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...

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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.

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