Abstract This article compares the preface of Luke’s Gospel to Philo’s preface to De Abrahamo and Arrian’s preface to his arrangement of the sayings of Epictetus. Scholars have usually sought ancient ...comparanda to Luke’s preface in order to identify the Gospel’s genre. This study moves beyond this traditional question of form (‘What ancient works bear the closest resemblance to the structure of Luke 1:1–4?’) and on to the question of function. The selected works of Philo and Arrian participate in different genres, but both belong to the rhetorical category of ‘philosophical protreptic’, a piece of writing intended to compel the reader towards a particular moral vision. I argue that Luke’s preface exhibits unexplored similarities with the prefaces of Arrian and Philo and can itself be fruitfully read as a kind of philosophical protreptic. This has implications for how we theorize about Luke’s audience and social situation.
Precise control of speed during locomotion is essential for adaptation of behavior in different environmental contexts 1–4. A central question in locomotion lies in understanding which neural ...populations set locomotor frequency during slow and fast regimes. Tackling this question in vivo requires additional non-invasive tools to silence large populations of neurons during active locomotion. Here we generated a stable transgenic line encoding a zebrafish-optimized botulinum neurotoxin light chain fused to GFP (BoTxBLC-GFP) to silence synaptic output over large populations of motor neurons or interneurons while monitoring active locomotion. By combining calcium imaging, electrophysiology, optogenetics, and behavior, we show that expression of BoTxBLC-GFP abolished synaptic release while maintaining characterized activity patterns and without triggering off-target effects. As chx10+ V2a interneurons (V2as) are well characterized as the main population driving the frequency-dependent recruitment of motor neurons during fictive locomotion 5–14, we validated our silencing method by testing the effect of silencing chx10+ V2as during active and fictive locomotion. Silencing of V2as selectively abolished fast locomotor frequencies during escape responses. In addition, spontaneous slow locomotion occurred less often and at frequencies lower than in controls. Overall, this silencing approach confirms that V2a excitation is critical for the production of fast stimulus-evoked swimming and also reveals a role for V2a excitation in the production of slower spontaneous locomotor behavior. Altogether, these results establish BoTxBLC-GFP as an ideal tool for in vivo silencing for probing the development and function of neural circuits from the synaptic to the behavioral level.
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•Optimized, genetically encoded botulinum neurotoxin silences synaptic output in vivo•Excitatory V2a interneurons drive high-frequency components of fast locomotion•Silencing of V2as shifts locomotor frequency downward during the slow regime
Silencing of neuronal populations in moving animals remains a challenge to investigating neural control of behavior. By developing an optimized botulinum toxin to block synaptic release in vivo, Sternberg, Severi et al. show that excitatory V2a interneurons contribute to locomotor frequency in distinct ways during slow or fast locomotion.
In mammals, light exerts pervasive effects on physiology and behavior in two ways: indirectly through clock synchronization and the phase adjustment of circadian rhythms, and directly through the ...promotion of alertness and sleep, respectively, in diurnal and nocturnal species. A recent report by Pilorz and colleagues describes an even more complex role for the acute effects of light. In mice, blue light acutely causes behavioral arousal, whereas green wavelengths promote sleep. These opposing effects are mediated by melanopsin-based phototransduction through different neural pathways. These findings reconcile nocturnal and diurnal species through a common alerting response to blue light. One can hypothesize that the opposite responses to natural polychromatic light in night- or day-active animals may reflect higher sensitivity of nocturnal species to green, and diurnals to blue wavelengths, resulting in hypnogenic and alerting effects, respectively. Additional questions remain to be clarified. How do different light wavelengths affect other behaviors such as mood and cognition? How do those results apply to humans? How does light pose either a risk or benefit, depending on whether one needs to be asleep or alert? Indeed, in addition to timing, luminance levels, and light exposure duration, these findings stress the need to understand how best to adapt the color spectrum of light to our needs and to take this into account for the design of daily lighting concepts-a key challenge for today's society, especially with the emergence of LED light technology.
