A Prolyl-Isomerase Mediates Dopamine-Dependent Plasticity and Cocaine Motor Sensitization

SummarySynaptic plasticity induced by cocaine and other drugs underlies addiction. Here we elucidate molecular events at synapses that cause this plasticity and the resulting behavioral response to cocaine in mice. In response to D1-dopamine-receptor signaling that is induced by drug administration, the glutamate-receptor protein metabotropic glutamate receptor 5 (mGluR5) is phosphorylated by microtubule-associated protein kinase (MAPK), which we show potentiates Pin1-mediated prolyl-isomerization of mGluR5 in instances where the product of an activity-dependent gene, Homer1a, is present to enable Pin1-mGluR5 interaction. These biochemical events potentiate N-methyl-D-aspartate receptor (NMDAR)-mediated currents that underlie synaptic plasticity and cocaine-evoked motor sensitization as tested in mice with relevant mutations. The findings elucidate how a coincidence of signals from the nucleus and the synapse can render mGluR5 accessible to activation with consequences for drug-induced dopamine responses and point to depotentiation at corticostriatal synapses as a possible therapeutic target for treating addiction

Promotion of protocell self-assembly from mixed amphiphiles at the origin of life

Vesicles formed from single-chain amphiphiles (SCAs) such as fatty acids probably played an important role in the origin of life. A major criticism of the hypothesis that life arose in an early ocean hydrothermal environment is that hot temperatures, large pH gradients, high salinity and abundant divalent cations should preclude vesicle formation. However, these arguments are based on model vesicles using 1–3 SCAs, even though Fischer–Tropsch-type synthesis under hydrothermal conditions produces a wide array of fatty acids and 1-alkanols, including abundant C10–C15 compounds. Here, we show that mixtures of these C10–C15 SCAs form vesicles in aqueous solutions between pH ~6.5 and >12 at modern seawater concentrations of NaCl, Mg2+ and Ca2+. Adding C10 isoprenoids improves vesicle stability even further. Vesicles form most readily at temperatures of ~70 °C and require salinity and strongly alkaline conditions to self-assemble. Thus, alkaline hydrothermal conditions not only permit protocell formation at the origin of life but actively favour it

Using a local low rank plus sparse reconstruction to accelerate dynamic hyperpolarized 13C imaging using the bSSFP sequence.

Acceleration of dynamic 2D (T2 Mapping) and 3D hyperpolarized 13C MRI acquisitions using the balanced steady-state free precession sequence was achieved with a specialized reconstruction method, based on the combination of low rank plus sparse and local low rank reconstructions. Methods were validated using both retrospectively and prospectively undersampled in vivo data from normal rats and tumor-bearing mice. Four-fold acceleration of 1-2 mm isotropic 3D dynamic acquisitions with 2-5 s temporal resolution and two-fold acceleration of 0.25-1 mm2 2D dynamic acquisitions was achieved. This enabled visualization of the biodistribution of [2-13C]pyruvate, [1-13C]lactate, [13C, 15N2]urea, and HP001 within heart, kidneys, vasculature, and tumor, as well as calculation of high resolution T2 maps

Simultaneous T1 and T2 mapping of hyperpolarized 13C compounds using the bSSFP sequence

As in conventional 1H MRI, T1 and T2 relaxation times of hyperpolarized (HP) 13C nuclei can provide important biomedical information. Two new approaches were developed for simultaneous T1 and T2 mapping of HP 13C probes based on balanced steady state free precession (bSSFP) acquisitions: a method based on sequential T1 and T2 mapping modules, and a model-based joint T1/T2 approach analogous to MR fingerprinting. These new methods were tested in simulations, HP 13C phantoms, and in vivo in normal Sprague-Dawley rats. Non-localized T1 values, low flip angle EPI T1 maps, bSSFP T2 maps, and Bloch-Siegert B1 maps were also acquired for comparison. T1 and T2 maps acquired using both approaches were in good agreement with both literature values and data from comparative acquisitions. Multiple HP 13C compounds were successfully mapped, with their relaxation time parameters measured within heart, liver, kidneys, and vasculature in one acquisition for the first time

Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques

The goal of this project was to develop and apply techniques for T2 mapping and 3D high resolution (1.5mm isotropic; 0.003cm3) 13C imaging of hyperpolarized (HP) probes [1-13C]lactate, [1-13C]pyruvate, [2-13C]pyruvate, and [13C,15N2]urea in vivo. A specialized 2D bSSFP sequence was implemented on a clinical 3T scanner and used to obtain the first high resolution T2 maps of these different hyperpolarized compounds in both rats and tumor-bearing mice. These maps were first used to optimize timings for highest SNR for single time-point 3D bSSFP acquisitions with a 1.5mm isotropic spatial resolution of normal rats. This 3D acquisition approach was extended to serial dynamic imaging with 2-fold compressed sensing acceleration without changing spatial resolution. The T2 mapping experiments yielded measurements of T2 values of >1s for all compounds within rat kidneys/vasculature and TRAMP tumors, except for [2-13C]pyruvate which was ~730ms and ~320ms, respectively. The high resolution 3D imaging enabled visualization the biodistribution of [1-13C]lactate, [1-13C]pyruvate, and [2-13C]pyruvate within different kidney compartments as well as in the vasculature. While the mouse anatomy is smaller, the resolution was also sufficient to image the distribution of all compounds within kidney, vasculature, and tumor. The development of the specialized 3D sequence with compressed sensing provided improved structural and functional assessments at a high (0.003cm3) spatial and 2s temporal resolution in vivo utilizing HP 13C substrates by exploiting their long T2 values. This 1.5mm isotropic resolution is comparable to 1H imaging and application of this approach could be extended to future studies of uptake, metabolism, and perfusion in cancer and other disease models and may ultimately be of value for clinical imaging

Spectrally selective three-dimensional dynamic balanced steady-state free precession for hyperpolarized C-13 metabolic imaging with spectrally selective radiofrequency pulses.

PurposeBalanced steady-state free precession (bSSFP) sequences can provide superior signal-to-noise ratio efficiency for hyperpolarized (HP) carbon-13 (13 C) magnetic resonance imaging by efficiently utilizing the nonrecoverable magnetization, but managing their spectral response is challenging in the context of metabolic imaging. A new spectrally selective bSSFP sequence was developed for fast imaging of multiple HP 13 C metabolites with high spatiotemporal resolution.Theory and methodsThis novel approach for bSSFP spectral selectivity incorporates optimized short-duration spectrally selective radiofrequency pulses within a bSSFP pulse train and a carefully chosen repetition time to avoid banding artifacts.ResultsThe sequence enabled subsecond 3D dynamic spectrally selective imaging of 13 C metabolites of copolarized [1-13 C]pyruvate and [13 C]urea at 2-mm isotropic resolution, with excellent spectral selectivity (∼100:1). The sequence was successfully tested in phantom studies and in vivo studies with normal mice.ConclusionThis sequence is expected to benefit applications requiring dynamic volumetric imaging of metabolically active 13 C compounds at high spatiotemporal resolution, including preclinical studies at high field and, potentially, clinical studies. Magn Reson Med 78:963-975, 2017. © 2016 International Society for Magnetic Resonance in Medicine