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Bioinformatics, Computational and Systems Biology

Omics methods, modeling, and analysis

Audio/Visual Stimulation Controls Both Immune and AD-related Gene Sets in a Frequency Dependent Manner

Friday, October 13, 2023

3:00 PM – 3:15 PM PDT

Location: 331 (Center, Level 3)

Presenting Author(s)

Sara Bitarafan, PhD (she/her/hers)

Graduate Research Assistant
Georgia institute of technology
Duluth, Georgia, United States

Co-Author(s)

AP

Alyssa Pybus

Graduate Research Assistant
Georgia Tech, United States
MA

Mohammad Adibi

Georgia Institute of Technology, United States
TF

Tina Franklin

Georgia Institute of Technology, United States
AS

Annabelle Singer

Georgia Institute of Technology, United States

Primary Investigator(s)

Levi B. Wood, PhD

Associate Professor
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology
Atlanta, Georgia, United States

Introduction:: Alzheimer’s disease is a chronic neurodegenerative disease characterized by Aβ plaque deposition and neurofibrillary tangles (NFT) formation (1). However, pharmaceutical strategies targeting these pathological markers have failed to improve cognitive dysfunction. Therefore, there is a need to target alternative aspects of the disease, such as dysregulated brain immune signaling orchestrated by fatigued brain immune cells. We previously showed that exposing wild-type mice to 40Hz gamma frequency visual flickering stimulation led to activation of MAPK pathway signaling in the visual cortex within 15mins of stimulation and up-regulation of cytokines/chemokines after 1hr (2). These data illustrate that sensory flicker stimulation can potentially modulate multiple aspects of the brain’s immune function. Previous studies focused on gamma frequency stimulation (40Hz), and little is known about the frequency dependency of the brain’s response to audio/visual flicker stimulation. Characterizing the brain’s response to each frequency will enable targeted therapies that choose stimulation frequency based on the desired neurological effect (e.g., brain immunity or synaptic function). Since 1hr of 40Hz flicker stimulation drives cytokine level changes, and different frequencies of stimulation are known to entrain different frequencies of electrical activity in the brain, we hypothesized here that 1hr of stimulation drives frequency-dependent transcriptional profiles that are each distinctive from ambient light (Light).

Materials and Methods:: 5xFAD amyloid beta mice were exposed to different frequencies of audio/visual flicker stimulation (ambient light, 10Hz, 20Hz, 40Hz) for 1hr, then bulk RNAseq was used to profile transcriptional changes within the visual cortex. Gene set variation analysis (GSVA) together with C2 curated gene sets from the Molecular Signatures Database were used to identify functional changes in response to different frequencies of flicker.

Results, Conclusions, and Discussions:: Principal component analysis (PCA) of the gene expression data revealed that 10Hz, 20Hz, and 40Hz stimulation all separate from constant light stimulation along principal component 1 (PC1) (Fig. 1A), illustrating the effect of audio/visual stimulation in driving a pronounced transcriptional change. We next asked if specific changes are conserved across different frequencies, or if there is a frequency-dependency effect across different groups. GSVA analysis followed by group comparison of immune and AD regulatory pathways, revealed that frequency modulates specific pathways related to immune function and AD pathogenesis. For example, IL-12 and APC-C pathways, which are both known to play an important role in modulating AD-onset, are only significantly changed (Up or Down compared to Light) at 40Hz. However, some other pathways such as MAPK and inflammatory pathways are significantly affected across all frequencies, demonstrating that certain pathways are modulated independent of frequency (Fig.1B).
Collectively, our data indicate that 1hr audio/visual stimulation can be used to elicit targeted changes in brain immunity and AD-related functions, supporting the importance of this non-invasive methodology to tune the brain for treatment of diverse neurological diseases.

Acknowledgements (Optional): : The Coins for Alzheimer’s Research Trust Fund (LBW/ACS), NSF CAREER 1944053 (LBW)

References (Optional): : 1. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Molecular Neurodegeneration. 2019;14(1):32. doi: 10.1186/s13024-019-0333-5. 2. Garza KM, Zhang L, Borron B, Wood LB, Singer AC. Gamma Visual Stimulation Induces a Neuroimmune Signaling Profile Distinct from Acute Neuroinflammation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2020;40(6):1211-25. Epub 2019/12/25. doi: 10.1523/jneurosci.1511-19.2019. PubMed PMID: 31871276; PMCID: PMC7002142.