Gamma Visual Stimulation Induces a Neuroimmune Signaling Profile Distinct from Acute Neuroinflammation

Abstract

Many neurodegenerative and neurological diseases are rooted in dysfunction of the neuroimmune system; therefore, manipulating this system has strong therapeutic potential. Prior work has shown that exposing mice to flickering lights at 40 Hz drives gamma frequency (ϳ40 Hz) neural activity and recruits microglia, the primary immune cells of the brain, revealing a novel method to manipulate the neuroimmune system. However, the biochemical signaling mechanisms between 40 Hz neural activity and immune recruitment remain unknown. Here, we exposed wild-type male mice to 5-60 min of 40 Hz or control flicker and assessed cytokine and phosphoprotein networks known to play a role in immune function. We found that 40 Hz flicker leads to increases in the expression of cytokines which promote microglial phagocytic states, such as IL-6 and IL-4, and increased expression of microglial chemokines, such as macrophagecolony-stimulating factor and monokine induced by interferon-␥. Interestingly, cytokine effects differed as a function of stimulation frequency, revealing a range of neuroimmune effects of stimulation. To identify possible mechanisms underlying cytokine expression, we quantified the effect of the flicker on intracellular signaling pathways known to regulate cytokine levels. We found that a 40 Hz flicker upregulates phospho-signaling within the nuclear factor-light-chain-enhancer of activated B cells (NF-B) and mitogen-activated protein kinase (MAPK) pathways. While cytokine expression increased after 1 h of 40 Hz flicker stimulation, protein phosphorylation in the NF-B pathway was upregulated within minutes. Importantly, the cytokine expression profile induced by 40 Hz flicker was different from cytokine changes in response to acute neuroinflammation induced by lipopolysaccharides. These results are the first, to our knowledge, to show how visual stimulation rapidly induces critical neuroimmune signaling in healthy animals.

WITHDRAWN: lncRNA HAND2-AS1 is Down Regulated in Osteoarthritis and Regulates IL‐6 Expression in Chondrocyte

“…33,34,35 Many studies showed that inhibition of IL-6 is a promising way to the treatment of in ammatory diseases. 36,37,38 We observed that HAND2-AS1 can regulate IL-6 in OA patients, which may be an upstream inhibitor of IL-6. However, this regulation could not be observed in controls groups, suggest that the inhibition of IL-6 by HAND2-AS1 is likely indirect and there may exist pathological mediators between HAND2-AS1 and IL-6.…”

RETRACTED ARTICLE: lncRNA HAND2-AS1 is downregulated in osteoarthritis and regulates IL-6 expression in chondrocytes

“…IL-6 is a proinflammatory cytokine and has been proved participate in many inflammatory diseases [ 33 – 35 ]. Many studies showed that inhibition of IL-6 is a promising way to the treatment of inflammatory diseases [ 36 – 38 ]. We observed that HAND2-AS1 can regulate IL-6 in OA patients, which may be an upstream inhibitor of IL-6.…”

Intermittent Light Exposures in Humans: A Case for Dual Entrainment in the Treatment of Alzheimer's Disease

“…Long-term (>6 weeks) daily exposure to 40 Hz flickering lights decreased microglia-mediated inflammation in P301S and CK-p25 mice, improved behavioral performance, and reduced loss of neurons in various parts of the brain (59,120). This was confirmed by Garza et al (121), who found that 40 Hz flickering light administered to healthy mice increased the expression of cytokines, which plays a central role in microglial recruitment. In a healthy brain, microglia exercise a protective function that restrains the accumulation of Aβ and may prevent neurodegeneration (122).…”