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.

Follow-up T 1 -weighted 3D gradient-echo MRI (2.35 T) of murine brain in vivo (N ‫؍‬ 5) at 120 m 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 Progress in neurogenetics has renewed interest in imaging neuroscience because 1) it can improve our understanding of the structure and function of the central nervous system in the context of genetic information, and 2) it can be used to evaluate novel therapeutic interventions in active animals. In either case, gene technology has led to the use of an increasing number of mutant mice, which requires the use of in vivo assessments such as, for example, those offered by noninvasive MRI techniques. Several in vivo MRI studies of mouse brain have demonstrated potential for providing detailed morphologic insights (1-6). Nevertheless, the anatomic information obtainable is limited and a considerable number of abnormalities may still have to be verified by other methods because of their microscopic size, sparse distribution, and/or poor MRI detectability caused by subtle alterations of MR properties. Therefore, additional means of achieving soft-tissue contrast enhancement or MRI staining (7) by exogenous compounds are highly desirable.Because common MRI contrast agents consist of chelated paramagnetic ions, their systemic application does not lead to a penetration of the blood-brain barrier (BBB). Such contrast agents are safe for human studies and can be used clinically to detect disturbances of the BBB. The situation differs for free divalent metal ions, which exhibit variable degrees of neurotoxicity. In particular, high-resolution autoradiography has demonstrated that manganese accumulates in the olfactory bulb, olfactory nuclei, inferior colliculi, amygdala, thalamus, hippocampal formation, and cerebellum (8 -12). Upon bolus injection, Mn 2ϩ enters the brain across the capillary endothelium (13-15) and leads to biologic halflives of 51-74 days (9). In conjunction with its well-known capabilities as a paramagnetic MRI contrast agent that effectively reduces the T 1 relaxation time of accessible water protons (16), these data suggest that Mn 2ϩ is a good candidate for MRI staining of animal brain after systemic administration.Previous MRI studies of manganese in animal brain addressed its regional distribution and cerebral toxicity during an acute phase 3-22 hr after Mn 2ϩ exposure in rat brain (17) or in response to chronic poisoning (of several months duration) in rabbits and monkeys (18,19). In contrast to the autoradiography results, however, the MRI studies failed to report any signal enhancement in structures such as the olfactory bulb or hippocampal formation. Most likely, however, this observation can be ascribed to the limited spatial resolution available and ...

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. Magn Reson Med 53: 3-8, 2005.

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.

This work demonstrates technical approaches to high-quality magnetic resonance imaging (MRI) of small structures of the mouse brain in vivo. It turns out that excellent soft-tissue contrast requires the reduction of partial volume effects by using 3D MRI at high (isotropic) resolution with linear voxel dimensions of about 100-150 microm. The long T(2)* relaxation times at relatively low magnetic fields (2.35 T) offer the benefit of a small receiver bandwidth (increased signal-to-noise) at a moderate echo time which together with the small voxel size avoids visual susceptibility artifacts. For measuring times of 1-1.5 h both T(1)-weighted (FLASH) and T(2)-weighted (Fast Spin-Echo) 3D MRI acquisitions exhibit detailed anatomical insights in accordance with histological sections from a mouse brain atlas. Preliminary applications address the identification of neuroanatomical variations in different mouse strains and the use of Mn(2+) as a T(1) contrast agent for neuroaxonal tracing of fiber tracts within the mouse visual pathway.

The neuropeptide substance P and its receptor, the neurokinin 1 receptor (NK 1 R) have been proposed as possible targets for new antidepressant therapies. The present study investigated the effect of the NK 1 R antagonist L-760,735 and the tricyclic antidepressant clomipramine in the chronic psychosocial stress paradigm of adult male tree shrews. Animals were subjected to a 7-day period of psychosocial stress before the onset of daily oral administration of L-760,735 (10 mg kg −1 day −1 ) or clomipramine (50 mg kg −1 day −1 ). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy. Cell proliferation in the dentate gyrus and hippocampal volume were measured post mortem. Stress significantly decreased in vivo concentrations of N-acetyl-aspartate (−14%), creatine and phosphocreatine (−15%) and choline-containing compounds (−15%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (−45%), and hippocampal volume was decreased (−14%). The stress-induced changes of brain metabolites, hippocampal volume and dentate cytogenesis rate were prevented by concomitant drug administration. Elevated myoinositol concentrations after both treatments hint to an astrocytic enhancement. These results suggest that-despite a different pharmacological profile-the NK 1 R antagonist L-760,735, a member of a novel class of antidepressant drugs, has comparable neurobiological efficacy to tricyclic antidepressants such as clomipramine. Molecular Psychiatry (2002) 7, 933-941.

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