Stress-induced structural remodeling in the adult hippocampus, involving debranching and shortening of dendrites and suppression of neurogenesis, provides a cellular basis for understanding the impairment of neural plasticity in the human hippocampus in depressive illness. Accordingly, reversal of structural remodeling may be a desirable goal for antidepressant therapy. The present study investigated the effect of tianeptine, a modified tricyclic antidepressant, in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri), a model with high validity for research on the pathophysiology of major depression. Animals were subjected to a 7-day period of psychosocial stress to elicit stress-induced endocrine and central nervous alterations before the onset of daily oral administration of tianeptine (50 mg͞kg). 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 was quantified by using BrdUrd immunohistochemistry, and hippocampal volume was measured post mortem. Chronic psychosocial stress significantly decreased in vivo concentrations of N-acetyl-aspartate (؊13%), creatine and phosphocreatine (؊15%), and choline-containing compounds (؊13%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (؊33%). These stress effects were prevented by the simultaneous administration of tianeptine yielding normal values. In stressed animals treated with tianeptine, hippocampal volume increased above the small decrease produced by stress alone. These findings provide a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in brain that have been reported in depressive disorders.neurogenesis ͉ proton magnetic resonance spectroscopy ͉ depression ͉ hippocampus ͉ tree shrew D epressive disorders are among the most common and lifethreatening illnesses and represent a significant public health problem (1). Despite extensive preclinical and clinical investigations, the exact neurobiological processes leading to depression and the mechanisms responsible for the therapeutic effects of antidepressant drugs are not completely understood (2).The hippocampus is one of the brain structures that has been extensively studied with regard to the actions of stress, depression and antidepressant actions (3, 4). Recent imaging studies in humans revealed that the hippocampus undergoes selective volume reduction in stress-related neuropsychiatric disorders such as recurrent depressive illness (5-7). Within the hippocampal formation, the dentate gyrus is one of the few brain structures where production of new neurons occurs even in the adult mammalian brain (8-10). Several experiential, neuroendocrine, and genetic factors that regulate neurogenesis in the adult dentate gyrus have been identified (11). One factor that potently suppresses adult granule cell prolife...

In vivo concentrations of cerebral metabolites were obtained by means of 52 single-voxel, localized proton magnetic resonance (MR) spectroscopic examinations of different regions of the brain performed in 26 healthy adults aged 21-32 years. The study was performed at 2.0 T with use of a circularly polarized head coil to ensure homogeneous radio-frequency excitation and signal reception. Proton MR spectra were obtained in the stimulated-echo acquisition mode under fully relaxed conditions (repetition time > or = 6,000 msec) and at short echo times (20 msec) to minimize corrections due to T1 and T2 attenuation and depict the spectra of metabolites with strongly coupled resonances. Absolute concentrations were obtained by means of calibration of resonance signal areas with those of pertinent metabolite solutions from separate studies and correction for coil loading and partial volume effects (eg, with perfused capillary networks and cerebrospinal fluid). The results provide a quantitative basis for studies of both normal human neurochemistry in vivo and metabolic alterations in diseases of the brain.

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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.

Hydrogen-1 MR spectroscopy enables identification of mild to moderate AD with a specificity and sensitivity that suggest clinical utility.

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This study describes the neuroaxonal tracing of the visual pathway in the living rat using high-resolution T 1 -weighted 3D gradient-echo MRI (195 ؋ 195 ؋ 125 In the visual system of mammals, which have eyes placed far laterally on the head, the great majority of the optic nerve fibers decussate at the chiasm (1). The fibers then enter the optic tract, which projects to three main subcortical targets (2,3): the lateral geniculate nucleus processes visual information that ultimately results in visual perception; the pretectal area of the midbrain uses retinal input to produce pupillary reflexes; and the superior colliculus generates eye movements (4). In addition, there is a direct retinohypothalamic projection to the suprachiasmatic nucleus (5,6) as the principal circadian pacemaker in mammals, which is responsible for the generation and regulation of rhythms in behavioral state, performance, hormonal secretion, and physiologic function (7-9).Conventional neuroanatomic techniques for tract tracing rely on sectioning of the brain and therefore preclude repeated measurements of the same animal. However, a method which is based on neuronal uptake and axonal transport of a suitable tracer compound can provide access to the neuroaxonal connectivity and, therefore, may develop into a functional tool that allows for multiple examinations of a specific tract in a living animal, e.g., at different stages after labeling or in response to various sensory or cognitive inputs. Considering this perspective, Pautler et al. (10) introduced manganese-enhanced MRI as an alternative method for neural tracing. The method utilizes free unchelated manganese ions (Mn 2ϩ ) which, analogous to calcium ions (Ca 2ϩ ), are taken up by neurons and transported along axons.Mn 2ϩ has long been used as an MRI contrast agent because the paramagnetic ion affects the longitudinal relaxation rate (1/T 1 ) of surrounding water protons (11). Provided that Mn 2ϩ remains compartmentalized after exogenous administration, it can be used for delineating targeted tissue elements. In fact, Sloot and Gramsbergen (12) provided evidence for the neuronal uptake and anterograde axonal transport of radioactive Mn 2ϩ after microinjection into the rat basal ganglia by revealing a regionspecific accumulation and retention for at least 72 h. Pautler et al. (10) demonstrated T 1 -weighted signal enhancement of the olfactory pathway after topical administration of MnCl 2 to the naris of mice as well as of the contralateral optic tract after intravitreal injection into a single eye. Extending neuroaxonal tract tracing in murine brain in situ, the purpose of the present work was to develop an in vivo protocol suitable for repeated studies of the visual pathway of behaving rodents using high-resolution 3D gradient-echo MRI with manganese-induced contrast.

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 ...