Normal aging of the brain differs from pathological conditions and is associated with increased risk for psychiatric and neurological disorders. In addition to its role in the etiology and treatment of mood disorders, altered serotonin (5-HT) signaling is considered a contributing factor to aging; however, no causative role has been identified in aging. We hypothesized that a deregulation of the 5-HT system would reveal its contribution to agerelated processes and investigated behavioral and molecular changes throughout adult life in mice lacking the regulatory presynaptic 5-HT 1B receptor (5-HT 1B R), a candidate gene for 5-HTmediated age-related functions. We show that the lack of 5-HT 1B R (Htr1b KO mice) induced an early age-related motor decline and resulted in decreased longevity. Analysis of life-long transcriptome changes revealed an early and global shift of the gene expression signature of aging in the brain of Htr1b KO mice. Moreover, molecular changes reached an apparent maximum effect at 18-months in Htr1b KO mice, corresponding to the onset of early death in that group. A comparative analysis with our previous characterization of aging in the human brain revealed a phylogenetic conservation of age-effect from mice to humans, and confirmed the early onset of molecular aging in Htr1b KO mice. Potential mechanisms appear independent of known central mechanisms (Bdnf, inflammation), but may include interactions with previously identified age-related systems (IGF-1, sirtuins). In summary, our findings suggest that the onset of age-related events can be influenced by altered 5-HT function, thus identifying 5-HT as a modulator of brain aging, and suggesting age-related consequences to chronic manipulation of 5-HT.

Mood disorders are influenced by genetic make-up and differentially affect men and women. The s/ l promoter polymorphism in the serotonin transporter (SERT) gene moderates both trait emotion and the vulnerability to develop depressive states in humans. Similarly, male mice lacking SERT (Knockout/KO) display an elevated emotionality phenotype. We now report that the SERT-KO phenotype is maintained throughout late-adulthood, and that female KO mice develop a larger emotionality phenotype with increasing age. Thus, to test the hypothesis that these findings reflected a putative sexual dimorphism in SERT-mediated modulation of emotionality, we submitted adult male and female wild-type, heterozygous (HZ) and KO mice to unpredictable chronic mild stress (UCMS) and assessed behavioral changes. In males, the elevated SERT-KO emotion-related behavior converged with other groups after UCMS. Conversely, female SERT-KO displayed a normal non-stressed baseline, but highest UCMS-induced emotionality. SERT-HZ displayed variable and intermediate phenotypes in both experiments. Thus, consistent results across different biological modalities (age, stress) revealed a high contribution of SERT genotype for baseline “trait” emotionality in males, and low contribution for female. In contrast, age-correlated and stress-induced behavioral changes resulted in a high SERT genotype-mediated behavioral variance in females, but low in males. This suggests that high emotionality states associated with low SERT were differentially achieved in males (high baseline/trait) compared to females (increased vulnerability to develop high emotionality). This sex-by-SERT double dissociation provides a framework to investigate molecular substrates of emotionality regulation in concert with serotonin function and may contribute to the sexually dimorphic features of mood disorders.

Gene expression profiling holds great promise for identifying molecular pathologies of central nervous system disorders. However, the analysis of brain tissue poses unique analytical challenges, as typical microarray signals represent averaged transcript levels across neuronal and glial cell populations. Here we have generated ratios of gene transcript levels between gray and adjacent white matter samples to estimate the relative cellular origins of expression. We show that incorporating these ratios into transcriptome analysis (i) provides new analytical perspectives, (ii) increases the potential for biological insight obtained from postmortem transcriptome studies, (iii) expands knowledge about glial and neuronal cellular programs and (iv) facilitates the generation of cell-type specific hypotheses. This approach represents a robust and cost-effective "add-on" to transcriptome analyses of the mammalian brain. As this approach can be applied post hoc, we provide tables of ratios for analysis of existing mouse and human brain datasets.

Background Evolutionarily conserved genes and their associated molecular pathways can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology. Methods Comparative gene array analysis in the amygdala and cingulate cortex between the serotonin transporter (SERT) knock-out mouse (SERTKO), a genetic animal model replicating features of human depression, and existing brain transcriptome data from postmortem tissue derived from clinically depressed humans, was conducted to identify gene with similar changes across species (i.e., conserved) that may help explain risk of depressive-like phenotypes. Human neuroimaging analysis was then used to investigate the impact of a common single-nucleotide polymorphism (rs1064448) in a gene with identified conserved human-mouse changes, adenylate cyclase 7 (ADCY7), on threat-associated amygdala reactivity in two large independent samples. Results Comparative analysis identified genes with conserved transcript changes in amygdala (n=29) and cingulate cortex (n=19), both critically involved in the generation and regulation of emotion. Selected results were confirmed by real-time quantitative PCR, including upregulation in the amygdala of transcripts for ADCY7, a gene previously implicated in human depression and associated with altered emotional responsiveness in mouse models. Translating these results back to living healthy human subjects, we show that genetic variation (rs1064448) in ADCY7 biases threat-related amygdala reactivity. Conclusions This converging cross-species evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression, together supporting a continuous dimensional approach to MDD and other affective disorders.

Our studies have demonstrated that altering serotonin (5-HT) signaling through the disruption of the 5-HT1B presynaptic autoreceptor can modulate the onset of selected age-related events in the central nervous system. A clear upregulation of sirtuin 5 (Sirt5) gene expression was identified in the brain of serotonin 1b receptor knock out (Htr1bKO) mice. Sirtuin genes are major cellular components of age-related pathways. The role of altered Sirt5 transcripts in the age-related phenotype in Htr1bKO mice is currently under investigation, including an early mechanism for altering the onset of age-related phenotypes, since Sirt5 transcript changes preceded the appearance of age-related behavioral and molecular changes. Representative color-coded photomicrographs of sirtuin 5 gene (Sirt5) 35 S in situ hybridization histochemistry at 3, 6, 18 and 24 months of age. Color barcode indicates increased signal intensity. For more information on this topic see the paper by Sibille et al. on pages 1042-1056.Molecular Psychiatry (2007) 12, 975