40Hz Light Flickering: the Adenosine Hypothesis and Translational Implications

40Hz Light Flickering: the Adenosine Hypothesis and Translational Implications

40Hz light flickering has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. As there is an intrinsic relationship of adenosine production and gamma oscillation after 40Hz flickering, we proposed and demonstrated that 40Hz light flickering frequency-dependently triggered an immediate and sustained increase in extracellular adenosine levels in the primary visual cortex (V1). We further uncovered the cellular source (i.e. glutamatergic and GABAergic) neurons) and molecular pathway (i.e. AMPK-associated energy metabolism pathways and adenosine efflux by equilibrative nucleoside transporter-2, ENT2) for extracellular adenosine generation.   Given the critical role of adenosine in modulating neurotransmitters and brain functions, the adenosine hypothesis of 40Hz flickering has important translational implications in developing non-invasive treatment for neuropsychiatric disorders. In the talk, I will also highlight the translational potential of 40Hz light flickering in modulating glymphatic activity, sleep regulation and neuroprotection against ischemic neuronal injury.