Paul’s speech to the Areopagus in Acts 17 places the apostle in philosophical dialogue with Stoics and Epicureans. This article identifies important points of contact between Paul’s speech and Middle ...Platonic exegesis of a famous Platonic phrase from Timaeus 28c. There, the philosopher declares that the maker and father of the world is hard to find, and even more difficult to talk about. Many later interpreters of Plato commented on the dictum. Middle Platonists such as Plutarch mused about the theological implications of naming god both “maker” and “father.” Jewish and Christian interpreters like Philo and Justin employed Plato’s phrase to describe their access to divine revelation. The first portion of this article argues that the Areopagus speech contains evidence of similar exegesis, both in its references to god’s roles as maker and father and in Paul’s claim to declare the unknown god. These resonances do more than clarify the author’s philosophical background; they also have previously unexplored implications for our understanding of Paul’s characterization in Acts 17. The second half of the article argues that in aligning Paul with the Platonic tradition, the author participates in an established Greco-Roman practice of depicting the Platonists, Stoics, and Epicureans in theological dialogue.
In the vertebrate spinal cord, cerebrospinal fluid-contacting neurons (CSF-cNs) are GABAergic neurons whose functions are only beginning to unfold. Recent evidence indicates that CSF-cNs detect ...local spinal bending and relay this mechanosensory feedback information to motor circuits, yet many CSF-cN targets remain unknown. Using optogenetics, patterned illumination, and in vivo electrophysiology, we show here that CSF-cNs provide somatic inhibition to fast motor neurons and excitatory sensory interneurons involved in the escape circuit. Ventral CSF-cNs respond to longitudinal spinal contractions and induce large inhibitory postsynaptic currents (IPSCs) sufficient to silence spiking of their targets. Upon repetitive stimulation, these IPSCs promptly depress, enabling the mechanosensory response to the first bend to be the most effective. When CSF-cNs are silenced, postural control is compromised, resulting in rollovers during escapes. Altogether, our data demonstrate how GABAergic sensory neurons provide powerful inhibitory feedback to the escape circuit to maintain balance during active locomotion.
•CSF-contacting neurons are recruited during spontaneous tail muscle contractions•CSF-contacting neurons project onto motor neurons and sensory interneurons of the escape circuit•GABAergic synapses on these targets are large and depress with repetitive stimuli•Silencing CSF-contacting neurons alters balance during fast locomotion
Hubbard et al. demonstrate here that GABAergic sensory neurons, referred to as cerebrospinal fluid-contacting neurons, locally project onto the escape circuit within the spinal cord to control posture during active locomotion in the zebrafish larva.
The timing and duration of sleep results from the interaction between a homeostatic sleep–wake-driven process and a periodic circadian process, and involves changes in gene regulation and expression. ...Unraveling the contributions of both processes and their interaction to transcriptional and epigenomic regulatory dynamics requires sampling over time under conditions of unperturbed and perturbed sleep. We profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a 3-d period, including a 6-h sleep deprivation (SD) on day 2. We used mathematical modeling to integrate time series of mRNA expression data with sleep–wake history, which established that a large proportion of rhythmic genes are governed by the homeostatic process with varying degrees of interaction with the circadian process, sometimes working in opposition. Remarkably, SD caused long-term effects on gene-expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a damped oscillation of most core clock genes, including Arntl/Bmal1, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Dynamics in distal regions, rather than promoters, correlated with mRNA expression, implying that changes in expression result from constitutively accessible promoters under the influence of enhancers or repressors. Serum response factor (SRF) was predicted as a transcriptional regulator driving immediate response, suggesting that SRF activity mirrors the build-up and release of sleep pressure. Our results demonstrate that a single, short SD has long-term aftereffects at the genomic regulatory level and highlights the importance of the sleep–wake distribution to diurnal rhythmicity and circadian processes.
