Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy for treatment-resistant symptoms, and protection against relapse ...distinguish it from prior antidepressants. Its discovery emerged from a reconceptualization of the neurobiology of depression and, in turn, insights from the elaboration of its mechanisms of action inform studies of the pathophysiology of depression and related disorders. It has been 25 y since we first presented our ketamine findings in depression. Thus, it is timely for this review to consider what we have learned from studies of ketamine and to suggest future directions for the optimization of rapid-acting antidepressant treatment.
Background Despite recent interest in glycogen synthase kinase-3β (GSK-3β) as a target for the treatment of mood disorders, there has been very little work related to these illnesses on the upstream ...signaling molecules that regulate this kinase as well as downstream targets. Methods With a focused microarray approach we examined the influence of different classes of antidepressants on Wnt signaling that controls GSK-3β activity as well as the transcription factors that contribute to the actions of GSK-3β. Results The results demonstrate that Wnt2 is a common target of different classes of antidepressants and also show differential regulation of Wnt-GSK-3β signaling genes. Increased expression and function of Wnt2 was confirmed by secondary measures. Moreover, with a viral vector approach we demonstrate that increased expression of Wnt2 in the hippocampus is sufficient to produce antidepressant-like behavioral actions in well-established models of depression and treatment response. Conclusions These findings demonstrate that Wnt2 expression and signaling is a common target of antidepressants and that increased Wnt2 is sufficient to produce antidepressant effects.
Stress is the response of an organism to demands for change, yet excessive or chronic stress contributes to nearly all psychiatric disorders. The advent of high-throughput transcriptomic methods such ...as single cell RNA sequencing poses new opportunities to understand the neurobiology of stress, yet substantial barriers to understanding stress remain. Stress adaptation is an organismal survival mechanism conserved across all organisms, yet there is an infinity of potential stressful experiences. Unraveling shared and separate transcriptional programs for adapting to stressful experience remains a challenge, despite methodological and analytic advances. Here we review the state of the field focusing on the technologies used to study the transcriptome for the stress neurobiologist, and also attempt to identify central questions about the heterogeneity of stress for those applying transcriptomic approaches. We further explore how postmortem transcriptome studies aided by preclinical animal models are converging on common molecular pathways for adaptation to aversive experience. Finally, we discuss approaches to integrate large genomic datasets with human neuroimaging and other datasets.
Abstract
Background
The molecular pathology underlying posttraumatic stress disorder (PTSD) remains unclear mainly due to a lack of human PTSD postmortem brain tissue. The orexigenic neuropeptides ...ghrelin, neuropeptide Y, and hypocretin were recently implicated in modulating negative affect. Drawing from the largest functional genomics study of human PTSD postmortem tissue, we investigated whether there were molecular changes of these and other appetitive molecules. Further, we explored the interaction between PTSD and body mass index (BMI) on gene expression.
Methods
We analyzed previously reported transcriptomic data from 4 prefrontal cortex regions from 52 individuals with PTSD and 46 matched neurotypical controls. We employed gene co-expression network analysis across the transcriptomes of these regions to uncover PTSD-specific networks containing orexigenic genes. We utilized Ingenuity Pathway Analysis software for pathway annotation. We identified differentially expressed genes (DEGs) among individuals with and without PTSD, stratified by sex and BMI.
Results
Three PTSD-associated networks (P < .01) contained genes in signaling families of appetitive molecules: 2 in females and 1 in all subjects. We uncovered DEGs (P < .05) between PTSD and control subjects stratified by sex and BMI with especially robust changes in males with PTSD with elevated vs normal BMI. Further, we identified putative upstream regulators (P < .05) driving these changes, many of which were enriched for involvement in inflammation.
Conclusions
PTSD-associated cortical transcriptomic modules contain transcripts of appetitive genes, and BMI further interacts with PTSD to impact expression. DEGs and inferred upstream regulators of these modules could represent targets for future pharmacotherapies for obesity in PTSD.
