Dentate gyrus neurogenesis ablation via cranial irradiation enhances morphine self-administration and locomotor sensitization.

Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.

Evaluation of gantry speed on image quality and imaging dose for 4D cone-beam CT acquisition.

BACKGROUND: This study investigates the effect of gantry speed on 4DCBCT image quality and dose for the Varian On-Board Imager®. METHODS: A thoracic 4DCBCT protocol was designed using a 125 kVp spectrum. Image quality parameters were evaluated for 4DCBCT acquisition using Catphan® phantom with real-time position management™ system for gantry speeds varying between 1.0 to 6.0°/s. Superior-inferior motion of the phantom was executed using a sinusoidal waveform with five second period. Scans were retrospectively sorted into 4 phases (CBCT-4 ph) and 10 phases (CBCT-10 ph); average 4DCBCT (CBCT-ave), using all image data from the 4DCBCT acquisitions was also evaluated. The 4DCBCT images were evaluated using the following image quality metrics: spatial resolution, contrast-to-noise ratio (CNR), and uniformity index (UI). Additionally, Hounsfield unit (HU) sensitivity compared to a baseline CBCT and percent differences and RMS errors (RMSE) of excursion were also determined. Imaging dose was evaluated using an IBA CC13 ion chamber placed within CIRS Thorax phantom using the same sinusoidal motion and image acquisition settings as mentioned above. RESULTS: Spatial resolution decreased linearly from 5.93 to 3.82 lp/cm as gantry speed increased from 1.0 to 6.0°/s. CNR decreased linearly from 4.80 to 1.82 with gantry speed increasing from 1.0 to 6.0°/s, respectively. No noteworthy variations in UI, HU sensitivity, or excursion metrics were observed with changes in gantry speed. Ion chamber dose rates measured ranged from 2.30 (lung) to 5.18 (bone) E-3 cGy/mAs. CONCLUSIONS: A quantitative analysis of the Varian OBI's 4DCBCT capabilities was explored. Changing gantry speed changes the number of projections used for reconstruction, affecting both image quality and imaging dose if x-ray tube current is held constant. From the results of this study, a gantry speed between 2 and 3°/s was optimal when considering image quality, dose, and reconstruction time. The future of 4DCBCT clinical utility relies on further investigation of image acquisition and reconstruction optimization.

An athymic rat model of cutaneous radiation injury designed to study human tissue-based wound therapy.

PURPOSE: To describe a pilot study for a novel preclinical model used to test human tissue-based therapies in the setting of cutaneous radiation injury. METHODS: A protocol was designed to irradiate the skin of athymic rats while sparing the body and internal organs by utilizing a non-occlusive skin clamp along with an x-ray image guided stereotactic irradiator. Each rat was irradiated both on the right and the left flank with a circular field at a 20 cm source-to-surface distance (SSD). Single fractions of 30.4 Gy, 41.5 Gy, 52.6 Gy, 65.5 Gy, and 76.5 Gy were applied in a dose-finding trial. Eight additional wounds were created using the 41.5 Gy dose level. Each wound was photographed and the percentage of the irradiated area ulcerated at given time points was analyzed using ImageJ software. RESULTS: No systemic or lethal sequelae occurred in any animals, and all irradiated skin areas in the multi-dose trial underwent ulceration. Greater than 60% of skin within each irradiated zone underwent ulceration within ten days, with peak ulceration ranging from 62.1% to 79.8%. Peak ulceration showed a weak correlation with radiation dose (r = 0.664). Mean ulceration rate over the study period is more closely correlated to dose (r = 0.753). With the highest dose excluded due to contraction-related distortions, correlation between dose and average ulceration showed a stronger relationship (r = 0.895). Eight additional wounds created using 41.5 Gy all reached peak ulceration above 50%, with all healing significantly but incompletely by the 65-day endpoint. CONCLUSIONS: We developed a functional preclinical model which is currently used to evaluate human tissue-based therapies in the setting of cutaneous radiation injury. Similar models may be widely applicable and useful the development of novel therapies which may improve radiotherapy management over a broad clinical spectrum.

Gold nanocages covered by smart polymers for controlled release with near-infrared light.

Photosensitive caged compounds have enhanced our ability to address the complexity of biological systems by generating effectors with remarkable spatial/temporal resolutions. The caging effect is typically removed by photolysis with ultraviolet light to liberate the bioactive species. Although this technique has been successfully applied to many biological problems, it suffers from a number of intrinsic drawbacks. For example, it requires dedicated efforts to design and synthesize a precursor compound for each effector. The ultraviolet light may cause damage to biological samples and is suitable only for in vitro studies because of its quick attenuation in tissue. Here we address these issues by developing a platform based on the photothermal effect of gold nanocages. Gold nanocages represent a class of nanostructures with hollow interiors and porous walls. They can have strong absorption (for the photothermal effect) in the near-infrared while maintaining a compact size. When the surface of a gold nanocage is covered with a smart polymer, the pre-loaded effector can be released in a controllable fashion using a near-infrared laser. This system works well with various effectors without involving sophisticated syntheses, and is well suited for in vivo studies owing to the high transparency of soft tissue in the near-infrared region.

Molecular photoacoustic tomography with colloidal nanobeacons.

Spotting clots: Vascularly constrained colloidal gold nanobeacons (GNBs; see picture) can be used as exogenous photoacoustic contrast agents for the targeted detection of fibrin, a major biochemical feature of thrombus. Fibrin-targeted GNBs provide a more than tenfold signal enhancement in photoacoustic tomography in the near-IR wavelength window, indicating their potential for diagnostic imaging.