Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: hemispheric asymmetry and reversal by fluoxetine treatment.

Profound neuroplastic changes have been demonstrated in various limbic structures after chronic stress exposure and antidepressant treatment in animal models of mood disorders. Here, we examined in rats the effect of chronic social stress and concomitant antidepressant treatment on cell proliferation in the medial prefrontal cortex (mPFC). We also examined possible hemispheric differences. Animals were subjected to 5 weeks of daily social defeat by an aggressive conspecific and received concomitant, daily, oral fluoxetine (10 mg/kg) during the last 4 weeks. Bromodeoxyuridine (BrdU) labeling and quantitative stereological techniques were used to evaluate the treatment effects on proliferation and survival of newborn cells in limbic structures such as the mPFC and the hippocampal dentate gyrus, in comparison with nonlimbic structures such as the primary motor cortex and the subventricular zone. Phenotypic analysis showed that neurogenesis dominated the dentate gyrus, whereas in the mPFC most newborn cells were glia, with smaller numbers of endothelial cells. Chronic stress significantly suppressed cytogenesis in the mPFC and neurogenesis in the dentate gyrus, but had minor effect in nonlimbic structures. Fluoxetine treatment counteracted the inhibitory effect of stress. Hemispheric comparison revealed that the rate of cytogenesis was significantly higher in the left mPFC of control animals, whereas stress inverted this asymmetry, yielding a significantly higher incidence of newborn cells in the right mPFC. Fluoxetine treatment abolished hemispheric asymmetry in both control and stressed animals. These pronounced changes in gliogenesis after chronic stress exposure may relate to the abnormalities of glial cell numbers reported in the frontolimbic areas of depressed patients.

Morphology of pyramidal neurons in the rat prefrontal cortex: lateralized dendritic remodeling by chronic stress.

The prefrontal cortex (PFC) plays an important role in the stress response. We filled pyramidal neurons in PFC layer III with neurobiotin and analyzed dendrites in rats submitted to chronic restraint stress and in controls. In the right prelimbic cortex (PL) of controls, apical and distal dendrites were longer than in the left PL. Stress reduced the total length of apical dendrites in right PL and abolished the hemispheric difference. In right infralimbic cortex (IL) of controls, proximal apical dendrites were longer than in left IL, and stress eliminated this hemispheric difference. No hemispheric difference was detected in anterior cingulate cortex (ACx) of controls, but stress reduced apical dendritic length in left ACx. These data demonstrate interhemispheric differences in the morphology of pyramidal neurons in PL and IL of control rats and selective effects of stress on the right hemisphere. In contrast, stress reduced dendritic length in the left ACx.

Aging is accompanied by a subfield-specific reduction of serotonergic fibers in the tree shrew hippocampal formation.

The hippocampal formation is a crucial structure for learning and memory, and serotonin together with other neurotransmitters is essential in these processes. Although the effects of aging on various neurotransmitter systems in the hippocampus have been extensively investigated, it is not entirely clear whether or how the hippocampal serotonergic innervation changes during aging. Rat studies, which have mostly focused on aging-related changes in the dentate gyrus, have implied a loss of hippocampal serotonergic fibers. We used the tree shrew (Tupaia belangeri), an intermediate between insectivores and primates, as a model of aging. We applied immunocytochemistry with an antibody against serotonin to assess serotonergic fiber densities in the various hippocampal subfields of adult (0.9-1.3 years) and old (5-7 years) tree shrews. Our results have revealed a reduction of serotonergic fiber densities in the stratum radiatum of CA1 and CA3, and in the stratum oriens of CA3. A partial depletion of serotonin in the hippocampal formation, as can be expected from our current observations, will probably have an impact on the functioning of hippocampal principal neurons. Our findings also indicate that the rat and the tree shrew hippocampal serotonergic innervation show some variations that seem to be differentially affected during aging.

