Brain serotonin (5-HT) has been implicated in a number of physiological processes and pathological conditions. These effects are mediated by at least 14 different 5-HT receptors. We have inactivated the gene encoding the 5-HT 1A receptor in mice and found that receptor-deficient animals have an increased tendency to avoid a novel and fearful environment and to escape a stressful situation, behaviors consistent with an increased anxiety and stress response. Based on the role of the 5-HT 1A receptor in the feedback regulation of the 5-HT system, we hypothesize that an increased serotonergic neurotransmission is responsible for the anxiety-like behavior of receptor-deficient animals. This view is consistent with earlier studies showing that pharmacological activation of the 5-HT system is anxiogenic in animal models and also in humans.Brain serotonin (5-HT) is implicated in the control of a wide variety of physiological processes such as nociception, cardiovascular function, and thermoregulation, as well as in different behavioral processes including feeding, aggression, and response to stress (reviewed in refs. 1-5). The 5-HT system also appears to be involved in the etiology of neuropsychiatric disorders such as depression and anxiety (reviewed in refs. 6 and 7). In recent years, our understanding of the physiological and pathological aspects of the 5-HT system has benefited from the identification, classification, and more recently the cloning of the 5-HT receptor subtypes (8). Among the receptor subtypes that have received the most attention is the 5-HT 1A receptor (5-HT 1A R). This was because of the availability of 5-HT 1A R agonists and the implication of the 5-HT 1A receptor in anxiety (6, 9).The 5-HT 1A R, like most of the 5-HT receptors, belongs to the superfamily of G-protein coupled receptors (10, 11). It is negatively coupled to adenyl cyclase. Brain 5-HT 1A R is located both pre-and postsynaptically. Presynaptic 5-HT 1A R is found mainly in the dorsal and median raphe nuclei. Activation of these receptors by agonists causes a reduction in the firing rate of serotonergic neurons (12-14) and leads to the suppression of 5-HT synthesis, 5-HT turnover, and 5-HT release in the diverse projection areas (15, 16). Postsynaptic 5-HT 1A R is found in limbic regions (such as hippocampus and septum) and in some cortical layers. As in the case of presynaptic receptors, activation of postsynaptic 5-HT 1A R is generally believed to induce a decrease in the firing rate of the postsynaptic cell (14).The 5-HT 1A R has been extensively studied by pharmacological methods. Activation of the receptor by agonists results in an anxiolytic effect (17, 18). Correlations were found among the time and dose dependency of the anxiolytic effect, the inhibition of serotonergic firing in the dorsal raphe nuclei, and the inhibition of 5-HT release after systemic administration of agonists (19,20). The 5-HT 1A R partial agonist buspirone and a series of congeners also produce this neurochemical effect and are used clinically for...

Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the postmortem brain of MDD subjects paired with matched controls (n=21 pairs). We focused on the lateral/basolateral/basomedian (LBNC) complex of the amygdala as a neural hub of mood regulation affected in MDD. Among the most robust findings were downregulated transcripts for genes coding for GABA interneuron-related peptides, including somatostatin (SST), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low BDNF. Changes were confirmed by quantitative PCR and not explained by demographic, technical or known clinical parameters. BDNF itself was significantly downregulated at the RNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile (including SST, NPY, TAC1, RGS4, CORT) is recapitulated by complementary patterns in mice with constitutive (BDNF-heterozygous) or activity-dependent (Exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low RNA/protein) and indirect (low BDNF-dependent gene pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression.

Defining anxiety- and depressive-like states in mice (“emotionality”) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would reduce the intrinsic variability of single tests and provide a robust characterization of the underlying “emotionality” of individual mouse, similarly as mood and related syndromes are defined in humans through various related symptoms over time. We describe the use of simple mathematical and integrative tools to help phenotype animals across related behavioral tests (syndrome diagnosis) and experiments (meta-analysis). We applied z-normalization across complementary measures of emotionality in different behavioral tests after unpredictable chronic mild stress (UCMS) or prolonged corticosterone exposure - two approaches to induce anxious-/depressive-like states in mice. Combining z-normalized test values, lowered the variance of emotionality measurement, enhanced the reliability of behavioral phenotyping, and increased analytical opportunities. Comparing integrated emotionality scores across studies revealed a robust sexual dimorphism in the vulnerability to develop high emotionality, manifested as higher UCMS-induced emotionality z-scores, but lower corticosterone-induced scores in females compared to males. Interestingly, the distribution of individual z-scores revealed a pattern of increased baseline emotionality in female mice, reminiscent of what is observed in humans. Together, we show that the z-scoring method yields robust measures of emotionality across complementary tests for individual mice and experimental groups, hence facilitating the comparison across studies and refining the translational applicability of these models.