Tuning metaplasticity in the adult visual cortex using flickering light

Synaptic connections in the brain are refined by sensory experience during an early postnatal critical period, but by adulthood synaptic connectivity is resistant to further changes. A consequence of lost plasticity is limited recovery from brain injury, disease, and adverse sensory experience. Thus, there is great interest in treatments that can promote synaptic modifications in the adult brain. In a wide variety of contexts, it has been established that the qualities of synaptic plasticity are not fixed but rather vary depending on the recent history of cellular or synaptic activity1. This plasticity of plasticity, or metaplasticity2 explains why temporary manipulations of brain activity (e.g., by drugs3, transcranial stimulation4, or sensory deprivation5) can set the stage for subsequent, potentially therapeutic, long-lasting synaptic modifications6. Here we tested the hypothesis that plasticity in the adult mouse visual cortex is influenced by prior exposure to temporally modulated light and discovered that different flicker frequencies have qualitatively different effects. Exposure to 60 Hz stimulation increased microglia density, depleted perineuronal nets (PNNs), and restored ocular dominance plasticity in response to brief monocular deprivation (MD). Exposure to 40 Hz flicker also enabled ocular dominance plasticity, but it did so in a distinct way and without PNN remodeling. A key distinction is that unlike 60 Hz flicker, which enabled depression of synaptic strength by MD, 40 Hz flicker promoted synaptic strengthening. Indeed, we found that 40 Hz flicker primed a rapid and robust recovery from the effects of long-term MD that failed to occur after 60 Hz flicker. Thus, metaplasticity can be non-invasively "tuned" by light flickering at different frequencies to encourage different forms of synaptic plasticity in the cerebral cortex, including modifications that enable recovery of function.