In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β ⁺ -sensitive microprobe

Abstract

Understanding brain disorders, the neural processes implicated in cognitive functions and their alterations in neurodegenerative pathologies, or testing new therapies for these diseases would benefit greatly from combined use of an increasing number of rodent models and neuroimaging methods specifically adapted to the rodent brain. Besides magnetic resonance (MR) imaging and functional MR, positron-emission tomography (PET) remains a unique methodology to study in vivo brain processes. However, current high spatialresolution tomographs suffer from several technical limitations such as high cost, low sensitivity, and the need of restraining the animal during image acquisition. We have developed a ␤ ؉ -sensitive high temporal-resolution system that overcomes these problems and allows the in vivo quantification of cerebral biochemical processes in rodents. This ␤-MICROPROBE is an in situ technique involving the insertion of a fine probe into brain tissue in a way very similar to that used for microdialysis and cell electrode recordings. In this respect, it provides information on molecular interactions and pathways, which is complementary to that produced by these technologies as well as other modalities such as MR or fluorescence imaging. This study describes two experiments that provide a proof of concept to substantiate the potential of this technique and demonstrate the feasibility of quantifying brain activation or metabolic depression in individual living rats with 2-[ 18 F]fluoro-2-deoxy-D-glucose and standard compartmental modeling techniques. Furthermore, it was possible to identify correctly the origin of variations in glucose consumption at the hexokinase level, which demonstrate the strength of the method and its adequacy for in vivo quantitative metabolic studies in small animals.A lterations in local cerebral metabolic rate of glucose (lCMRglc) have been reported in several human brain conditions such as psychiatric disorders or neurodegenerative diseases. Understanding the cellular mechanisms involved in these diseases and the development of new therapeutic strategies will advance more rapidly through the use of animal models. The quantitation of metabolic rates in the rodent brain was achieved initially by using the 2-deoxy-D-[ 14 C]glucose autoradiographic method (1). Although efficient, this technique requires the sacrifice of several animals to obtain each time point and thus can provide only ex vivo, averaged kinetic constants calculated from values obtained from various animals. As an alternative, positron-emission tomography (PET), an imaging technology designed to use compounds labeled with positron-emitting radioisotopes to image and measure biochemical processes in vivo, has been adapted to use in small animals. The implementation of several high spatial-resolution PET scanners within the last several years (2-9) has enabled the adaptation of the 2-deoxy-D-[ 14 C]glucose method to in vivo imaging of small animals by using 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) as a tracer. However, such PE...

In Vivo Measurement of Glucose Utilization in Rats using a β-Microprobe: Direct Comparison with Autoradiography

“…These results indicate that a histologic control has to be performed for each experiment, not only to ensure the correct implantation of the probe, but to exclude the presence of a hematoma. Our use of 0.5-mm-diameter probes, in comparison to the 1-mm-diameter probes used by Pain et al (Pain et al, 2002), may explain the variability of the ␤P measurements, because a larger probe can be more invasive than a smaller probe.…”

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

“…While spatial and temporal resolution are improving at a rapid rate in this relatively young technology, with recent reports showing sub-millimeter resolution in fMRI signals (Moon et al 2007), at present, both temporal and spatial resolution for PET are sub-optimal. A possible complementary approach to facilitate higher temporal resolution of radioligand binding is the newly developed β + -sensitive microprobe (Pain et al 2002). This microprobe measures radioactivity, and has been used with 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG), a commonly used tracer for glucose used as an indirect measure of brain activity, and [ 11 C]raclopride, commonly used to measure dopamine D 2 receptor and receptor occupancy levels (Mauger et al 2005).…”

A positron-probe system for arterial input function quantification for positron emission tomography in humans

“…It is a modification of the positron probe of Pain et al 20 The system has two probes: one placed intra-arterially and one placed outside the body, which monitors the 511 keV background. The background probe was completely covered by a light-tight black sheath.…”

“…20,28,32,33 Positron-probe systems require a pair of detectors: one for counting the tissue site of interest ͑e.g., arterial blood͒; and, the other for measuring background noise from various sources, which is subtracted from the tissue curve. A commercially available probe ͑␤-MicroProbe, Biospace, Newark, NJ͒ is fabricated from two types of plastic fiber: a ␤ + -sensitive scintillating fiber; and, a light-conducting, nonscintillating fiber.…”

“…The commercially available positron-probe system has been validated for obtaining ATACs in a rodent model 20 using 18 F-deoxy-glucose ͑ 18 FDG͒. 18 FDG, although widely used for PET imaging, does not place high demands on performance of a positron-probe system, as follows.…”