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1.
Cell ; 155(2): 285-95, 2013 Oct 10.
Article in English | MEDLINE | ID: mdl-24094650

ABSTRACT

Atopic dermatitis (AD) is a chronic itch and inflammatory disorder of the skin that affects one in ten people. Patients suffering from severe AD eventually progress to develop asthma and allergic rhinitis, in a process known as the "atopic march." Signaling between epithelial cells and innate immune cells via the cytokine thymic stromal lymphopoietin (TSLP) is thought to drive AD and the atopic march. Here, we report that epithelial cells directly communicate to cutaneous sensory neurons via TSLP to promote itch. We identify the ORAI1/NFAT calcium signaling pathway as an essential regulator of TSLP release from keratinocytes, the primary epithelial cells of the skin. TSLP then acts directly on a subset of TRPA1-positive sensory neurons to trigger robust itch behaviors. Our results support a model whereby calcium-dependent TSLP release by keratinocytes activates both primary afferent neurons and immune cells to promote inflammatory responses in the skin and airways.


Subject(s)
Cytokines/metabolism , Dermatitis, Atopic/pathology , Signal Transduction , Animals , Calcium/metabolism , Cells, Cultured , Dermatitis, Atopic/metabolism , Humans , Immunoglobulins/metabolism , Keratinocytes/metabolism , Pruritus/immunology , Receptors, Cytokine/metabolism , Sensory Receptor Cells/metabolism , Skin/metabolism , Skin/pathology , TRPA1 Cation Channel , Transient Receptor Potential Channels/metabolism , Thymic Stromal Lymphopoietin
2.
Nat Neurosci ; 16(12): 1857-1863, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24162654

ABSTRACT

The basal forebrain provides the primary source of cholinergic input to the cortex, and it has a crucial function in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking; these changes could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception.


Subject(s)
Action Potentials/physiology , Cholinergic Neurons/physiology , Prosencephalon/cytology , Visual Perception/physiology , Acetylcholine/metabolism , Action Potentials/drug effects , Animals , Archaeal Proteins/metabolism , Channelrhodopsins , Cholera Toxin/metabolism , Choline O-Acetyltransferase/genetics , Exercise Test , Glutamate Decarboxylase/genetics , Halorhodopsins/metabolism , Luminescent Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neural Pathways/physiology , Photic Stimulation , RNA, Untranslated/genetics
3.
J Neurosci ; 33(22): 9283-94, 2013 May 29.
Article in English | MEDLINE | ID: mdl-23719797

ABSTRACT

Chronic itch is a debilitating condition that affects one in 10 people. Little is known about the molecules that mediate chronic itch in primary sensory neurons and skin. We demonstrate that the ion channel TRPA1 is required for chronic itch. Using a mouse model of chronic itch, we show that scratching evoked by impaired skin barrier is abolished in TRPA1-deficient animals. This model recapitulates many of the pathophysiological hallmarks of chronic itch that are observed in prevalent human diseases such as atopic dermatitis and psoriasis, including robust scratching, extensive epidermal hyperplasia, and dramatic changes in gene expression in sensory neurons and skin. Remarkably, TRPA1 is required for both transduction of chronic itch signals to the CNS and for the dramatic skin changes triggered by dry-skin-evoked itch and scratching. These data suggest that TRPA1 regulates both itch transduction and pathophysiological changes in the skin that promote chronic itch.


Subject(s)
Pruritus/physiopathology , Transient Receptor Potential Channels/physiology , Animals , Chronic Disease , Data Interpretation, Statistical , Gene Expression , Homeostasis/physiology , Hyperplasia/pathology , Male , Mice , Mice, Inbred C57BL , Microarray Analysis , Pruritus/genetics , Pruritus/pathology , Real-Time Polymerase Chain Reaction , Sensory Receptor Cells , Skin/innervation , Skin/pathology , TRPA1 Cation Channel , Transient Receptor Potential Channels/genetics
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