Aptamer-Engineered Galvanic Potentiometry for Resolving Serotonin Dynamics Under Psychosocial Stress

Serotonin is important neurotransmitter in mood, stress, motivation, cognition, however, despite its significant role in neuroscience, serotonin remains surprisingly difficult to observe directly while it is doing its work. The field knows a great deal about receptors, transporters, and long-term adaptations, but much less about how serotonin release actually unfolds in real time, especially under psychosocial stress. Most of the tools traditionally used to study serotonergic signaling were not designed with dynamics in mind. Biochemical assays and molecular readouts are excellent for telling us what is present or upregulated, but they tend to average signals over space and time. What gets lost are short-lived release events and region-specific fluctuations that may matter disproportionately for behavior. Electrochemical sensing has long promised to address this limitation by offering direct, in situ access to neurotransmitter dynamics. In practice, however, serotonin has proven to be a difficult target. One challenge is chemical because the electrochemical signature of serotonin overlaps with that of endogenous species such as vitamin C, which is present in brain tissue at much higher concentrations. Another challenge is physical. Implanted electrodes do not remain pristine and tissue responses accumulate and even when these issues are partially controlled, many high-resolution techniques such as fast-scan cyclic voltammetry and transistor-based probes among them require applied potentials. This raises a persistent concern that the measurement itself may influence local neuronal activity, complicating interpretation.

Self-powered electrochemical strategies have emerged as a way around some of these constraints. Galvanic redox potentiometry, in particular, is appealing because it operates close to equilibrium and avoids externally imposed currents. In principle, this reduces both electrical interference and surface passivation. In practice, early versions revealed another limitation: selectivity. Under biologically realistic conditions, especially in the presence of high vitamin C levels, reliable discrimination of serotonin remained elusive. As a result, these approaches struggled to move beyond simplified models, leaving a clear mismatch between sensor performance and the complexity of stress-related neurobiology. To this end, new research paper published in Angewandte Chemie International Edition  and conducted by Dr. Fenghui Zhu, Dr. Yinghuan Liu, Dr. Zhining Sun, Dr.  Jiping Ni, and led by Professor Ying Jiang from the College of Chemistry at Beijing Normal University, the researchers developed a self-powered, aptamer-engineered galvanic potentiometric sensor capable of real-time serotonin monitoring in the intact brain. By integrating phosphorothioate-modified serotonin aptamers with a redox-driven potentiometric mechanism, the platform achieves exceptional selectivity and stability under physiologically realistic conditions.  

The research team constructed a micrometer-scale bipolar carbon fiber electrode configured to operate under galvanic redox potentiometry, embedding the cathodic compartment within a reversible iridium chloride redox couple while functionalizing the anodic surface with serotonin-specific aptamers. These aptamers were further modified through phosphorothioate substitution, a deliberate design choice that conferred resistance to nuclease degradation and prolonged operational stability in biological environments. Upon exposure to serotonin, the favorable redox potential difference between serotonin oxidation and iridium reduction generated a spontaneous potential shift, allowing signal transduction without external polarization. The authors performed in vitro studies which demonstrated that this molecular interface fundamentally altered sensor behavior. They found the aptamer-engineered device have rapid equilibration, minimal baseline drift over extended periods, and a linear response across physiologically relevant serotonin concentrations even in the presence of excess vitamin C. Additionally, the authors noticed the sensor maintained strong discrimination against structurally related metabolites and redox-active interferents, which highlights the role of aptamer-mediated molecular recruitment rather than reliance on kinetic separation alone. These results marked a decisive improvement over earlier galvanic sensors, which suffered from substantial vitamin C interference. They found the sensor retained its performance after implantation into murine brain tissue. Stereotaxic insertion into the medial prefrontal cortex and dorsal raphe nucleus produced stable recordings without evidence of acute inflammation or functional degradation. Local chemical stimulation evoked concentration-dependent serotonin release, whereas control injections elicited no detectable response, confirming in vivo selectivity.

The team also evaluated the sensing capability to a psychosocial stress paradigm based on social hierarchy formation by using mice occupying dominant social ranks displayed elevated serotonin release in both the medial prefrontal cortex and dorsal raphe nucleus. However, these increases were accompanied by region-specific neuronal activity patterns: reduced spontaneous firing in the medial prefrontal cortex contrasted with heightened firing in the dorsal raphe nucleus which suggests that serotonergic signaling does not exert uniform effects across stress-related circuits, but instead participates in spatially differentiated modulation. Further manipulation of social rank reinforced this conclusion. When subordinate animals were forced into dominance, their serotonergic and electrophysiological profiles shifted accordingly, whereas dominant animals subjected to forced defeat exhibited selective resilience in cortical circuits but altered serotonergic output in brainstem nuclei.  

In conclusion, the new work of Professor Ying Jiang and colleagues advances neurochemical sensing by demonstrating that molecular recognition and electrochemical transduction need not be treated as independent optimization problems. The authors successfully overcome long-standing obstacles associated with interference, biofouling, and electrical perturbation by embedding aptamer specificity directly into a self-powered galvanic architecture and the resulting platform operates within native brain environments without pretreatment, a feature that substantially enhances its translational relevance. Indeed, the system enables simultaneous neurochemical and electrophysiological interrogation of stress-related circuits. This work establishes a generalizable framework for molecularly intelligent in vivo electrochemical sensing. Moreover, the new findings challenge simplified models of serotonergic function under stress and rather than acting as a uniform signal of mood or anxiety, serotonin release emerges here as a context-dependent variable whose effects depend on anatomical location and circuit state. The opposing correlations between serotonin levels and neuronal firing in cortical versus brainstem regions underscore the inadequacy of single-site measurements for interpreting neuromodulatory function. Further, the work sets a precedent for integrating chemical stability, biological compatibility, and mechanistic insight within a single experimental framework. The use of phosphorothioate-modified aptamers suggests a broader strategy for constructing long-lived molecular interfaces capable of operating in vivo over behaviorally meaningful timescales. Moreover, the near-zero-current operating mode offers a pathway toward multiplexed sensing that minimizes cross-talk with electrophysiological recordings. The implications extend beyond serotonin. The galvanic potentiometric architecture is, in principle, agnostic to analyte identity, provided suitable recognition elements can be developed. This opens opportunities for probing other neuromodulators that have remained difficult to measure dynamically, including neuropeptides and redox-silent transmitters.