Roles of white matter in central nervous system pathophysiologies

The phylogenetic enlargement of cerebral cortex culminating in the human brain imposed greater communication needs that have been met by the massive expansion of WM (white matter). Damage to WM alters brain function, and numerous neurological diseases feature WM involvement. In the current review, we discuss the major features of WM, the contributions of WM compromise to brain pathophysiology, and some of the mechanisms mediating WM injury. We will emphasize the newly appreciated importance of neurotransmitter signalling in WM, particularly glutamate and ATP signalling, to understanding both normal and abnormal brain functions. A deeper understanding of the mechanisms leading to WM damage will generate much-needed insights for developing therapies for acute and chronic diseases with WM involvement.     

Inflammation in central nervous system injury

Inflammation is a key component of host defence responses to peripheral inflammation and injury, but it is now also recognized as a major contributor to diverse, acute and chronic central nervous system (CNS) disorders. Expression of inflammatory mediators including complement, adhesion molecules, cyclooxygenase enzymes and their products and cytokines is increased in experimental and clinical neurodegenerative disease, and intervention studies in experimental animals suggest that several of these factors contribute directly to neuronal injury. Most notably, specific cytokines, such as interleukin-1 (IL-1), have been implicated heavily in acute neurodegeneration, such as stroke and head injury. In spite of their diverse presentation, common inflammatory mechanisms may contribute to many neurodegenerative disorders and in some (e.g. multiple sclerosis) inflammatory modulators are in clinical use. Inflammation may have beneficial as well as detrimental actions in the CNS, particularly in repair and recovery. Nevertheless, several anti-inflammatory targets have been identified as putative treatments for CNS disorders, initially in acute conditions, but which may also be appropriate to chronic neurodegenerative conditions.     

Fast axonal transport in central nervous system and peripheral nervous system axons following axotomy

After axotomy, changes in the composition of fast axonally transported proteins ( FTP ) within the peripheral nervous system (PNS) axons have been reported. The most significant and reproducible changes involved polypeptides found within the molecular weight range of 31.0 to 14.5 kilodaltons ( Bisby , 1980). We wished to determine whether similar changes following axotomy occur in axons of the central nervous system (CNS). Intracranial axotomy of the left optic tract was performed stereotaxically in rats. Six days post axotomy 50 muCi 35[S]-methionine was injected into the vitreous body of both eyes. FTP were isolated within the optic nerves 2 h after isotope injection. The nerve segments were processed for SDS-PAGE, fluorography, and compared to similarly prepared fluorographs of normal and eight day post-axotomy sciatic nerve segments. The labelling of 5 major polypeptide bands (S1, MW congruent to 28,000; S2a , MW congruent to 25,000; S2b , MW congruent to 23,000; T1, MW congruent to 20,200; and T2, MW congruent to 17,000) was studied by laser densitometry. Band S2b showed a highly significant (p less than 0.001) increase in concentration, while bands S1 and T1 demonstrated highly significant decreases in concentration following axotomy of the sciatic nerve. In contrast, after axotomy of the retinal ganglion cell axons the only significant change was a decrease (p less than 0.05) in T1. We suggest that failure of CNS axons to respond similarly to PNS axons following axotomy may be related to the failure of CNS axons to regenerate.     

Extracellular regulators of axonal growth in the adult central nervous system

Robust axonal growth is required during development to establish neuronal connectivity. However, stable fibre patterns are necessary to maintain adult mammalian central nervous system (CNS) function. After adult CNS injury, factors that maintain axonal stability limit the recovery of function. Extracellular molecules play an important role in preserving the stability of the adult CNS axons and in restricting recovery from pathological damage. Adult axonal growth inhibitors include a group of proteins on the oligodendrocyte, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein and ephrin-B3, which interact with axonal receptors, such as NgR1 and EphA4. Extracellular proteoglycans containing chondroitin sulphates also inhibit axonal sprouting in the adult CNS, particularly at the sites of astroglial scar formation. Therapeutic perturbations of these extracellular axonal growth inhibitors and their receptors or signalling mechanisms provide a degree of axonal sprouting and regeneration in the adult CNS. After CNS injury, such interventions support a partial return of neurological function.     

Integrins promote axonal regeneration after injury of the nervous system

Integrins are cell surface receptors that form the link between extracellular matrix molecules of the cell environment and internal cell signalling and the cytoskeleton. They are involved in several processes, e.g. adhesion and migration during development and repair. This review focuses on the role of integrins in axonal regeneration. Integrins participate in spontaneous axonal regeneration in the peripheral nervous system through binding to various ligands that either inhibit or enhance their activation and signalling. Integrin biology is more complex in the central nervous system. Integrins receptors are transported into growing axons during development, but selective polarised transport of integrins limits the regenerative response in adult neurons. Manipulation of integrins and related molecules to control their activation state and localisation within axons is a promising route towards stimulating effective regeneration in the central nervous system.     

