially expressed in the core (ventromedial) vs. shell (dorsolateral) SCN subregions and both are known to be important for neuronal synchronisation within the SCN and circadian rhythmicity. In the motor cortex (area M1/M2), there was increased inter-individual variability in cFos levels during the evening period, mirroring the increased inter-individual variability in locomotor activity under nocturnal light. Finally, in the spontaneous odour recognition task GluA1 knockouts' short-term memory was impaired due to enhanced attention to the recently encountered familiar odour. These abnormalities due to altered AMPA-receptor-mediated signalling resemble and may contribute to sleep and circadian rhythm disruption and attentional deficits in different modalities in schizophrenia.
Assuntos
Ritmo Circadiano , Receptores de AMPA , Animais , Sinais (Psicologia) , Camundongos , Núcleo Supraquiasmático , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiônicoRESUMO
Cortical and subcortical circuitry are thought to play distinct roles in the generation of sleep oscillations and global state control, respectively. Here we silenced a subset of neocortical layer 5 pyramidal and archicortical dentate gyrus granule cells in male mice by ablating SNAP25. This markedly increased wakefulness and reduced rebound of electroencephalographic slow-wave activity after sleep deprivation, suggesting a role for the cortex in both vigilance state control and sleep homeostasis.
Assuntos
Giro Denteado/fisiologia , Neocórtex/fisiologia , Neurônios/fisiologia , Sono/fisiologia , Vigília/fisiologia , Animais , Masculino , Camundongos , Camundongos Transgênicos , Proteína 25 Associada a Sinaptossoma/deficiênciaRESUMO
Body temperature is an important physiological parameter in many studies of laboratory mice. Continuous assessment of body temperature has traditionally required surgical implantation of a telemeter, but this invasive procedure adversely impacts animal welfare. Near-infrared thermography provides a non-invasive alternative by continuously measuring the highest temperature on the outside of the body (Tskin), but the reliability of these recordings as a proxy for continuous core body temperature (Tcore) measurements has not been assessed. Here, Tcore (30 s resolution) and Tskin (1 s resolution) were continuously measured for three days in mice exposed to ad libitum and restricted feeding conditions. We subsequently developed an algorithm that optimised the reliability of a Tskin-derived estimate of Tcore. This identified the average of the maximum Tskin per minute over a 30-min interval as the optimal way to estimate Tcore. Subsequent validation analyses did however demonstrate that this Tskin-derived proxy did not provide a reliable estimate of the absolute Tcore due to the high between-animal variability in the relationship between Tskin and Tcore. Conversely, validation showed that Tskin-derived estimates of Tcore reliably describe temporal patterns in physiologically-relevant Tcore changes and provide an excellent measure to perform within-animal comparisons of relative changes in Tcore.
Assuntos
Temperatura Corporal/fisiologia , Pele/fisiopatologia , Animais , Regulação da Temperatura Corporal/fisiologia , Dietoterapia/métodos , Métodos de Alimentação , Temperatura Alta , Camundongos , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Termografia/métodosRESUMO
Light exerts a wide range of effects on mammalian physiology and behavior. As well as synchronizing circadian rhythms to the external environment, light has been shown to modulate autonomic and neuroendocrine responses as well as regulating sleep and influencing cognitive processes such as attention, arousal, and performance. The last two decades have seen major advances in our understanding of the retinal photoreceptors that mediate these non-image forming responses to light, as well as the neural pathways and molecular mechanisms by which circadian rhythms are generated and entrained to the external light/dark (LD) cycle. By contrast, our understanding of the mechanisms by which lighting influences cognitive processes is more equivocal. The effects of light on different cognitive processes are complex. As well as the direct effects of light on alertness, indirect effects may also occur due to disrupted circadian entrainment. Despite the widespread use of disrupted LD cycles to study the role circadian rhythms on cognition, the different experimental protocols used have subtly different effects on circadian function which are not always comparable. Moreover, these protocols will also disrupt sleep and alter physiological arousal, both of which are known to modulate cognition. Studies have used different assays that are dependent on different cognitive and sensory processes, which may also contribute to their variable findings. Here, we propose that studies addressing the effects of different lighting conditions on cognitive processes must also account for their effects on circadian rhythms, sleep, and arousal if we are to fully understand the physiological basis of these responses.
RESUMO
In two experiments rats received training on an object-in-context (OIC) task, in which they received preexposure to object A in context x, followed by exposure to object B in context y. In a subsequent test both A and B are presented in either context x or context y. Usually more exploration is seen of the object that has not previously been paired with the test context, an effect attributed to the ability to remember where an object was encountered. However, in the typical version of this task, object A has also been encountered less recently than object B at test. This is precisely the arrangement in tests of 'relatively recency' (RR), in which more remotely presented objects are explored more than objects experienced more recently. RR could contaminate performance on the OIC task, by enhancing the OIC effect when animals are tested in context y, and masking it when the test is in context x. This possibility was examined in two experiments, and evidence for superior performance in context y was obtained. The implications of this for theoretical interpretations of recognition memory and the procedures used to explore it are discussed.
