A population of gap junction-coupled neurons drives recurrent network activity in a developing visual circuit.

In many regions of the vertebrate brain, microcircuits generate local recurrent activity that aids in the processing and encoding of incoming afferent inputs. Local recurrent activity can amplify, filter, and temporally and spatially parse out incoming input. Determining how these microcircuits function is of great interest because it provides glimpses into fundamental processes underlying brain computation. Within the Xenopus tadpole optic tectum, deep layer neurons display robust recurrent activity. Although the development and plasticity of this local recurrent activity has been well described, the underlying microcircuitry is not well understood. Here, using a whole brain preparation that allows for whole cell recording from neurons of the superficial tectal layers, we identified a physiologically distinct population of excitatory neurons that are gap junctionally coupled and through this coupling gate local recurrent network activity. Our findings provide a novel role for neuronal coupling among excitatory interneurons in the temporal processing of visual stimuli.

Multivariate analysis of electrophysiological diversity of Xenopus visual neurons during development and plasticity.

Biophysical properties of neurons become increasingly diverse over development, but mechanisms underlying and constraining this diversity are not fully understood. Here we investigate electrophysiological characteristics of Xenopus tadpole midbrain neurons across development and during homeostatic plasticity induced by patterned visual stimulation. We show that in development tectal neuron properties not only change on average, but also become increasingly diverse. After sensory stimulation, both electrophysiological diversity and functional differentiation of cells are reduced. At the same time, the amount of cross-correlations between cell properties increase after patterned stimulation as a result of homeostatic plasticity. We show that tectal neurons with similar spiking profiles often have strikingly different electrophysiological properties, and demonstrate that changes in intrinsic excitability during development and in response to sensory stimulation are mediated by different underlying mechanisms. Overall, this analysis and the accompanying dataset provide a unique framework for further studies of network maturation in Xenopus tadpoles.

Pet-1 deficiency alters the circadian clock and its temporal organization of behavior.

The serotonin and circadian systems are two important interactive regulatory networks in the mammalian brain that regulate behavior and physiology in ways that are known to impact human mental health. Previous work on the interaction between these two systems suggests that serotonin modulates photic input to the central circadian clock (the suprachiasmatic nuclei; SCN) from the retina and serves as a signal for locomotor activity, novelty, and arousal to shift the SCN clock, but effects of disruption of serotonergic signaling from the raphe nuclei on circadian behavior and on SCN function are not fully characterized. In this study, we examined the effects on diurnal and circadian behavior, and on ex vivo molecular rhythms of the SCN, of genetic deficiency in Pet-1, an ETS transcription factor that is necessary to establish and maintain the serotonergic phenotype of raphe neurons. Pet-1⁻/⁻ mice exhibit loss of rhythmic behavioral coherence and an extended daily activity duration, as well as changes in the molecular rhythms expressed by the clock, such that ex vivo SCN from Pet-1⁻/⁻ mice exhibit period lengthening and sex-dependent changes in rhythmic amplitude. Together, our results indicate that Pet-1 regulation of raphe neuron serotonin phenotype contributes to the period, precision and light/dark partitioning of locomotor behavioral rhythms by the circadian clock through direct actions on the SCN clock itself, as well as through non-clock effects.

Shift work in nurses: contribution of phenotypes and genotypes to adaptation.

BACKGROUND: Daily cycles of sleep/wake, hormones, and physiological processes are often misaligned with behavioral patterns during shift work, leading to an increased risk of developing cardiovascular/metabolic/gastrointestinal disorders, some types of cancer, and mental disorders including depression and anxiety. It is unclear how sleep timing, chronotype, and circadian clock gene variation contribute to adaptation to shift work. METHODS: Newly defined sleep strategies, chronotype, and genotype for polymorphisms in circadian clock genes were assessed in 388 hospital day- and night-shift nurses. RESULTS: Night-shift nurses who used sleep deprivation as a means to switch to and from diurnal sleep on work days (∼25%) were the most poorly adapted to their work schedule. Chronotype also influenced efficacy of adaptation. In addition, polymorphisms in CLOCK, NPAS2, PER2, and PER3 were significantly associated with outcomes such as alcohol/caffeine consumption and sleepiness, as well as sleep phase, inertia and duration in both single- and multi-locus models. Many of these results were specific to shift type suggesting an interaction between genotype and environment (in this case, shift work). CONCLUSIONS: Sleep strategy, chronotype, and genotype contribute to the adaptation of the circadian system to an environment that switches frequently and/or irregularly between different schedules of the light-dark cycle and social/workplace time. This study of shift work nurses illustrates how an environmental "stress" to the temporal organization of physiology and metabolism can have behavioral and health-related consequences. Because nurses are a key component of health care, these findings could have important implications for health-care policy.

Perinatal photoperiod imprints the circadian clock.

Using real-time gene expression imaging and behavioral analysis, we found that the perinatal photoperiod has lasting effects on the circadian rhythms expressed by clock neurons as well as on mouse behavior, and sets the responsiveness of the biological clock to subsequent changes in photoperiod. These developmental gene × environment interactions tune circadian clock responses to subsequent seasonal photoperiods and may contribute to the influence of season on neurobehavioral disorders in humans.

Population encoding by circadian clock neurons organizes circadian behavior.

Mammalian circadian rhythms are orchestrated by the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN are composed of circadian clock neurons, but the mechanisms by which these populations of neuronal oscillators encode rhythmic behavior are incompletely understood. We have used ex vivo real-time gene expression imaging of the neural correlates of circadian behavior, combined with genetic disruption of vasoactive intestinal polypeptide, a key SCN signaling molecule, to examine the neural basis of circadian organization in the SCN. We show that the coherence and timing of clock neuron rhythms are correlated with the coherence and timing of behavioral rhythms within individual mice and that the degree of disruption of SCN neuronal organization correlates with the degree of behavioral disruption within individuals. Our results suggest that the SCN encode circadian phase as a temporal population vector of its constituent neurons; such that as the neuronal population becomes desynchronized, phase information becomes ambiguous.

Genetic differences in human circadian clock genes among worldwide populations.

The daily biological clock regulates the timing of sleep and physiological processes that are of fundamental importance to human health, performance, and well-being. Environmental parameters of relevance to biological clocks include (1) daily fluctuations in light intensity and temperature, and (2) seasonal changes in photoperiod (day length) and temperature; these parameters vary dramatically as a function of latitude and locale. In wide-ranging species other than humans, natural selection has genetically optimized adaptiveness along latitudinal clines. Is there evidence for selection of clock gene alleles along latitudinal/photoperiod clines in humans? A number of polymorphisms in the human clock genes Per2, Per3, Clock, and AANAT have been reported as alleles that could be subject to selection. In addition, this investigation discovered several novel polymorphisms in the human Arntl and Arntl2 genes that may have functional impact upon the expression of these clock transcriptional factors. The frequency distribution of these clock gene polymorphisms is reported for diverse populations of African Americans, European Americans, Ghanaians, Han Chinese, and Papua New Guineans (including 5 subpopulations within Papua New Guinea). There are significant differences in the frequency distribution of clock gene alleles among these populations. Population genetic analyses indicate that these differences are likely to arise from genetic drift rather than from natural selection.