Transgenic mouse model for central nervous system demyelination.

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.     

Several new aspects of bubble-induced central nervous system injury

Ischaemia is a major mechanism underlying central nervous system (c.n.s.) damage in decompression sickness. Some recent experimental observations on the effect of bubble-induced ischaemia on c.n.s. tissue sharpen and extend our understanding of the pathophysiology of decompression sickness. After bubble-induced brain ischaemia, a measurable increase in 111In-labelled leucocytes occurs in the injured hemisphere. By 4 h into the recovery period the cells are concentrated in zones of low blood flow, as measured by the [14C]iodoantipyrine technique. The presence of these cells during the critical early hours of c.n.s. ischaemia suggests that they may contribute to the evolution of neuronal damage. Oedema is often cited as the cause of clinical deterioration after c.n.s. ischaemia or trauma. Recent evidence indicates that the presence and degree of circumscribed brain oedema is not a good predictor of the amount of nerve cell recovery (by using cortical sensory evoked response) after bubble-induced brain ischaemia. This brings into question the role of circumscribed oedema of the c.n.s. in dysfunction of post-ischemic nerve cells.     

Neuroanatomical technique for studying long axonal projections in the central nervous system: combined axonal staining and pre-labeling in parasagittal gerbil brain slices

A method is described for studying the morphological features of extensive axonal projections within the central nervous system of the gerbil, Meriones anguiculatus. Potentially long descending axonal projections between the auditory thalamus and lower brainstem were used as a model. The inferior colliculus (IC) in the tectum was injected in vivo with a fluorescent retrograde tracer, Fluoro-Gold, to label cells in the medial geniculate body (MGB) that had descending projections to the IC, and cells in the superior olivary complex (SOC) that had ascending projections to the IC. Another fluorescent retrograde tracer, fast blue, was injected into the cochlea to label olivocochlear (OC) cells in the SOC. Inferomedially curved parasagittal slices containing ipsilateral auditory cell groups from the thalamus to the brainstem were cut and descending axons of the pre-labeled MGB cells were traced anterogradely with Biocytin. After visualizing histologically the injected Biocytin, discretely labeled IC-projecting axons of the MGB cells were traced including their collaterals that extended further into the SOC. In the SOC, these axons terminated on pre-labeled cells including OC cells. The combination of anterograde and retrograde tracing in the slice preparations described here demonstrated extensive descending axonal projections from the thalamus to their targets in the lower brainstem that had known ascending/descending projections within the auditory system.     

ADAMTS expression and function in central nervous system injury and disorders

The components of the adult extracellular matrix in the central nervous system form a lattice-like structure that is deposited as perineuronal nets, around axon initial segments and as synapse-associated matrix. An abundant component of this matrix is the lecticans, chondroitin sulfate-bearing proteoglycans that are the major substrate for several members of the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) family. Since lecticans are key regulators of neural plasticity, ADAMTS cleavage of lecticans would likely also contribute to neuroplasticity. Indeed, many studies have examined the neuroplastic contribution of the ADAMTSs to damage and recovery after injury and in central nervous system disease. Much of this data supports a role for the ADAMTSs in recovery and repair following spinal cord injury by stimulating axonal outgrowth after degradation of a glial scar and improving synaptic plasticity following seizure-induced neural damage in the brain. The action of the ADAMTSs in chronic diseases of the central nervous system appears to be more complex and less well-defined. Increasing evidence indicates that lecticans participate in synaptic plasticity in neurodegenerative disease states. It will be interesting to examine how ADAMTS expression and action would affect the progression of these diseases.     

Ephaptic coupling in white matter fibre bundles modulates axonal transmission delays

Axonal connections are widely regarded as faithful transmitters of neuronal signals with fixed delays. The reasoning behind this is that extracellular potentials caused by spikes travelling along axons are too small to have an effect on other axons. Here we devise a computational framework that allows us to study the effect of extracellular potentials generated by spike volleys in axonal fibre bundles on axonal transmission delays. We demonstrate that, although the extracellular potentials generated by single spikes are of the order of microvolts, the collective extracellular potential generated by spike volleys can reach several millivolts. As a consequence, the resulting depolarisation of the axonal membranes increases the velocity of spikes, and therefore reduces axonal delays between brain areas. Driving a neural mass model with such spike volleys, we further demonstrate that only ephaptic coupling can explain the reduction of stimulus latencies with increased stimulus intensities, as observed in many psychological experiments.