Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes.

Oligodendrocytes myelinate axons for rapid impulse conduction and contribute to normal axonal functions in the central nervous system. In multiple sclerosis, demyelination is caused by autoimmune attacks, but the role of oligodendroglial cells in disease progression and axon degeneration is unclear. Here we show that oligodendrocytes harbor peroxisomes whose function is essential for maintaining white matter tracts throughout adult life. By selectively inactivating the import factor PEX5 in myelinating glia, we generated mutant mice that developed normally, but within several months showed ataxia, tremor and premature death. Absence of functional peroxisomes from oligodendrocytes caused widespread axonal degeneration and progressive subcortical demyelination, but did not interfere with glial survival. Moreover, it caused a strong proinflammatory milieu and, unexpectedly, the infiltration of B and activated CD8+ T cells into brain lesions. We conclude that peroxisomes provide oligodendrocytes with an essential neuroprotective function against axon degeneration and neuroinflammation, which is relevant for human demyelinating diseases.

Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin.

In humans, neurotrauma is suspected to cause brain atrophy and accelerate slowly progressive neurodegenerative disorders, such as Alzheimer's disease or schizophrenia. However, a direct link between brain injury and subsequent delayed global neurodegeneration has remained elusive. Here we show that juvenile (4-week-old) mice that are given a discrete unilateral lesion of the parietal cortex, develop to adulthood without obvious clinical symptoms. However, when monitored 3 and 9 months after lesioning, using high-resolution three-dimensional MRI and behavioural testing, the same mice display global neurodegenerative changes. Surprisingly, erythropoietin, a haematopoietic growth factor with potent neuroprotective activity, prevents behavioural abnormalities, cognitive dysfunction and brain atrophy when given for 2 weeks after acute brain injury. This demonstrates that a localized brain lesion is a primary cause of delayed global neurodegeneration that can be efficiently counteracted by neuroprotection.

Use of phased array coils for a determination of absolute metabolite concentrations.

This work describes the use of phased array coils for a quantification of absolute metabolite concentrations. The method is demonstrated for single-voxel localized proton MRS of human brain with an eight-element receive-only head coil. It is based on the transmitter reference amplitude of the body coil used for RF transmission. A relative sensitivity of every element of the phased array coil is derived from a combination of two reference scans without water suppression that correspond to either the body coil in transmit-receive mode or the phased array coil in conjunction with body coil excitation. Experimental results were obtained at 2.9 T for both phantoms and 12 human subjects in different locations of gray and white matter. The data demonstrate that the procedure is technically robust and without a penalty in measuring time. Moreover, it takes full advantage of the signal-to-noise gain for quantitative proton MRS and may be extended to other phased array coils without the need for a recalibration.

In vivo 3D MRI of insect brain: cerebral development during metamorphosis of Manduca sexta.

High-resolution 3D MRI of male pupae of Manduca sexta was performed at 2.35 T in order to evaluate its potential for an in vivo characterization of insect brain during metamorphosis. T1-weighted 3D FLASH (TR/TE = 20/7.8 ms, 25 degrees flip angle) and T2-weighted 3D fast SE MRI data sets (TR/TEeff = 3000/100 ms) were acquired at different developmental stages with an isotropic resolution of 100 microm. Both T1- and T2-weighted 3D MRI allowed for the identification of cerebral structures such as the antennal nerve, antennal and optical lobe, and central brain. Pronounced developmental alterations of the morphology were observed during metamorphosis. The results demonstrate the feasibility of 3D MRI at nanoliter resolution to identify major brain systems of M. sexta and respective changes during pupal development from caterpillar to sphinx moth. Together with the use of suitable contrast agents, this approach may provide new ways for studying the axonal connectivity and neural function of the developing insect brain.

In vivo 3D MRI staining of the mouse hippocampal system using intracerebral injection of MnCl2.

The morphology and function of the hippocampal system of C57BL/6J mice (n = 8) was studied in vivo using T1-weighted 3D magnetic resonance imaging (MRI) (117 microm isotropic resolution) after bilateral injection of MnCl(2) (0.25 microl, 5 or 200 mM) into the posterior hippocampal formation. The neuronal uptake of the T1-shortening Mn(2+) ions resulted in a pronounced MRI signal enhancement within the CA3 subfield and dentate gyrus with milder increases in CA1 and subiculum. This finding is in line with differences in the excitability of hippocampal neurons previously reported using electrophysiologic recordings. The subsequent axonal transport of Mn(2+) highlighted the principal extrinsic projections from the posterior hippocampal formation via the fimbria and the precommissural fornix to the dorsal part of the lateral septal nucleus. A strong MRI signal enhancement was also observed in the ventral hippocampal commissure. A time-course analysis revealed unsaturated conditions of Mn(2+) accumulation at about 2 h after injection and optimal contrast-to-noise ratios at about 6 h after injection. The present results using Mn(2+)-enhanced 3D MRI open new ways for studying the role of the hippocampal system in specific aspects of learning and memory in normal and mutant mice.

Localized proton MRS of cerebral metabolite profiles in different mouse strains.

Localized proton MR spectroscopy (MRS) was used to quantify cerebral metabolite concentrations in NMRI (n = 8), BALB/c (n = 7), and C57BL/6 (n = 8) mice in vivo and 1 hr after global irreversible ischemia (2.35 T, STEAM, TR/TE/TM = 6000/20/10 ms, 4 x 3 x 4 mm(3) volume, corrections for cerebrospinal fluid). Anatomical MRI and proton MRS revealed significant differences of the C57BL/6 strain in comparison with both BALB/c and NMRI mice. While MRI volumetry yielded larger ventricular spaces of the C57BL/6 strain, proton MRS resulted in elevated concentrations of N-acetylaspartate (tNAA), creatine and phosphocreatine (tCr), choline-containing compounds (Cho), glucose (Glc), and lactate (Lac) relative to BALB/c mice and elevated Glc relative to NMRI mice. Apart from the expected decrease of Glc and increase of Lac 1 hr post mortem, C57BL/6 mice presented with significant reductions of tNAA, tCr, and Cho, whereas these metabolites remained unchanged in BALB/c and NMRI mice. The results support the hypothesis that the more pronounced vulnerability of C57BL/6 mice to brain ischemia is linked to strain-dependent differences of the cerebral energy metabolism.

In vivo 3D MRI staining of mouse brain after subcutaneous application of MnCl2.

Follow-up T(1)-weighted 3D gradient-echo MRI (2.35 T) of murine brain in vivo (N = 5) at 120 microm isotropic resolution revealed spatially distinct signal increases 6-48 hr after subcutaneous application of MnCl(2) (20 mg/kg). The effects result from a shortening of the water proton T(1) relaxation time due to the presence of unchelated paramagnetic Mn(2+) ions, which access the brain by systemic circulation and crossing of the blood-brain barrier (BBB). A pronounced Mn(2+)-induced signal enhancement was first seen in structures without a BBB, such as the choroid plexus, pituitary gland, and pineal gland. Within 24 hr after administration, Mn(2+) contrast highlighted the olfactory bulb, inferior colliculi, cerebellum, and the CA3 subfield of the hippocampus. The affinity of Mn(2+) to various brain systems suggests the neuronal uptake of Mn(2+) ions from the extracellular space and subsequent axonal transport. Thus, at least part of the Mn(2+) contrast reflects a functional brain response of behaving animals, for example, in the olfactory system. In vivo MRI staining of the brain by systemic administration of MnCl(2) may contribute to phenotyping mutant mice with morphologic and functional alterations of the central nervous system.