N-methyl-D-aspartate receptor (NMDAR) modulators have recently received increased attention as potential therapeutics for posttraumatic stress disorder (PTSD). Here, we tested a novel NMDAR-positive ...modulator, NYX-783, in the following two rodent models of PTSD: an auditory fear-conditioning model and a single-prolonged stress (SPS) model. We examined the ability of NYX-783 to reduce subsequent fear-based behaviors by measuring enhanced fear extinction and reduced spontaneous recovery (spontaneous return of fear) in male mice. NYX-783 administration significantly reduced spontaneous recovery in both PTSD models and enhanced fear extinction in the SPS model. Furthermore, NYX-783 increased the NMDA-induced inward currents of excitatory and inhibitory neurons in the infralimbic medial prefrontal cortex (IL mPFC) and that the GluN2B subunit of NMDARs on pyramidal neurons in the IL mPFC is required for its effect on spontaneous recovery. The downstream expression of brain-derived neurotrophic factor was required for NYX-783 to achieve its behavioral effect. These results elucidate the cellular targets of NYX-783 and the molecular mechanisms underlying the inhibition of spontaneous recovery. These preclinical findings support the hypothesis that NYX-783 may have therapeutic potential for PTSD treatment and may be particularly useful for inhibiting spontaneous recovery.
Suicide is a societal and public health concern of global scale. Identifying genetic risk factors for suicide attempt can characterize underlying biology and enable early interventions to prevent ...deaths. Recent studies have described common genetic variants for suicide-related behaviors. Here, we advance this search for genetic risk by analyzing the association between suicide attempt and uncommon variation exome-wide in a large, ancestrally diverse sample.
We sequenced whole genomes of 13,584 soldiers from the Army STARRS (Army Study to Assess Risk and Resilience in Servicemembers), including 979 individuals with a history of suicide attempt. Uncommon, nonsilent protein–coding variants were analyzed exome-wide for association with suicide attempt using gene-collapsed and single-variant analyses.
We identified 19 genes with variants enriched in individuals with history of suicide attempt, either through gene-collapsed or single-variant analysis (Bonferroni padjusted < .05). These genes were CIB2, MLF1, HERC1, YWHAE, RCN2, VWA5B1, ATAD3A, NACA, EP400, ZNF585A, LYST, RC3H2, PSD3, STARD9, SGMS1, ACTR6, RGS7BP, DIRAS2, and KRTAP10-1. Most genes had variants across multiple genomic ancestry groups. Seventeen of these genes were expressed in healthy brain tissue, with 9 genes expressed at the highest levels in the brain versus other tissues. Brains from individuals deceased from suicide aberrantly expressed RGS7BP (padjusted = .035) in addition to nominally significant genes including YWHAE and ACTR6, all of which have reported associations with other mental disorders.
These results advance the molecular characterization of suicide attempt behavior and support the utility of whole-genome sequencing for complementing the findings of genome-wide association studies in suicide research.
γ-aminobutyric acid (GABA) inhibitory interneurons play a key role in efferent and afferent control of principle neuron activity in the prefrontal cortex (PFC), thereby regulating signal integrity of ...cognitive and behavioral processes. Recent evidence suggests that specific subtypes of interneurons in the PFC mediate stress-induced depressive-like behaviors. Abnormalities of GABA interneurons, particularly the somatostatin (human, SST; mouse, Sst) subtype, have been reported in postmortem brains of depressed subjects and include sex differences that could explain the increased incidence of depression in women. Here, we analyze the transcriptional profiles and the effects of chronic stress in males vs. females on GABA interneuron subtypes in the PFC. Using Sst- and Parvalbumin-fluorescence tagged reporter mice and fluorescence-activated cell sorting (FACS) combined with RNA sequencing, we identify distinct transcriptome profiles for these interneuron subtypes in the medial PFC. Based on evidence that SST interneurons are altered in depression, we then determined the effects of chronic stress on this interneuron subtype. Chronic stress causes significant dysregulation of several key pathways, including sex-specific differences in the Sst interneuron profiles. The transcriptional pathways altered by chronic stress in males overlap with enriched pathways in non-stressed females. These changes occurred predominantly in decreased expression of elongation initiation factor 2 (EIF2) signaling, suggesting that dysfunction of the translational machinery of SST interneurons could be critical to the development of depressive-like behaviors in males. In addition, SST interneurons from females exposed to chronic stress show dysregulation of different, growth factor signaling pathways.
PDF
