The Neuroscientist

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has become a powerful and widespread analytical tool in all fields of life science. The wide mass range (1-300 kDa), high accuracy, and sensitivity make it a superior method for analysis of all kinds of biomolecules including proteins, nucleic acids, and carbohydrates. In combination with 2D-gelelectrophoresis, MALDI-TOF-MS is particularly suitable for the identification of protein spots via mass fingerprint or microsequencing. Furthermore, the method allows a detailed analysis of posttranslational protein modifications. Recently, the method was also successfully applied to DNA sequencing as well as screening for mutations. Thus, high-throughput genotyping of single nucleotide polymorphisms has the potential to become a routine method for both laboratory and clinical applications.

Neurotrophic factors have an established developmental role in regulating the survival and specification of sensory neurons. However, these factors continue to exert an important influence on sensory neurons throughout the postnatal period and into adult life. In adulthood, approximately one-half of nociceptors are dependent on nerve growth factor (NGF) for trophic support, whereas the other half are sensitive to glial cell line-derived neurotrophic factor (GDNF). It is now known that many chronic pain states are maintained by widespread changes in the anatomy, neurochemistry, and function of the sensory nervous system both at the level of the primary sensory neuron and the dorsal horn of the spinal cord. Trophic factors appear to orchestrate many of these dynamic changes. This review highlights some of the key roles played by these molecules and in particular the role of NGF in the peripheral sensitization of nociceptors and brain-derived neurotrophic factor (BDNF) as a central pain modulator.

The design of database models and schemas for storing, cross-referencing, and retrieving neuroscience information faces issues that are similar but more complex than most of the other biomedical disciplines, such as genomics and proteonomics. Specifically, the visualization and manipulation of very large and diverse image data, such as digital brain atlases and functional magnetic resonance images, play a unique role in neuroscience while much of the associated information is textually recorded. Nongraphical information can include the annotation of large brain structures ranging from anatomical regions to intracellular structures, the description of cellular functional properties, and their various interrelationships, such as fiber connections. It is necessary that the heterogeneous and distributed types of data be cross-referenced to each other so that this diverse information can be efficiently retrieved, shared, and exchanged among the different neuroscientific disciplines. Continued advances in computers and Internet technologies appear to indicate that increasingly large data sets will be maintained on local or regional file servers and that informational interoperability will be achieved using a networked information system infrastructure. The authors and others have proposed and implemented models of semantically organized information systems that utilize centrally stored and highly structured archival information to index, cross-reference, and retrieve diverse, Web-based data sets.

Motor and sensory functions are lost after spinal cord injury because neurons die or atrophy and axons fail to regenerate. Until fairly recently, it was believed that damaged neurons could not be replaced and injured axons could not regenerate, and, therefore, functions dependent on injured neurons could not be recovered. We now know that damaged neurons can be rescued by providing therapeutic factors or replaced by grafting. In addition, the adult CNS contains a population of precursor cells with a potential to generate new neural cells, whose numbers and composition can be modified by extrinsic factors. The pioneering studies of Aguayo demonstrated that CNS axons could regenerate in the right environment. Subsequent studies have revealed the identity of some of the inhibitory molecules in myelin and scar tissue, and we now have a better understanding of how the CNS environment can be modified to become more permissive to regeneration. Axons that regenerate must find an appropriate target, but it may not be essential to reestablish the precise topography for some functions to be restored. There are now new and promising strategies for delivery of therapeutic genes to protect neurons and to stimulate regeneration. The ability to engineer cells by gene therapy combines the therapeutic values of cell transplantation and gene delivery. These remarkable developments from many disciplines have generated a new level of optimism in the search for a cure for CNS injury and in particular spinal cord injury. In this review, the authors summarize recent progress in these strategies and some of the challenges that remain in elucidating the most efficacious protocols for rescuing injured neurons, encouraging regeneration of their axons, and promoting recovery of function.

Voltage-gated sodium channels are glycoprotein complexes responsible for initiation and propagation of action potentials in excitable cells such as central and peripheral neurons, cardiac and skeletal muscle myocytes, and neuroendocrine cells. Mammalian sodium channels are heterotrimers, composed of a central, pore-forming α subunit and two auxiliary β subunits. The α subunits form a gene family with at least 10 members. Mutations in α subunit genes have been linked to paroxysmal disorders such as epilepsy, long QT syndrome, and hyperkalemic periodic paralysis in humans, and motor endplate disease and cerebellar ataxia in mice. Three genes encode sodium channel β subunits with at least one alternative splice product. A mutation in the β1 subunit gene has been linked to generalized epilepsy with febrile seizures plus type 1 (GEFS + 1) in a human family with this disease. Sodium channel β subunits are multifunctional. They modulate channel gating and regulate the level of channel expression at the plasma membrane. More recently, they have been shown to function as cell adhesion molecules in terms of interaction with extracellular matrix, regulation of cell migration, cellular aggregation, and interaction with the cytoskeleton. Structure-function studies have resulted in the preliminary assignment of functional domains in the β1 subunit. A sodium channel signaling complex is proposed that involves β subunits as channel modulators as well as cell adhesion molecules, other cell adhesion molecules such as neurofascin and contactin, RPTPβ, and extracellular matrix molecules such as tenascin.

The olfactory pathway has emerged recently as an effective model for studying general principles of axon extension and regeneration. A variety of both trophic as well as repulsive molecules are found in the olfactory pathway and are being characterized for their roles in promoting the high capacity for plasticity and growth in olfactory receptor cell axons. In addition, olfactory ensheathing cells, which line the olfactory nerve, have been shown to promote axon extension not only in the olfactory pathway but also in the injured spinal cord. This review summarizes some of our current knowledge of these mechanisms and how they may function collectively to promote axon plasticity.

Functional magnetic resonance imaging (fMRI) is an emerging methodology for studying regional brain function in vivo at relatively high spatial and temporal resolution. Because MRI methods are comparatively inexpensive and entirely noninvasive, fMRI has rapidly become one of the most popular approaches for brain mapping in cognitive and systems neuroscience. There has also been great interest in using fMRI to assist in clinical diagnosis and management, with promising demonstrations of feasibility in a number of applications. Both resting and task-specific regional brain activity can be measured, primarily utilizing alterations in regional cerebral blood flow (CBF) as a surrogate marker for neural function. This article reviews the biophysical and physiological bases of fMRI and its applications to the clinical neurosciences, with particular attention to potential challenges of fMRI under pathophysiological conditions. Carefully controlled prospective evaluation of clinical fMRI in its various potential applications will be required for fMRI to be validated as a clinically useful tool. Because the technology for fMRI is widely available, its impact could be substantial.

The past few years have seen the elucidation of several neurological diseases caused by inherited mutations of ion channels. In contrast to many other types of genetic disorders, the “channelopathies” can be studied with high precision by applying electrophysiological methods. This review evaluates the success of this approach in explaining the mechanisms of two forms of episodic ataxia that are known to be caused by mutations of ion channels: episodic ataxia type 1 (EA1, caused by K⁺ channel mutations) and episodic ataxia type 2 (EA2, caused by Ca²⁺ channel mutations). Although both of these disorders are rare, they raise many important questions about the roles of identified channels in brain function. Indeed, a resolution of the mechanisms by which both diseases occur will represent a major milestone in understanding diseases of the CNS, in addition to opening the way to novel possible treatments.