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Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1. Mice that are globally deficient in CYP46A1 exhibited hypoactivity at young ages and unexpected increases in conditioned fear memory. Despite strong reductions in hippocampal 24S-HC in mice with selective loss of CYP46A1 in VGLUT1-positive cells, behavioral effects were not recapitulated in these conditional knockout mice. Global knockout produced strong, developmentally dependent transcriptional effects on select cholesterol metabolism genes. These included paradoxical changes in Liver X Receptor targets. Again, conditional knockout was insufficient to recapitulate most changes. Overall, our results highlight the complex effects of 24S-HC in an in vivo setting that are not fully predicted by known mechanisms. The results also demonstrate that the complete inhibition of enzymatic activity may be needed for a detectable, therapeutically relevant impact on gene expression and behavior. [ABSTRACT FROM AUTHOR]

The article provides information on the sense of touch in vertebrates, particularly focusing on mechanosensory corpuscles and hair follicle-associated lanceolate complexes in the skin. It discusses recent findings suggesting that terminal Schwann cells (TSCs) in these structures may have mechanosensitivity and could serve as additional sensory elements for touch.

Afferents of peripheral mechanoreceptors innervate the skin of vertebrates, where they detect physical touch via mechanically gated ion channels (mechanotransducers). While the afferent terminal is generally understood to be the primary site of mechanotransduction, the functional properties of mechanically activated (MA) ionic current generated by mechanotransducers at this location remain obscure. Until now, direct evidence of MA current and mechanically induced action potentials in the mechanoreceptor terminal has not been obtained. Here, we report patch-clamp recordings from the afferent terminal innervating Grandry (Meissner) corpuscles in the bill skin of a tactile specialist duck. We show that mechanical stimulation evokes MA current in the afferent with fast kinetics of activation and inactivation during the dynamic phases of the mechanical stimulus. These responses trigger rapidly adapting firing in the afferent detected at the terminal and in the afferent fiber outside of the corpuscle. Our findings elucidate the initial electrogenic events of touch detection in the mechanoreceptor nerve terminal. [ABSTRACT FROM AUTHOR]

The sense of touch is ubiquitous in vertebrates and relies upon the detection of mechanical forces in the skin by the tactile end-organs of low-threshold mechanoreceptors. Significant progress has been made in understanding the mechanism of tactile end-organ function using mammalian models, but the detailed mechanics of touch sensation in Meissner and Pacinian corpuscles, the principal detectors of transient touch and vibration, remain obscure. The avian homologs of these corpuscles present an opportunity for functional study of mechanosensation in these structures, due to their relative accessibility and high abundance in the bill skin of tactile-foraging waterfowl. Here, we review the current knowledge of mechanosensory end-organs in birds and highlight the utility of the avian model to understand general principles of touch detection in the glabrous skin of vertebrates. • The neurophysiology of touch sensation is conserved across birds and mammals. • Bird mechanoreceptors innervate Grandry (Meissner) and Herbst (Pacinian) corpuscles. • Grandry and Herbst corpuscles densely populate the bill skin of tactile foragers. • Grandry and Herbst corpuscles detect transient touch, velocity, and vibration. • Lamellar cells are critical to sensory corpuscle structure and function. [ABSTRACT FROM AUTHOR]