Wiring economy can account for cell body placement across species and brain areas.

The placement of neuronal cell bodies relative to the neuropile differs among species and brain areas. Cell bodies can be either embedded as in mammalian cortex or segregated as in invertebrates and some other vertebrate brain areas. Why are there such different arrangements? Here we suggest that the observed arrangements may simply be a reflection of wiring economy, a general principle that tends to reduce the total volume of the neuropile and hence the volume of the inclusions in it. Specifically, we suggest that the choice of embedded versus segregated arrangement is determined by which neuronal component - the cell body or the neurite connecting the cell body to the arbor - has a smaller volume. Our quantitative predictions are in agreement with existing and new measurements.

Assessment of sphingosine-1-phosphate receptor expression and associated intracellular signaling cascades in primary cells of the human central nervous system.

Measuring the effects of sphingosine-1-phosphate (S1P) receptor modulators on human primary neural cells is of particular interest given the recent application of these central nervous system-accessible agents to the treatment of neurodegenerative diseases, such as multiple sclerosis. Issues to consider in experimental studies include the ability of some of these modulators to bind multiple S1P receptor subtypes simultaneously, the nonspecificity of commercially available S1P receptor antibodies, and activation of multiple intracellular signaling cascades by a given S1P receptor. Here, we discuss how to assay S1P receptor expression and activation using multiple agonists/antagonists, by linking the results of real-time reverse transcriptase polymerase chain reaction with the assessment of intracellular signaling derived from Western blot analyses.

In vivo assessment of macrophage CNS infiltration during disruption of the blood-brain barrier with focused ultrasound: a magnetic resonance imaging study.

Focused ultrasound has been discovered to locally and reversibly increase permeability of the blood-brain barrier (BBB). However, inappropriate sonication of the BBB may cause complications, such as hemorrhage and brain tissue damage. Tissue damage may be controlled by selecting optimal sonication parameters. In this study, we sought to investigate the feasibility of labeling cells with superparamagnetic iron oxide particles to assess the inflammatory response during focused-ultrasound-induced BBB opening. We show that infiltration of phagocytes does not occur using optimal parameters of sonication. Taken together, the results of our study support the usefulness and safety of focused-ultrasound-induced BBB opening for enhancing drug delivery to the brain. These findings may have implications for the optimization of sonication parameters.

A biomathematical modeling approach to central nervous system radioligand discovery and development.

UNLABELLED: The development of a successful PET or SPECT molecular imaging probe is a complex, time-consuming, and expensive process that suffers from high attrition. To address this problem, we have developed a biomathematical modeling approach that aims to predict the in vivo performance of radioligands directly from in silico/in vitro data. METHODS: The method estimates the in vivo nondisplaceable and total uptake of a ligand in a target tissue using a standard input function and a 1-tissue-compartment model with a parsimonious parameter set (influx rate constant K(1), efflux rate constant k(2), and binding potential BP(ND)) whose values are predicted from in silico/in vitro data including lipophilicity, molecular volume, free fraction in plasma and tissue, target density, affinity, perfusion, capillary surface area, and apparent aqueous volume in plasma and tissue. The coefficient of variation of the BP(ND) (%COV[BP(ND)]) metric, derived from Monte Carlo simulations, is used to estimate the in vivo performance of candidate compounds. A total of 28 compounds for 10 targets was evaluated using our method to predict their in vivo performance and validated against measured in vivo PET data in the Yorkshire/Danish Landrace pig. RESULTS: The predicted K(1), k(2), and BP(ND) values were generally consistent with the values estimated from in vivo PET data. The model resulted in small %COV[BP(ND)] values for widely accepted good ligands such as (11)C-flumazenil (2.02%) and (11)C-raclopride (2.55%), whereas higher values resulted from poor ligands such as (11)C-(R)-PK11195 (13.34%). Of 4 candidates for the GlyT1 transporter, the model selected (11)C-GSK931145 (2.11%) as the most promising ligand, which was consistent with historical decisions made on the in vivo PET data. CONCLUSION: A biomathematical modeling approach has the potential to predict the in vivo performance of ligands from in silico/in vitro data and aid in the development of molecular imaging probes.

Chapter 8 - Nanoparticles: Transport across the olfactory epithelium and application to the assessment of brain function in health and disease.

The exciting advances within nanotechnology are beginning to be harnessed by the medical field. Nanoparticles have been used for drug delivery into the brain and have been explored for imaging, sensing, and analytical purposes. The science of nanoparticles encompasses a vast array of biological, chemical, physical, and engineering research, different aspects of which are specifically addressed in each of the chapters of this volume. Nanomaterials such as nanospheres, nanotubes, nanowires, fullerene derivatives (buckyballs), and quantum dots (Qdots) are at the forefront of scientific attention, as they provide new consumer products and advance the scientific development of novel analytical tools in medicine and in the physical sciences. This chapter will briefly survey some aspects of nanoparticle biology focusing on the following: (1) the role of olfactory nanoparticle transport into the central nervous system (CNS), both as a potential route for effective drug delivery and as a route for the passage of noxious substances into the brain proper; (2) nanoparticles as sensors of cell function and toxicity; and (3) some adverse effects of nanoparticles on the dysregulation of brain redox status.

Extracellular space diffusion in central nervous system: anisotropic diffusion measured by elliptical surface photobleaching.

Diffusion in the extracellular space (ECS) is crucial for normal central nervous system physiology. The determinants of ECS diffusion include viscous interactions with extracellular matrix/plasma membranes ("viscosity") and ECS geometry ("tortuosity"). To resolve viscosity versus tortuosity effects, we measured direction-dependent (anisotropic) diffusion in ECS in mouse spinal cord by photobleaching using an elliptical spot produced by a cylindrical lens in the excitation path. Anisotropic diffusion slowed fluorescence recovery when the long axis of the ellipse was parallel versus perpendicular to the direction of faster diffusion. A mathematical model was constructed to deduce diffusion coefficients (D(x), D(y)) from fluorescence recovery measured for parallel and perpendicular orientations of the long axis of the ellipse. Elliptical spot photobleaching was validated by photobleaching aqueous-phase fluorophores on a diffraction grating, where diffusion is one-dimensional. Measurement of the diffusion of 70 kDa FITC-dextran in spinal cord in living mice indicated that viscosity slows diffusion by approximately 1.8-fold compared with its diffusion in solution. ECS geometry hinders diffusion across (but not along) axonal fibers in spinal cord further by approximately fivefold. In cerebral cortex, however, approximately 50% of the hindrance to ECS diffusion comes from viscosity and approximately 50% from tortuosity. We suggest that the extracellular matrix might have evolved to facilitate rather than hinder diffusion even for large molecules.

Non-invasive assessment of the pyramidal tract and motor pathway of primates.

Non-invasive direct stimulation of the motor cortex of cynomolgus monkeys has been used to assess in awake and anesthetized animals the central and peripheral conduction times of the motor pathway and to measure the latencies of the descending spinal volley of the pyramidal tracts. Repetitive stimulation failed to induce convulsive activity or detectable pathological changes. Peripheral latencies were comparable with those obtained from F-wave analysis. Central conduction times for corticospinal tracts regulating the upper and lower limbs were 2.7 msec and 5.4 msec, respectively, the estimated conduction velocity (67.5 m/sec) corresponding to results obtained by invasive methods. These studies provide a new and apparently safe technique to assess non-invasively the functional status of the central motor pathway in primates, a method that might also find utility in clinical practice.