🔥A New Preprint : Sensory stimulation rescues microglia depletion associated brain rhythm impairments

Microglia are the resident brain immune cells that responds to systemic inflammatory insults and play critical role in brain inflammation. Brain inflammation is tightly linked with progression of Alzheimer’s disease (AD). Depletion of microglia can alleviate inflammation and thus has been proposed as a potential therapeutic strategy to alleviate inflammation and slow disease progression.

Synchronous firing of many connected neurons in the healthy brain create neuronal oscillations that are known as brain rhythms or waves. These rhythms, which span a range of frequencies from low to high, are fundamental for higher-order brain functions such as attention, learning, memory formation-retreival, and sensory perception. Among them, gamma waves are particularly critical. In Alzheimer’s disease, these gamma oscillations are disrupted, contributing to cognitive decline. In this latest study at MIT´s Picower Institute for Learning and Memory led by Dr Chinnakkaruppan Adaikkan, Dr. Md Rezaul Islam, and Dr. P. Lorenzo Bozzelli, authors explored the previously unknown role of microglia depletion on gamma oscillations.

Authors first utilized Plx3397, a CSF1R inhibitor approved by the FDA for certain tumors, to selectively reduce microglia. Chronic administration of Plx3397 in the 5xFAD mouse model of AD successfully decreased neuroinflammation (Fig 1) and increased synaptic density. However, this microglial depletion unexpectedly disrupted the ability of neurons to fire in rhythm with the gamma brain waves known as phase-locking, potentially compromising cognitive function.

Fig 1: Chronic Plx3397 and GENUS administration reduced microglia. Confocal images show IBA1 immunosignals. Scale bar = 50μm.

To address this microglia depletion associated brain rhythm impairments, authors applied a non-invasive sensory stimulation protocol known as GENUS (Gamma ENtrainment Using Sensory stimulation), delivering 40 Hz visual flicker to entrain gamma oscillations. Remarkably, this sensory stimulation restored gamma synchronization, corrected neural network disruptions, and improved cognitive performance in memory tasks (Fig 2).

Fig. 2: Mice occupancy heatmaps during NOR test in 5xFAD mice. Novelty index during NOR test was higher Plx3397+GENUS treated 5xFAD mice (ANOVA, F (3, 31) = 3.456, P = 0.0282).

At the molecular single cell level, combining Plx3397 and GENUS led to enhanced expression of genes associated with synaptic organization, neuronal resilience, and myelination. These changes included upregulation of MEF2C, a transcription factor critical for synaptic health, and cognitive resilience.

Our findings suggest that while pharmacologically reducing microglia can alleviate neuroinflammation and improve synaptic density, it must be paired with interventions that preserve or restore neural network synchronization. This combinatorial strategy offers a promising avenue for developing therapies aimed at preserving cognitive function in Alzheimer's disease.

Fig 3: A graphical abstract of the study.