Near-infrared nanosensors enable optical imaging of oxytocin with selectivity over vasopressin in acute mouse brain slices.

Oxytocin plays a critical role in regulating social behaviors, yet our understanding of its function in both neurological health and disease remains incomplete. Real-time oxytocin imaging probes with spatiotemporal resolution relevant to its endogenous signaling are required to fully elucidate oxytocin's role in the brain. Herein, we describe a near-infrared oxytocin nanosensor (nIROXT), a synthetic probe capable of imaging oxytocin in the brain without interference from its structural analogue, vasopressin. nIROXT leverages the inherent tissue-transparent fluorescence of single-walled carbon nanotubes (SWCNT) and the molecular recognition capacity of an oxytocin receptor peptide fragment to selectively and reversibly image oxytocin. We employ these nanosensors to monitor electrically stimulated oxytocin release in brain tissue, revealing oxytocin release sites with a median size of 3 µm in the paraventricular nucleus of C57BL/6 mice, which putatively represents the spatial diffusion of oxytocin from its point of release. These data demonstrate that covalent SWCNT constructs, such as nIROXT, are powerful optical tools that can be leveraged to measure neuropeptide release in brain tissue.

Emerging methods and applications of ultra-high field MR spectroscopic imaging in the human brain.

Magnetic Resonance Spectroscopic Imaging (MRSI) of the brain enables insights into the metabolic changes and fluxes in diseases such as tumors, multiple sclerosis, epilepsy, or hepatic encephalopathy, as well as insights into general brain functionality. However, the routine application of MRSI is mostly hampered by very low signal-to-noise ratios (SNR) due to the low concentrations of metabolites, about 10000 times lower than water. Furthermore, MRSI spectra have a dense information content with many overlapping metabolite resonances, especially for proton MRSI. MRI scanners at ultra-high field strengths, like 7 T or above, offer the opportunity to increase SNR, as well as the separation between resonances, thus promising to solve both challenges. Yet, MRSI at ultra-high field strengths is challenged by decreased B0- and B1-homogeneity, shorter T2 relaxation times, stronger chemical shift displacement errors, and aggravated lipid contamination. Therefore, to capitalize on the advantages of ultra-high field strengths, these challenges must be overcome. This review focuses on the challenges MRSI of the human brain faces at ultra-high field strength, as well as the possible applications to this date.

Stochastic Simulation of Dopamine Neuromodulation for Implementation of Fluorescent Neurochemical Probes in the Striatal Extracellular Space.

Imaging the dynamic behavior of neuromodulatory neurotransmitters in the extracelluar space that arise from individual quantal release events would constitute a major advance in neurochemical imaging. Spatial and temporal resolution of these highly stochastic neuromodulatory events requires concurrent advances in the chemical development of optical nanosensors selective for neuromodulators in concert with advances in imaging methodologies to capture millisecond neurotransmitter release. Herein, we develop and implement a stochastic model to describe dopamine dynamics in the extracellular space (ECS) of the brain dorsal striatum to guide the design and implementation of fluorescent neurochemical probes that record neurotransmitter dynamics in the ECS. Our model is developed from first-principles and simulates release, diffusion, and reuptake of dopamine in a 3D simulation volume of striatal tissue. We find that in vivo imaging of neuromodulation requires simultaneous optimization of dopamine nanosensor reversibility and sensitivity: dopamine imaging in the striatum or nucleus accumbens requires nanosensors with an optimal dopamine dissociation constant (Kd) of 1 µM, whereas Kds above 10 µM are required for dopamine imaging in the prefrontal cortex. Furthermore, as a result of the probabilistic nature of dopamine terminal activity in the striatum, our model reveals that imaging frame rates of 20 Hz are optimal for recording temporally resolved dopamine release events. Our work provides a modeling platform to probe how complex neuromodulatory processes can be studied with fluorescent nanosensors and enables direct evaluation of nanosensor chemistry and imaging hardware parameters. Our stochastic model is generic for evaluating fluorescent neurotransmission probes, and is broadly applicable to the design of other neurotransmitter fluorophores and their optimization for implementation in vivo.