Role of Nuclear Imaging to Understand the Neural Substrates of Brain Disorders in Laboratory Animals: Current Status and Future Prospects

Abstract

Molecular imaging, which allows the real-time visualization, characterization and measurement of biological processes, is becoming increasingly used in neuroscience research. Scintigraphy techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) provide qualitative and quantitative measurement of brain activity in both physiological and pathological states. Laboratory animals, and rodents in particular, are essential in neuroscience research, providing plenty of models of brain disorders. The development of innovative high-resolution small animal imaging systems together with their radiotracers pave the way to the study of brain functioning and neurotransmitter release during behavioral tasks in rodents. The assessment of local changes in the release of neurotransmitters associated with the performance of a given behavioral task is a turning point for the development of new potential drugs for psychiatric and neurological disorders. This review addresses the role of SPECT and PET small animal imaging systems for a better understanding of brain functioning in health and disease states. Brain imaging in rodent models faces a series of challenges since it acts within the boundaries of current imaging in terms of sensitivity and spatial resolution. Several topics are discussed, including technical considerations regarding the strengths and weaknesses of both technologies. Moreover, the application of some of the radioligands developed for small animal nuclear imaging studies is discussed. Then, we examine the changes in metabolic and neurotransmitter activity in various brain areas during task-induced neural activation with special regard to the imaging of opioid, dopaminergic and cannabinoid receptors. Finally, we discuss the current status providing future perspectives on the most innovative imaging techniques in small laboratory animals. The challenges and solutions discussed here might be useful to better understand brain functioning allowing the translation of preclinical results into clinical applications.

Keywords: PET - positron emission tomography; SPECT; behavioral neuroscience; brain disorders; neuroimaging; small animal imaging.

Figure 1

Comparison between the brain size of humans and rats (Bakker et al., 2015).

Figure 2

Dedicated SPECT system for in-vivo preclinical molecular imaging; (A) 3D rendering of the system. (B) Inner structure that shows the eight detector heads mounted on a rotary stage.

Figure 3

Example of high-resolution SPECT image of a rat injected with [¹²³I] DATSCAN. (A) Reconstruction of the animal's skin carried out by a laser scanner. (B) SPECT image obtained 24 h after the injection. (C–E) Early SPECT image obtained ~1 h after the injection (different color maps).

Figure 4

SPECT brain images obtained by Monte Carlo simulations, using the WHS SD Rat Brain V 2.0 phantom. (A) Slice images of the activated striatum and cerebral cortex for the opioid system; (B) Slice images of the activated striatum for the dopaminergic system; (C) Slice images of the activated thalamus, cerebellum and globus pallidus for the endocannabinoid system; (D–F) 3D SPECT reconstructions.

Figure 5

Schematic illustration of a potential experiment to map neuronal activity by using a SPECT system. After the radiotracer is injected via the tail vein, the experimental subject undergoes behavioral testing and the neuronal response can be obtained from changes in receptor occupancy levels using SPECT imaging. Images shows changes in receptors signal following the behavioral responses.

Figure 6

Sketches of two systems designed to eliminate the need for anesthesia in rodent studies. (A) The RatCAP tomograph (rat conscious animal PET) consisting of a miniaturized full-ring PET scanner which is attached directly to the head, covering nearly the entire brain; (B) The open-field PET system, based on a commercial preclinical scanner, enables brain scans of rodents in motion due to an optical motion tracking and a custom designed motion-adaptive animal enclosure attached to a robotic arm.