Decoding Early Neurochemical Dynamics in Circuit Dysfunction of Parkinson’s Disease <i>via</i> Synergetic SERS and Electrophysiological Probe Suite

The pathological mechanisms underlying neurodegenerative diseases remain poorly defined, largely due to the lack of tools capable of detecting molecular alterations before the onset of clinical symptoms. Here we successfully achieve targeted profiling of dopamine (DA) and nontargeted profiling of amino acid (AA) molecules in the lesioned substantia nigra of Parkinson’s disease (PD) mouse by intergrating ex vivo surface-enhanced Raman spectroscopy (SERS) probes with concurrent in vivo electrophysiological recordings in the primary motor cortex. The PD model was established by stereotaxic unilateral injection of 6-hydroxydopamine (6-OHDA) into the right striatum of mice, while the left sham side was used as the reference. At early stage of PD model, a sandwich-structured SERS tag enables highly specific targeted profiling of picomolar-level DA, and a feedforward neural network resolves highly overlapping AA spectra, allowing reliable identification of AA components at physiological micromolar concentrations. In the lesioned substantia nigra, results reveal a rapid decline in DA levels within 6 h after 6-OHDA injection, followed by a marked elevation of glutamate (Glu) at 9 h; while the primary motor cortex at 9 h starts to emerge pathological β-band hypersynchronization and abnormal β–γ phase amplitude coupling. These molecular and circuit-level disturbances clearly precede overt motor asymmetry that becomes evident only at 27 h postlesion. Integrated transcriptomic and qPCR analysis identifies Glu as a central molecular hub linking early neurochemical imbalance to subsequent neural circuit dysfunction. The findings indicate a DA-depletion–triggered and Glu-centered excitotoxic cascade, and also prospect a early therapeutic window during which restoring Glu homeostasis, enhancing metabolic resilience, or mitigating oxidative stress may help prevent subsequent network destabilization. This synergistic SERS–electrophysiology suite enables time-resolved chemical-to-neurophysiological mapping and provides a general framework for investigating molecular-to-circuit transitions in neurodegenerative disorders.