Kynurenine pathway and white matter microstructure in bipolar disorder.

Decreased availability of serotonin in the central nervous system has been suggested to be a central factor in the pathogenesis of depression. Activation of indoleamine 2-3 dioxygenase following a pro-inflammatory state could reduce the amount of tryptophan converted to serotonin and increase the production of tryptophan catabolites such as kynurenic acid, an antagonist of ionotropic excitatory aminoacid receptors, whose levels are reduced in bipolar disorder. Abnormalities in white matter (WM) integrity have been widely reported in BD. We then hypothesized that metabolites involved in serotoninergic turnover in BD could influence DTI measures of WM microstructure. Peripheral levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxy-kynurenine, and 5-HIAA were analysed in 22 patients affected by BD and 15 healthy controls. WM microstructure was evaluated using diffusion tensor imaging and tract-based spatial statistics with threshold-free cluster enhancement only in bipolar patients. We observed that kynurenic acid and 5-HIAA were reduced in BD and associated with DTI measures of WM integrity in several association fibres: inferior and superior longitudinal fasciculus, cingulum bundle, corpus callosum, uncus, anterior thalamic radiation and corona radiata. Our results seem to suggest that higher levels of 5-HIAA, a measure of serotonin levels, and higher levels of kynurenic acid, which protects from glutamate excitotoxicity, could exert a protective effect on WM microstructure. Reduced levels of these metabolites in BD thus seem to confirm a crucial role of serotonin turnover in BD pathophysiology.

Regulatory mechanisms of testosterone-stimulated song in the sensorimotor nucleus HVC of female songbirds.

BACKGROUND: In male birds, influence of the sex steroid hormone testosterone and its estrogenic metabolites on seasonal song behavior has been demonstrated for many species. In contrast, female song was only recently recognized to be widespread among songbird species, and to date, sex hormone effects on singing and brain regions controlling song development and production (song control nuclei) have been studied in females almost exclusively using domesticated canaries (Serinus canaria). However, domesticated female canaries hardly sing at all in normal circumstances and exhibit only very weak, if any, song seasonally under the natural photoperiod. By contrast, adult female European robins (Erithacus rubecula) routinely sing during the winter season, a time when they defend feeding territories and show elevated circulating testosterone levels. We therefore used wild female European robins captured in the fall to examine the effects of testosterone administration on song as well as on the anatomy and the transcriptome of the song control nucleus HVC (sic). The results obtained from female robins were compared to outcomes of a similar experiment done in female domesticated canaries. RESULTS: Testosterone treatment induced abundant song in female robins. Examination of HVC transcriptomes and histological analyses of song control nuclei showed testosterone-induced differentiation processes related to neuron growth and spacing, angiogenesis and neuron projection morphogenesis. Similar effects were found in female canaries treated with testosterone. In contrast, the expression of genes related to synaptic transmission was not enhanced in the HVC of testosterone treated female robins but was strongly up-regulated in female canaries. A comparison of the testosterone-stimulated transcriptomes indicated that brain-derived neurotrophic factor (BDNF) likely functions as a common mediator of the testosterone effects in HVC. CONCLUSIONS: Testosterone-induced singing of female robins correlated with cellular differentiation processes in the HVC that were partially similar to those seen in the HVC of testosterone-treated female canaries. Other modes of testosterone action, notably related to synaptic transmission, appeared to be regulated in a more species-specific manner in the female HVC. Divergent effects of testosterone on the HVC of different species might be related to differences between species in regulatory mechanisms of the singing behavior.