Optogenetics in neurobiology and neurodegenerative disorders: from neural circuit mechanisms to precision neuromodulation

Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and stroke, are characterized by progressive neuronal dysfunction, synaptic impairment and neural circuit degeneration, leading to severe cognitive and motor deficits. Although considerable progress has been made in understanding their molecular pathology, the circuit level mechanisms driving disease onset and progression remain incompletely understood. Optogenetics, which combines microbial opsins, genetic engineering and optical stimulation, enables reversible, cell-specific control of neuronal activity with millisecond precision and has transformed neuroscience from observational analysis to causal investigation of neural circuits. This review summarizes recent advances in the molecular basis of optogenetics, microbial opsins, gene delivery strategies and optical stimulation technologies, together with their applications in basic neurobiology and neurodegenerative disease research. We discuss how optogenetics has advanced understanding of neural circuit organization, synaptic plasticity, memory, neurodevelopment, sleep regulation, protein aggregation, synaptic dysfunction, neuroinflammation, mitochondrial impairment, oxidative stress and regulated cell death. Although these studies have generated important mechanistic insights and demonstrated functional improvements in experimental models, translation into human therapies remains investigational due to challenges associated with gene delivery, long-term opsin expression, immune compatibility and optical accessibility. Emerging therapeutic strategies, including closed-loop neuromodulation, wireless photostimulation, artificial intelligence-assisted neural decoding, nanotechnology enabled light delivery and brain computer interfaces, are critically evaluated with emphasis on their current evidence status, translational challenges and limitations for clinical implementation. Collectively, optogenetics provides an unprecedented platform for deciphering disease mechanisms and evaluating circuit-based neuromodulation strategies, while continued technological and biological validation will determine its future role in precision therapies for neurodegenerative disorders.