Coding principles of dopaminergic transmission modes

Science Advances, Год журнала: 2025, Номер 11(22)

Опубликована: Май 28, 2025

Dopaminergic neurons influence diverse behaviors with varied firing patterns, yet the precise mechanisms remain unclear. We introduce a multiplexed genetically encoded sensor–based imaging and voltammetry method to simultaneously record synaptic, perisynaptic, extrasynaptic dopaminergic transmission at mouse central neurons. Using this alongside image analysis program, we found that heterogeneous patterns create various modes, encoding frequency, number, synchrony of pulses using neurotransmitter quantity, releasing synapse count, synaptic and/or volume transmission. Under both tonic low-frequency phasic activities, transporters effectively reuptake dopamine perisynaptic sites, confining within clefts mediate In contrast, under high-frequency, particularly synchronized activity or transporter inhibition, released may overwhelm transporters, escaping from via one three outlet channels, triggering Our study illuminates collaborative mechanism enclosures, properties, defines coding principles pattern–dependent modes.

Язык: Английский

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Rapid C–S⁺ Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Июнь 4, 2025

Peptides and proteins are invaluable therapeutics biological tools, where stimuli-responsive fully reversible conjugation chemistry is essential to advances in drug delivery systems chemical biology. However, methods that allow precise conjugation, efficient regulation of biochemical functions, customized recovery parent peptides remain underdeveloped. Here, we introduce a straightforward yet powerful strategy targeting methionine (Met), widespread low abundance amino acid proteins. By selectively alkylating Met-containing under weakly acidic conditions, form stable C-S+ bond, which can be cleaved rapidly via 1,6-benzyl elimination upon stimulus. This versatile demonstrated diverse applications: (i) PEGylated prodrugs antimicrobial with reduced toxicity enhanced enzymatic stability, (ii) esterase-responsive peptide-peptide inhibitor conjugates (PPICs) improved cell membrane permeability therapeutic effects, (iii) reversibly stapled switchable conformations for both intra- extracellular sites, (iv) bioorthogonal control C-terminal Met-caged neuropeptides. Overall, this work describes, the first time, valuable traceless modification promises greatly benefit peptide community advance field

Язык: Английский

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GESIAP3.0: Sensor-based Image Analysis Program for Transmission Visualization In Vivo

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 31, 2024

Synaptic transmission mediated by various neurotransmitters influences a wide range of behaviors. However, understanding how neuromodulatory transmitters encode diverse behaviors and affect their functions remains challenging. Here, we introduce GESIAP3.0, an advanced, third-generation image analysis program based on genetically encoded sensors. This tool enables precise quantitative in both awake, freely moving animals immobilized subjects. GESIAP3.0 incorporates movement correction algorithms that effectively eliminate displacement behaving while optimizing synaptic information extraction simplifying computations commodity computers. Quantitative cholinergic, dopaminergic, serotonergic transmission, corrected for tissue movement, revealed properties consistent with measurements from ex vivo wide-field two-photon imaging under stable conditions. validates the applicability analyzing animals.

Язык: Английский

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