Brief sleep disruption alters synaptic structures among hippocampal and neocortical somatostatin-expressing interneurons.

Brief sleep loss can disrupt cognition, including information processing in neocortex and hippocampus. Recent studies have identified alterations in synaptic structures of principal neurons within these circuits 1-3 . However, while in vivo recording and bioinformatic data suggest that inhibitory interneurons are more strongly affected by sleep loss 4-9 , it is unclear how sleep and sleep deprivation affect interneurons' synapses. Recent data suggest that activity among hippocampal somatostatin-expressing (SST+) interneurons is selectively increased by experimental sleep disruption 8 . We used Brainbow 3.0 10 to label SST+ interneurons in the dorsal hippocampus, prefrontal cortex, and visual cortex of SST-CRE transgenic mice, then compared synaptic structures in labeled neurons after a 6-h period of ad lib sleep, or gentle handling sleep deprivation (SD) starting at lights on. We find that dendritic spine density among SST+ interneurons in both hippocampus and neocortex was altered in a subregion-specific manner, with increased overall and thin spine density in CA1, decreased mushroom spine density in CA3, and decreased overall and stubby spine density in V1 after SD. Spine size also changed significantly after SD, with dramatic increases in spine volume and surface area in CA3, and small but significant decreases in CA1, PFC and V1. Together, our data suggest that the synaptic connectivity of SST+ interneurons is significantly altered, in a brain region-specific manner, by a few hours of sleep loss. Further, they suggest that sleep loss can disrupt cognition by altering the balance of excitation and inhibition in hippocampal and neocortical networks. Significance Statement: Changes to the function of somatostatin-expressing (SST+) interneurons have been implicated in the etiology of psychiatric and neurological disorders in which both cognition and sleep behavior are affected. Here, we measure the effects of very brief experimental sleep deprivation on synaptic structures of SST+ interneurons in hippocampus and neocortex, in brain structures critical for sleep-dependent memory processing. We find that only six hours of sleep deprivation restructures SST+ interneurons' dendritic spines, causing widespread and subregion-specific changes to spine density and spine size. These changes have the potential to dramatically alter excitatory-inhibitory balance across these brain networks, leading to cognitive disruptions commonly associated with sleep loss.

Epigenetic mechanisms of inner ear development.

Epigenetic factors are critically important for embryonic and postnatal development. Over the past decade, substantial technological advancements have occurred that now permit the study of epigenetic mechanisms that govern all aspects of inner ear development, from otocyst patterning to maturation and maintenance of hair cell stereocilia. In this review, we highlight how three major classes of epigenetic regulation (DNA methylation, histone modification, and chromatin remodeling) are essential for the development of the inner ear. We highlight open avenues for research and discuss how new tools enable the employment of epigenetic factors in regenerative and therapeutic approaches for hearing and balance disorders.

Sleep loss drives acetylcholine- and somatostatin interneuron-mediated gating of hippocampal activity to inhibit memory consolidation.

Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type-specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type-specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss-driven inhibitory gate on hippocampal information processing.

Chromatin remodeler CHD7 is critical for cochlear morphogenesis and neurosensory patterning.

Epigenetic regulation of gene transcription by chromatin remodeling proteins has recently emerged as an important contributing factor in inner ear development. Pathogenic variants in CHD7, the gene encoding Chromodomain Helicase DNA binding protein 7, cause CHARGE syndrome, which presents with malformations in the developing ear. Chd7 is broadly expressed in the developing mouse otocyst and mature auditory epithelium, yet the pathogenic effects of Chd7 loss in the cochlea are not well understood. Here we characterized cochlear epithelial phenotypes in mice with deletion of Chd7 throughout the otocyst (using Foxg1Cre/+ and Pax2Cre), in the otic mesenchyme (using TCre), in hair cells (using Atoh1Cre), in developing neuroblasts (using NgnCre), or in spiral ganglion neurons (using ShhCre/+). Pan-otic deletion of Chd7 resulted in shortened cochleae with aberrant projections and axonal looping, disorganized, supernumerary hair cells at the apical turn and a narrowed epithelium with missing hair cells in the middle region. Deletion of Chd7 in the otic mesenchyme had no effect on overall cochlear morphology. Loss of Chd7 in hair cells did not disrupt their formation or organization of the auditory epithelium. Similarly, absence of Chd7 in spiral ganglion neurons had no effect on axonal projections. In contrast, deletion of Chd7 in developing neuroblasts led to smaller spiral ganglia and disorganized cochlear neurites. Together, these observations reveal dosage-, tissue-, and time-sensitive cell autonomous roles for Chd7 in cochlear elongation and cochlear neuron organization, with minimal functions for Chd7 in hair cells. These studies provide novel information about roles for Chd7 in development of auditory neurons.