Persistent Light-Induced Reduction of Neuronal Excitability: Implications for Non-Optogenetic control of Brain Actvity
Visible light is widely used in neuroscience, yet its direct effects on neuronal activity in the absence of optogenetic manipulation remain incompletely understood. Here, we investigated whether light stimulation can induce sustained changes in neuronal excitability. Using ex vivo electrophysiological recordings, we show that repeated pulses of blue light (5 s, 430-495 nm, 19 mW) produce a robust and persistent reduction in evoked firing activity in cortical neurons from both male and female mice, with an average decrease of [~]60% relative to baseline. This inhibitory effect persisted for more than 20 minutes following stimulation and was associated with changes in both passive membrane properties and active ion channel conductance. In human cortical neurons, responses were more heterogeneous. While a subset of neurons exhibited similar inhibitory effects, others showed increased excitability, with this response occurring more frequently in neurons from female patients, suggesting a potential sex-dependent effect. In addition, a transient depolarizing response to light was observed in a minority of human neurons but not in mice. These findings indicate that visible light, independently of exogenous opsins, can induce long-lasting modulation of neuronal activity without evidence of acute cytotoxicity under the conditions tested. This raises the possibility that visible light may provide a previously underappreciated, opsin-independent mechanism for modulating neuronal activity, with potential relevance for disorders characterized by neuronal hyperexcitability. We outline a framework for future investigations, including validation in human systems, in vivo studies, optimization of stimulation parameters, and assessment of therapeutic potential in pathological models.