Abstract
Targeted manipulations of neural activity are essential approaches in neuroscience and neurology, but monitoring such procedures in the living brain remains a significant challenge. Here we introduce a paramagnetic analog of the drug muscimol that enables targeted neural inactivation to be performed with feedback from magnetic resonance imaging. We validate pharmacological properties of the compound in vitro, and show that its distribution in vivo reliably predicts perturbations to brain activity.
Highlights
Targeted manipulations of neural activity are essential approaches in neuroscience and neurology, but monitoring such procedures in the living brain remains a significant challenge
magnetic resonance imaging (MRI) measurements at 7 T and room temperature indicate that the r1 of paramagnetic muscimol analog (ParaMus) is 5.0 ± 0.2 mM−1 s−1; this value is somewhat larger than the r1 value of 3.6 ± 0.3 mM−1 s−1 for gadoteridol6, a contrast agent that approximates the Gd-DOTA moiety of ParaMus, and indicates that conjugation to muscimol does not compromise contrast-inducing properties of the gadolinium complex (Supplementary Fig. 2)
Postmortem analysis of brain tissue after an imaging experiment permits identification of ParaMus by mass spectrometry and reveals that the contrast agent remains intact during the experimental period (Supplementary Fig. 8). These results demonstrate that ParaMus combines the pharmacological properties of muscimol with the MRI properties of commercial contrast agents, enabling imaging-based assessment and control over neural manipulations in the living brain
Summary
Targeted manipulations of neural activity are essential approaches in neuroscience and neurology, but monitoring such procedures in the living brain remains a significant challenge. We introduce a paramagnetic analog of the drug muscimol that enables targeted neural inactivation to be performed with feedback from magnetic resonance imaging. 1234567890():,; Neuromodulation methods are widely used for perturbations of neural activity in both basic science and clinical practice, but monitoring the time course and spatial extent of modulatory tools in living subjects is challenging. We apply the principle to muscimol, an agonist of γaminobutyric acid (GABA) A receptors that is widely used for targeted inactivation of neural structures, and that has previously been applied as a fluorescent conjugate for postmortem histological imaging. By chemically conjugating muscimol to a gadolinium chelate, we sought to create a paramagnetic muscimol analog (ParaMus) whose distribution could be imaged in real time in vivo, while offering pharmacological properties comparable to muscimol itself
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