Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca2+ elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca2+ elevations in mouse astroglia are profoundly inhibited by ethanol, an effect that can be reversed by enhancing norepinephrine release. Vigilance-dependent astroglial activation is abolished by deletion of α1A-adrenergic receptor from astroglia, indicating that norepinephrine acts directly on these ubiquitous glial cells. Ethanol reduces vigilance-dependent Ca2+ transients in noradrenergic terminals, but has little effect on astroglial responsiveness to norepinephrine, suggesting that ethanol suppresses their activation by inhibiting norepinephrine release. Since abolition of astroglia Ca2+ activation does not affect motor coordination, global suppression of astroglial networks may contribute to the cognitive effects of alcohol intoxication.
Oligodendrocyte precursor cells (OPCs) represent the most abundant group of proliferating cells in the adult central nervous system. OPCs serve as progenitors for oligodendrocyte (OLs) throughout the life, and contribute to developmental and adaptive myelination, and myelin repair during diseased state. OPCs make synaptic and extra-synaptic contacts with axons, and detect and respond to neuronal activity. How OPCs translate the information relayed by the neuronal activity into Ca2+ signals, which in turn influence their fate and survival, is less understood. We developed novel transgenic mouse lines expressing a cytosolic and membrane anchored variants of genetically encoded Ca2+ sensors (GCaMP6f or mGCaMP6s) in OPCs, performed 2-photon microscopy in the somatosensory cortex of the awake behaving mice, and simultaneously monitored intracellular Ca2+ signals and their cell-fate progression. We found Ca2+ signals in OPCs mainly occur within processes and confine to micrometer-size segments called Ca2+ microdomains. Microdomain Ca2+ signals enhanced in OPCs when mice engage in exploratory behavior. OPCs exhibit distinct Ca2+ signals while they proliferate to maintain their precursor pool or differentiate to generate new OL. When mice engaged in exploratory behavior, the cortical projections of noradrenergic neurons in locus coeruleus showed increased firing rate and norepinephrine release. Norepinephrine activated all three subtypes of alpha1 adrenergic receptor expressed by OPCs and evoked intracellular Ca2+ increase in OPCs. A chemogenetic activation of noradrenergic neurons, promoted differentiation of cortical OPCs into OL, and at the same time suppressed OPC proliferation rate. Hence, we uncovered that various cell types of oligodendrocyte lineage exhibits unique signatures of Ca2+ activity, which these cells might integrate for making their fate decisions, and norepinephrine signaling can be a potent regulator of OPC fate.
SignificanceOur study adds new dimensions to the repertoire of functions that Y-heterochromatin has with respect to autosomal gene regulation in male fertility. We describe a novel sex and species-specific ncRNA, Pirmy, transcribed from mouse Y-chromosome, with unprecedented alternative splicing. Mice with deletions of Y-long arm (Yq) were reported to exhibit differential sterility and sperm abnormalities. We identify sperm proteins that are deregulated in Yq-deleted mice; corresponding genes map to autosomes and display sequence homology to piRNAs derived from Pirmy in their UTRs. Thus, piRNAs from species-specific repeats appear to regulate autosomal genes involved in reproduction. The male sterility phenotypes of Yq-deleted mice and crossspecies hybrids are comparable, indicating a larger role for species-specific repeats from Y-chromosome in speciation and evolution. ABSTRACTRepeats from the male-specific long arm of mouse Y-chromosome (MSYq) transcribe protein coding and noncoding RNAs. Majority of genes expressed during spermatogenesis are autosomal. Mice with different deletions of Yq show sub-fertility and sterility, depending on the length of deletion. The connection between Yq deletion and autosomal gene regulation was not well studied before. We describe a novel multi-copy mouse Yq-derived long noncoding RNA, Pirmy (piRNA from mouse Y All rights reserved. No reuse allowed without permission.
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