Preservation of hippocampal neuron numbers and hippocampal subfield volumes in behaviorally characterized aged tree shrews.

Aging is associated with a decreased ability to store and retrieve information. The hippocampal formation plays a critical role in such memory processes, and its integrity is affected during normal aging. We used tree shrews (Tupaia belangeri) as an animal model of aging, because in many characteristics, tree shrews are closer to primates than they are to rodents. Young and aged male tree shrews performed a holeboard spatial memory task, which permits assessment of reference and working memory. Upon completion of the behavioral measurements, we carried out modified stereological analyses of neuronal numbers in various subdivisions of the hippocampus and used the Cavalieri method to calculate the volumes of these subfields. Results showed that the working memory of aged tree shrews was significantly impaired compared with that of young animals, whereas the hippocampus-dependent reference memory remained unchanged by aging. Estimation of the number of neurons revealed preserved neuron numbers in the subiculum, in the subregions CA1, CA2, CA3, and in the hilus of the dentate gyrus. Volume measurements showed no aging-related changes in the volume of any of these hippocampal subregions, or in the molecular and granule cell layers of the dentate gyrus of tree shrews. We conclude that the observed changes in memory performance in aging tree shrews are not accompanied by observable reductions of hippocampal neuron numbers or hippocampal volume, rather, the changes in memory performance are more likely the result of modified subcellular mechanisms that are affected by the aging process.

A cytoarchitectonic study of the hippocampal formation of the tree shrew (Tupaia belangeri).

Tree shrews constitute an interesting animal model to study the impact of stress or aging on the hippocampal formation, a brain structure known to be affected under such environmental or internal influences. To perform detailed investigations of the hippocampal formation, adequate knowledge of its anatomy should be present. Until now, the hippocampal formation of the tree shrew has not yet been studied extensively. The main objective of this study, therefore, was to describe the subfield boundaries in various levels of the dorsoventral hippocampal axis of the tree shrew (Tupaia belangeri) in detail. The secondary aim was to clarify whether a separate CA2 field can actually be distinguished in the tree shrew hippocampus, a fact that was denied in former reports. In addition, we aimed at investigating whether or not a CA4 subfield can be identified in the tree shrew's hippocampus. The immunocytochemical distribution of microtubule-associated protein 2 and the calcium-binding proteins, parvalbumin and calbindin, and the characteristics of Nissl staining in adjacent sections were compared. Because of the rather dorsoventral orientation of the long hippocampal axis in tree shrews, staining patterns were analyzed mainly in horizontal sections. The subiculum and the hippocampal CA1 and CA3 areas were easily identified. Moreover, we were able to demonstrate the existence of a distinct CA2 subfield in the tree shrew's Ammon's horn, contrary to previous reports. However, our results indicate that a CA4 field in the tree shrew hippocampal formation cannot be identified with the methods that we used. Therefore, supposed CA4 pyramidal neurons should be included into the CA3 field.

Preservation of hippocampal neuron numbers in aged rhesus monkeys.

To investigate whether or not aging of nonhuman primates is accompanied by a region-specific neuron loss in the hippocampal formation, we used the optical fractionator technique to obtain stereological estimates of unilateral neuron numbers of the hippocampi of eight young (0-4 years) and five aged (18-31 years) male rhesus monkeys (Macaca mulatta). Our results show a preservation of neurons (mean x 10 (3)+/-S.D.x10(3)) in the subiculum (young=588+/-124, aged=612+/-207), CA1 (young=1051+/-249, aged=1318+/-311), CA2 (young=100+/-18, aged=113+/-12), CA3 (young=478+/-125, aged=509+/-139), hilus (young=337+/-115, aged=394+/-90), and dentate gyrus (young=5550+/-1725, aged=7799+/-2087) of the hippocampal formation. These results confirm a previous stereological study in rhesus monkeys, but are in conflict with data for humans, showing age-dependent region-specific alterations in the hippocampal formation.