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.

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With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.

In a research environment dominated by reductionist approaches to brain disease mechanisms, gene network analysis provides a complementary framework in which to tackle the complex dysregulations that occur in neuropsychiatric and other neurological disorders. Gene-gene expression correlations are a common source of molecular networks because they can be extracted from high-dimensional disease data and encapsulate the activity of multiple regulatory systems. However, the analysis of gene coexpression patterns is often treated as a mechanistic black box, in which looming “hub genes” direct cellular networks, and where other features are obscured. By examining the biophysical bases of coexpression and gene regulatory changes that occur in disease, recent studies suggest it is possible to use coexpression networks as a multi-omic screening procedure to generate novel hypotheses for disease mechanisms. Because technical processing steps can affect the outcome and interpretation of coexpression networks, we examine the assumptions and alternatives to common patterns of coexpression analysis and discuss additional topics such as acceptable datasets for coexpression analysis, the robust identification of modules, disease-related prioritization of genes and molecular systems and network meta-analysis. To accelerate coexpression research beyond modules and hubs, we highlight some emerging directions for coexpression network research that are especially relevant to complex brain disease, including the centrality-lethality relationship, integration with machine learning approaches and network pharmacology.

Objective The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cortex dysfunction is not known. Method Using polymerase chain reaction, we first assessed the degree to which BDNF controls mRNA expression (defined as BDNF dependency) of 15 genes relating to GABA and neuropeptide functions in the cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous [Bdnf +/−] mice and BDNF exon-IV knockout [Bdnf KIV] mice). Gene expression was then quantified in the subgenual anterior cingulate cortex of 51 postmortem subjects with major depressive disorder and comparison subjects (total subjects, N=102; 49% were women) and compared with previous amygdala results. Results Based on the results in Bdnf +/− and Bdnf KIV mice, genes were sorted into high, intermediate, and no BDNF dependency sets. In postmortem human subjects with major depression, BDNF receptor (TRKB) expression, but not BDNF, was reduced. Postmortem depressed subjects exhibited down-regulation in genes with high and intermediate BDNF dependency, including markers of dendritic targeting interneurons (SST, NPY, and CORT) and a GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB and GAD1). Changes were greater in men (potentially because of low baseline expression in women), displayed notable differences from prior amygdala results, and were not explained by demographic or clinical factors other than sex. Conclusions These parallel human/ mouse analyses provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in the subgenual anterior cingulate cortex in individuals with major depressive disorder, implicate dendritic targeting GABA neurons and GABA synthesis, and, together, suggest a common BDNF-/GABA-related pathology in major depression with sex- and brain region-specific features.

The functional integration of external and internal signals forms the basis of information processing and is essential for higher cognitive functions. This occurs in finely-tuned cortical microcircuits whose functions are balanced at the cellular level by excitatory glutamatergic pyramidal neurons and inhibitory γ-aminobutyric acid (GABA) interneurons. The balance of excitation and inhibition, from cellular processes to neural network activity, is characteristically disrupted in multiple neuropsychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BPD), anxiety disorders, and schizophrenia (SCZ). Specifically, nearly three decades of research demonstrate a role for reduced inhibitory GABA level and function across disorders. In MDD, recent evidence from human postmortem and animal studies suggests a selective vulnerability of GABAergic interneurons that co-express the neuropeptide somatostatin (“SST cells/interneurons”). Advances in cell type-specific molecular genetics have now helped to elucidate several important roles for SST interneurons in cortical processing (regulation of pyramidal cell excitatory input) and behavioral control (mood and cognition). Here, we review evidence for altered inhibitory function arising from GABAergic deficits across disorders, and specifically in MDD. We then focus on properties of the cortical microcircuit, wherein SST-positive GABA interneuron deficits may disrupt functioning in several ways. Finally, we discuss the putative origins of SST cell deficits, as informed by recent research, and implications for therapeutic approaches. We conclude that deficits in SST interneurons represent a contributing cellular pathology, and therefore a promising target for normalizing altered inhibitory function in MDD and other disorders with reduced SST cell and GABA functions.