Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus, and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

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Background and Purpose Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor (BDNF) stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B (TrkB) and p75 neurotrophin (p75NTR) receptors. However, BDNF is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets TrkB would promote neurogenesis and functional recovery after stroke. Methods Four-month-old mice were trained on motor tasks prior to stroke. After stroke, functional test results were used to randomize mice into two equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for ten weeks. Results LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation. Conclusion A small molecule agonist of TrkB improves functional recovery from stroke and increases neurogenesis when administered beginning three days after stroke. These findings provide proof-of-concept that targeting of TrkB alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as “pro-recovery” therapeutic agents for stroke.

In male golden hamsters (Mesocricetus auratus), attack frequency decreases during puberty. As serotonin inhibits offensive responses in adult hamsters, it is hypothesized that the serotonin system becomes upregulated in the hypothalamus during puberty. This hypothesis was tested through acute treatment with fluoxetine, a serotonin reuptake inhibitor, as well as through analysis of serotonin innervation in specific brain areas. In adults, fluoxetine treatment inhibited aggressive behavior. In juveniles, high doses of fluoxetine only reduced offensive responses (i.e., frequency and repetition of attacks), whereas low doses enhanced them. Juveniles also showed a dose-specific maturation of attack targets. In addition, the density of serotonin innervation of the hypothalamus was 20% higher in adult hamsters compared with juveniles. On the basis of these data, it is proposed that the developing serotonergic system shapes the development of offensive behaviors in male golden hamsters.

In hamsters, the maturation of aggression during puberty is associated with a gradual reduction of offensive responses. The purpose of this study was to analyze the changes during this decrease to provide an enhanced description of the behavior. During early puberty, play-fighting is characterized by long and continuous contact duration throughout the encounter and repetitive attacks within bouts of agonistic interaction. By mid-puberty, adult patterns of offensive behavior emerge. Contact time becomes shorter in duration and shifts to the beginning of the test, while attacks become less repetitive per bout. In late puberty, animals show an enhanced efficiency of behavior, as indicated by an increased percentage of attacks followed by bites. This study provides a better understanding of the development of aggression by characterizing the differences between juvenile play-fighting and adult aggression and the process of the maturation of aggression. ß 2006 Wiley Periodicals, Inc. Dev Psychobiol 49: 87-97, 2007.