Rocking has long been known to promote sleep in infants and, more recently, also in adults, increasing NREM sleep stage N2 and enhancing EEG slow waves and spindles. Nevertheless, whether rocking ...also promotes sleep in other species, and what the underlying mechanisms are, has yet to be explored. In the current study, C57BL/6J mice equipped with EEG and EMG electrodes were rocked laterally during their main sleep period, i.e., the 12-h light phase. We observed that rocking affected sleep in mice with a faster optimal rate than in humans (1.0 versus 0.25 Hz). Specifically, rocking mice at 1.0 Hz increased time spent in NREM sleep through the shortening of wake episodes and accelerated sleep onset. Although rocking did not increase EEG activity in the slow-wave and spindle-frequency ranges in mice, EEG theta activity (6–10 Hz) during active wakefulness shifted toward slower frequencies. To test the hypothesis that the rocking effects are mediated through the vestibular system, we used the otoconia-deficient tilted (tlt) mouse, which cannot encode linear acceleration. Mice homozygous for the tlt mutation were insensitive to rocking at 1.0 Hz, while the sleep and EEG response of their heterozygous and wild-type littermates resembled those of C57BL/6J mice. Our findings demonstrate that rocking also promotes sleep in the mouse and that this effect requires input from functional otolithic organs of the vestibule. Our observations also demonstrate that the maximum linear acceleration applied, and not the rocking rate per se, is key in mediating the effects of rocking on sleep.
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•Rhythmic mechanosensory stimulation (aka rocking) promotes sleep also in the mouse•Linear acceleration applied to the head encodes the rocking stimulus•The rocking effects on sleep are acceleration and time specific•The otolithic organs of the vestibular system mediate the rocking effects on sleep
Kompotis et al. demonstrate for the first time that rocking promotes sleep in a species other than the human: i.e., the mouse. They also provide the first evidence that the vestibular otolithic organs mediate sleep promotion and that this effect depends on the linear acceleration applied, and not on the rocking frequency.
Dynactin subunit 1 is the largest subunit of the dynactin complex, an activator of the molecular motor protein complex dynein. Reduced levels of DCTN1 mRNA and protein have been found in sporadic ...amyotrophic lateral sclerosis (ALS) patients, and mutations have been associated with disease, but the role of this protein in disease pathogenesis is still unknown.
We characterized a Dynactin1a depletion model in the zebrafish embryo and combined in vivo molecular analysis of primary motor neuron development with live in vivo axonal transport assays in single cells to investigate ALS-related defects. To probe neuromuscular junction (NMJ) function and organization we performed paired motor neuron-muscle electrophysiological recordings and GCaMP calcium imaging in live, intact larvae, and the synapse structure was investigated by electron microscopy.
Here we show that Dynactin1a depletion is sufficient to induce defects in the development of spinal cord motor neurons and in the function of the NMJ. We observe synapse instability, impaired growth of primary motor neurons, and higher failure rates of action potentials at the NMJ. In addition, the embryos display locomotion defects consistent with NMJ dysfunction. Rescue of the observed phenotype by overexpression of wild-type human DCTN1-GFP indicates a cell-autonomous mechanism. Synaptic accumulation of DCTN1-GFP, as well as ultrastructural analysis of NMJ synapses exhibiting wider synaptic clefts, support a local role for Dynactin1a in synaptic function. Furthermore, live in vivo analysis of axonal transport and cytoskeleton dynamics in primary motor neurons show that the phenotype reported here is independent of modulation of these processes.
Our study reveals a novel role for Dynactin1 in ALS pathogenesis, where it acts cell-autonomously to promote motor neuron synapse stability independently of dynein-mediated axonal transport.
Sleep-wake driven changes in non-rapid-eye-movement sleep (NREM) sleep (NREMS) EEG delta (δ-)power are widely used as proxy for a sleep homeostatic process. Here, we noted frequency increases in ...δ-waves in sleep-deprived mice, prompting us to re-evaluate how slow-wave characteristics relate to prior sleep-wake history. We identified two classes of δ-waves; one responding to sleep deprivation with high initial power and fast, discontinuous decay during recovery sleep (δ2) and another unrelated to time-spent-awake with slow, linear decay (δ1). Reanalysis of previously published datasets demonstrates that δ-band heterogeneity after sleep deprivation is also present in human subjects. Similar to sleep deprivation, silencing of centromedial thalamus neurons boosted subsequent δ2-waves, specifically. δ2-dynamics paralleled that of temperature, muscle tone, heart rate, and neuronal ON-/OFF-state lengths, all reverting to characteristic NREMS levels within the first recovery hour. Thus, prolonged waking seems to necessitate a physiological recalibration before typical NREMS can be reinstated.
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