Sleep has a profound impact on brain plasticity, pathologies, and repair processes, and is critical for one's wellbeing. Although interleukin-1? (IL1) is a well-characterized sleep regulatory substance and has important roles in these processes, knowledge is lacking as to IL1 sleep signaling mechanisms and brain cell types expressing IL1 that are involved. The broad hypothesis tested in this application is that the neuron-specific IL1 receptor accessory protein (AcPb) plays a role in physiological sleep and is required for responses to sleep loss via signaling pathways in neurons that include Src phosphorylation. The alternatively spliced isoform of AcPb, AcP, is hypothesized to recruit additional IL1 signaling pathways during pathology including Src, p38MAPkinase and I?B phosphorylation in neurons and astrocytes which leads to a robust cytokine response and triggers sleep fragmentation. This application is focused on how AcPb and AcP signaling mechanisms manifest as emergent neuronal/glial properties that characterize sleep both in vivo and in vitro.
In Aim 1 we use wild type (WT), AcPb knockout (-/-), or AcP-/- mice and determine responses to sleep loss, quantify cytokine mRNA and protein in brain, and measure phosphorylation of Src, p38MAPkinase, and I?B.
In Aims 2 and 3, we use a neuronal/glial cell culture model derived from the three strains of mice. We will characterize several in vitro electrophysiological parameters that manifest in sleep of intact animals; they include action potential burstiness (BI ? burstiness index), synchronization (SYN) of slow waves (SW) (0.5-3.5 Hz), SW power (V2) and enhanced evoked response potential (ERP) amplitudes. Over the course of neuronal/glial culture development these parameters emerge as the networks mature. If cultured networks are stimulated electrically, BI, SYN and SW power decrease suggesting a more wake-like state. Cultures also exhibit sleep homeostasis; after electrical stimulation a rebound increase in BI, SYN and SW power occurs. Preliminary data indicate that if cultures are treated with IL1, these parameters and ERPs increase indicating a deeper sleep-like state. Further, cultures derived from AcPb-/- mice fail to ?wake up? if electrically stimulated, have distinct ERP responses to IL1, and fail to phosphorylate Src if IL1-stimulated. These data suggest that the in vivo sleep rebound deficits in AcPb-/- mice are directly linked to the in vitro response deficits.
In Aims 2 and 3, cultures are stimulated electrically, with IL1, and optogenetically to test the hypotheses that mild sleep loss and low doses of IL1 elicit their sleep responses via AcPb-mediated Src phosphorylation. Further, by optogenetically stimulating neurons and astrocytes separately we will determine the contributions of these cell types to IL1-AcPb mediated responses.
In Aim 4, we also use the three mouse strains to stimulate astroglial G-coupled proteins using DREADDs technology to determine the influence of IL1-mediated astroglial stimulation on these biochemical measures. The projects use cutting-edge techniques including; optogenetics, DREADDs, multi electrode arrays, and in vivo mouse recordings to elucidate IL1 sleep signaling mechanisms.
Sleep is critical for many brain processes and sleep loss aggravates and/or causes multiple neuropathologies. The proposed experiments will determine how interleukin-1 (IL1) and its neuron-specific receptor accessory protein (AcPb) contribute to state transitions in whole animals and small neuronal networks. IL1 has many brain functions, including sleep regulation, plasticity and tissue repair. The knowledge gained will permit new therapeutic approaches to sleep and other neuropathologies by providing molecular and genetic answers to the questions of how is sleep initiated and regulated.
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