Sleep Promotes, and Sleep Loss Inhibits, Selective Changes in Firing Rate, Response Properties and Functional Connectivity of Primary Visual Cortex Neurons

Recent studies suggest that sleep differentially alters the activity of cortical neurons based on firing rates during preceding wake—increasing the firing rates of sparsely firing neurons and decreasing those of faster firing neurons. Because sparsely firing cortical neurons may play a specialized role in sensory processing, sleep could facilitate sensory function via selective actions on sparsely firing neurons. To test this hypothesis, we analyzed longitudinal electrophysiological recordings of primary visual cortex (V1) neurons across a novel visual experience which induces V1 plasticity (or a control experience which does not), and a period of subsequent ad lib sleep or partial sleep deprivation. We find that across a day of ad lib sleep, spontaneous and visually-evoked firing rates are selectively augmented in sparsely firing V1 neurons. These sparsely firing neurons are more highly visually responsive, and show greater orientation selectivity than their high firing rate neighbors. They also tend to be “soloists” instead of “choristers”—showing relatively weak coupling of firing to V1 population activity. These population-specific changes in firing rate are blocked by sleep disruption either early or late in the day, and appear to be brought about by increases in neuronal firing rates across bouts of rapid eye movement (REM) sleep. Following a patterned visual experience that induces orientation-selective response potentiation (OSRP) in V1, sparsely firing and weakly population-coupled neurons show the highest level of sleep-dependent response plasticity. Across a day of ad lib sleep, population coupling strength increases selectively for sparsely firing neurons—this effect is also disrupted by sleep deprivation. Together, these data suggest that sleep may optimize sensory function by augmenting the functional connectivity and firing rate of highly responsive and stimulus-selective cortical neurons, while simultaneously reducing noise in the network by decreasing the activity of less selective, faster-firing neurons

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Form and Function of Sleep Spindles across the Lifespan

Since the advent of EEG recordings, sleep spindles have been identified as hallmarks of non-REM sleep. Despite a broad general understanding of mechanisms of spindle generation gleaned from animal studies, the mechanisms underlying certain features of spindles in the human brain, such as “global” versus “local” spindles, are largely unknown. Neither the topography nor the morphology of sleep spindles remains constant throughout the lifespan. It is likely that changes in spindle phenomenology during development and aging are the result of dramatic changes in brain structure and function. Across various developmental windows, spindle activity is correlated with general cognitive aptitude, learning, and memory; however, these correlations vary in strength, and even direction, depending on age and metrics used. Understanding these differences across the lifespan should further clarify how these oscillations are generated and their function under a variety of circumstances. We discuss these issues, and their translational implications for human cognitive function. Because sleep spindles are similarly affected in disorders of neurodevelopment (such as schizophrenia) and during aging (such as neurodegenerative conditions), both types of disorders may benefit from therapies based on a better understanding of spindle function

Sex differences within sleep in gonadally intact rats.

Sleep impacts diverse physiological and neural processes and is itself affected by the menstrual cycle; however, few studies have examined the effects of the estrous cycle on sleep in rodents. Studies of disease mechanisms in females therefore lack critical information regarding estrous cycle influences on relevant sleep characteristics. We recorded electroencephalographic (EEG) activity from multiple brain regions to assess sleep states as well as sleep traits such as spectral power and interregional spectral coherence in freely cycling females across the estrous cycle and compared with males. Our findings show that the high hormone phase of proestrus decreases the amount of nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep and increases the amount of time spent awake compared with other estrous phases and to males. This spontaneous sleep deprivation of proestrus was followed by a sleep rebound in estrus which increased NREM and REM sleep. In proestrus, spectral power increased in the delta (0.5-4 Hz) and the gamma (30-60 Hz) ranges during NREM sleep, and increased in the theta range (5-9 Hz) during REM sleep during both proestrus and estrus. Slow-wave activity (SWA) and cortical sleep spindle density also increased in NREM sleep during proestrus. Finally, interregional NREM and REM spectral coherence increased during proestrus. This work demonstrates that the estrous cycle affects more facets of sleep than previously thought and reveals both sex differences in features of the sleep-wake cycle related to estrous phase that likely impact the myriad physiological processes influenced by sleep

Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome.

OBJECTIVE:Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP. METHODS:Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed. RESULTS:We observed a 2-fold increase in both transient and persistent Na(+) current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin-resistant Na(+) current, likely Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia. INTERPRETATION:These data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients

Altered Heart Rates Precede Death.

<p>A. DS mice exhibit significant QT prolongation (50 - 90%). B. Heart rates in DS mice decrease 100 min before death, followed by a sharp increase just prior to the terminal event, while the WT heart rates remains high and constant. (100 minutes = 10:16 PM in WT-1 and DS-1; 7:46 PM in WT-2 and DS-2). C. WT-3 and DS-3 HR cycling, followed by DS exhibiting sudden drops in heart rate in the 72 h preceding death. D and E. Increased R-R variability 60 min prior to SUDEP in DS-1 (blue) and DS-2 (red), respectively, with further increased variability immediately preceding the lethal arrhythmia, while 1 day prior at the same time the R-R interval was constant (black). F. Progressive bradycardia and increased R-R variability in DS-3 at several time points preceding an agonal state and euthanasia (denoted by colored arrows in C).</p

Isolation of TTX-R and TTX-S I_Na Biophysical Properties.

<p>A. Boltzman curves for the voltage dependence of I_Na availability and conductance for the total cardiac I_Na (TTX-S + TTX-R I_Na; reproduction of the curve-fits from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077843#pone-0077843-g001" target="_blank">Figure 1C</a>). In both WT and DS myocytes the V_½ values of TTX-R I_Na (closed circles, following blockade of TTX-S I_Na with 100 nM TTX) and TTX-S I_Na (open circles, defined as total I_Na minus TTX-R I_Na) are plotted. Pharmacological separation of TTX-S and TTX-R I_Na was confirmed by the loss of difference in the V_½ values between WT vs DS, and the development of a significant difference between the TTX-S vs. TTX-R V ½ values for I_Na availability and conductance. B. Zoom-in of the boxed region in A.</p

DS Mice Undergo SUDEP.

<p>A. Kaplan-Meier survival curves for WT and DS mice (N = 75 for each group, p < 0.0001, Log-rank, Mantel-Cox, Survival Test). B. Percent survival in WT (N = 8) and DS (N = 13) mice implanted with radiotelemetry units. SUDEP or near-SUDEP in 3 DS mice (at P41, P45, and P51, respectively).</p

mScn5a and Nav1.5 levels are unchanged in DS mutant hearts.

<p>A. Heart RNA from biological replicates (DS mice, n = 4; WT mice, n = 5) were used to generate two independent cDNAs per animal. The cDNAs were assayed using qPCR in quadruplicate with two independent <i>Scn5a</i> TaqMan primer sets and normalized to 18s RNA. B. Western blots of membrane proteins isolated from DS and WT ventricular CMs. 50 µg of protein was loaded in each lane, and probed with anti-Na_v1.5 (Mohler 1:1000), and anti-α-actin (Sigma 1:500), which served as the loading control. C. Quantification of Na_v1.5 expression normalized to α-actin expression.</p