Assuntos
Comportamento de Escolha/fisiologia , Condicionamento Clássico/fisiologia , Discriminação Psicológica/fisiologia , Memória/fisiologia , Animais , Comportamento Animal/fisiologia , Masculino , Reconhecimento Visual de Modelos/fisiologia , Ratos , Ratos Endogâmicos , Reconhecimento Psicológico/fisiologiaRESUMO
Schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia-relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (Vipr2) knockout mice, and neuregulin 1 (Nrg1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core clock genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual-process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (Nrg1 deficiency) seem to be inconsistent with each other. Schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but Nrg1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted.
Assuntos
Ritmo Circadiano , Memória , Psicologia do Esquizofrênico , Sono , Animais , Modelos Animais de Doenças , Humanos , CamundongosRESUMO
Sleep and/or circadian rhythm disruption (SCRD) is seen in up to 80% of schizophrenia patients. The co-morbidity of schizophrenia and SCRD may in part stem from dysfunction in common brain mechanisms, which include the glutamate system, and in particular, the group II metabotropic glutamate receptors mGlu2 and mGlu3 (encoded by the genes Grm2 and Grm3). These receptors are relevant to the pathophysiology and potential treatment of schizophrenia, and have also been implicated in sleep and circadian function. In the present study, we characterised the sleep and circadian rhythms of Grm2/3 double knockout (Grm2/3-/-) mice, to provide further evidence for the involvement of group II metabotropic glutamate receptors in the regulation of sleep and circadian rhythms. We report several novel findings. Firstly, Grm2/3-/- mice demonstrated a decrease in immobility-determined sleep time and an increase in immobility-determined sleep fragmentation. Secondly, Grm2/3-/- mice showed heightened sensitivity to the circadian effects of light, manifested as increased period lengthening in constant light, and greater phase delays in response to nocturnal light pulses. Greater light-induced phase delays were also exhibited by wildtype C57Bl/6J mice following administration of the mGlu2/3 negative allosteric modulator RO4432717. These results confirm the involvement of group II metabotropic glutamate receptors in photic entrainment and sleep regulation pathways. Finally, the diurnal wheel-running rhythms of Grm2/3-/- mice were perturbed under a standard light/dark cycle, but their diurnal rest-activity rhythms were unaltered in cages lacking running wheels, as determined with passive infrared motion detectors. Hence, when assessing the diurnal rest-activity rhythms of mice, the choice of assay can have a major bearing on the results obtained.
Assuntos
Ritmo Circadiano , Luz , Condicionamento Físico Animal , Receptores de Glutamato Metabotrópico/fisiologia , Regulação Alostérica , Animais , Locomoção , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glutamato Metabotrópico/genética , SonoRESUMO
Rats were administered 3 versions of an object recognition task: In the spontaneous object recognition task (SOR) animals discriminated between a familiar object and a novel object; in the temporal order task they discriminated between 2 familiar objects, 1 of which had been presented more recently than the other; and, in the object-in-place task, they discriminated among 4 previously presented objects, 2 of which were presented in the same locations as in preexposure and 2 in different but familiar locations. In each task animals were tested at 2 delays (5 min and 2 hr) between the sample and test phases in the SOR and object-in-place task, and between the 2 sample phases in the temporal order task. Performance in the SOR was poorer with the longer delay, whereas in the temporal order task performance improved with delay. There was no effect of delay on object-in-place performance. In addition the performance of animals with neurotoxic lesions of the dorsal hippocampus was selectively impaired in the object-in-place task at the longer delay. These findings are interpreted within the framework of Wagner's (1981) model of memory.
Assuntos
Aprendizagem por Associação/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Reconhecimento Psicológico/fisiologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Hipocampo/lesões , Hipocampo/fisiologia , Ácido Ibotênico/toxicidade , Masculino , Aprendizagem em Labirinto , Neurotoxinas/toxicidade , Reconhecimento Visual de Modelos/efeitos dos fármacos , Éteres Fosfolipídicos/toxicidade , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia , Fatores de TempoRESUMO
Two appetitive conditioning experiments with rats investigated the mechanisms and properties of unblocking that results from the surprising omission of an expected post-trial unconditioned stimulus (US). Experiment 1 demonstrated unblocking under circumstances in which differences in the contribution of generalization decrement and within-compound associations are equated across experimental and control groups. Following Stage 1 training in which a conditioned stimulus (CS) A was followed by a US and a post-trial US, in Experiment 2 we arranged for the post-trial US to be present on some trials with AX but not others. Under these circumstances an enhancement of unblocking to X was observed, relative to a group who received standard unblocking by US omission. The implications of these results for attentional and US-processing theories of associative learning are discussed.