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Posttraumatic stress disorder (PTSD) is a debilitating neuropsychiatric disease that is highly comorbid with major depressive disorder (MDD) and bipolar disorder. The overlap in symptoms is hypothesized to stem from partially shared genetics and underlying neurobiological mechanisms. To delineate conservation between transcriptional patterns across PTSD and MDD, the authors examined gene expression in the human cortex and amygdala in these disorders.RNA sequencing was performed in the postmortem brain of two prefrontal cortex regions and two amygdala regions from donors diagnosed with PTSD (N=107) or MDD (N=109) as well as from neurotypical donors (N=109).The authors identified a limited number of differentially expressed genes (DEGs) specific to PTSD, with nearly all mapping to cortical versus amygdala regions. PTSD-specific DEGs were enriched in gene sets associated with downregulated immune-related pathways and microglia as well as with subpopulations of GABAergic inhibitory neurons. While a greater number of DEGs associated with MDD were identified, most overlapped with PTSD, and only a few were MDD specific. The authors used weighted gene coexpression network analysis as an orthogonal approach to confirm the observed cellular and molecular associations.These findings provide supporting evidence for involvement of decreased immune signaling and neuroinflammation in MDD and PTSD pathophysiology, and extend evidence that GABAergic neurons have functional significance in PTSD.

Background: The lateral septum (LS) is a critical social behavior node. The LS is activated by social novelty, and perturbing LS activity impairs social recognition. However, the neural circuits and cell signaling pathways that converge on the LS to mediate this behavior aren9t known. We identify brain-derived neurotrophic factor (BDNF) in projection neurons from the basolateral amgydala (BLA) to the LS, and tropomyosin kinase B receptor (TrkB) signaling in LS neurons, as required for social novelty recognition. Methods: We used single-molecule fluorescent in-situ hybridization to quantify Ntrk2 expression in LS. Viral transgenesis was used to induce cre-recombinase mediated TrkB knockdown in LS to evaluate impact on social recognition behavior, and social novelty-induced c-Fos expression in the LS. We used viral approaches for projection-specific ablation and BDNF-depletion in BLA-LS projection neurons to assess the role of this circuit in social recognition behavior. Results: The majority of GABAergic neurons in LS express TrkB. TrkB knockdown in LS abolishes social novelty recognition, and decreases LS activation in response to social novelty. Selectively ablating BLA-LS projection neurons abolishes social novelty recognition behavior, an effect that is phenocopied by depleting BDNF in this circuit. Conclusions: BLA-LS projection neurons depend on BDNF expression to regulate social recognition in the mouse. Within the LS, neurons require intact TrkB receptor signaling to mediate this behavior.

Background Calcium imaging is a powerful technique for recording cellular activity across large populations of neurons. However, analysis methods capable of single-cell resolution in cultured neurons, especially for cultures derived from human induced pluripotent stem cells (hiPSCs), are lacking. Existing methods lack scalability to accommodate high-throughput comparisons between multiple lines, across developmental timepoints, or across pharmacological manipulations. Results To address this need we developed CaPTure, a scalable, automated Ca2+ imaging analysis pipeline (https://github.com/LieberInstitute/CaPTure). CaPTuredetects neurons, classifies and quantifies spontaneous activity, quantifies synchrony metrics, and generates cell- and network-specific metrics that facilitate phenotypic discovery. The method is compatible with parallel processing on computing clusters without requiring significant user input or parameter modification. Conclusion CaPTure allows for rapid assessment of neuronal activity in cultured cells at cellular resolution, rendering it amenable to high-throughput screening and phenotypic discovery. The platform can be applied to both human- and rodent-derived neurons and is compatible with many imaging systems.

Calcium imaging is a powerful technique for recording cellular activity across large populations of neurons. However, analysis methods capable of single-cell resolution in cultured neurons, especially for cultures derived from human induced pluripotent stem cells (hiPSCs), are lacking. Existing methods lack scalability to accommodate high-throughput comparisons between multiple lines, across developmental timepoints, or across pharmacological manipulations.To address this need we developed CaPTure, a scalable, automated CaCaPTure allows for rapid assessment of neuronal activity in cultured cells at cellular resolution, rendering it amenable to high-throughput screening and phenotypic discovery. The platform can be applied to both human- and rodent-derived neurons and is compatible with many imaging systems.

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric disease with a projected lifetime risk of 8.7%. PTSD is highly comorbid with depressive disorders including major depressive disorder (MDD) and bipolar disorder (BD). It is hypothesized that the overlap in symptoms stems from partially shared underlying neurobiological mechanisms. To better understand shared and unique transcriptional patterns of PTSD and MDD we performed RNA-sequencing in the postmortem brain of two prefrontal cortex (PFC) regions and two amygdala (AMY) regions, from neurotypical donors (N=109) as well as donors with diagnoses of PTSD (N=107) or MDD (N=109) across 1285 RNA-seq samples. We identified a small number of differentially expressed genes (DEGs) specific to PTSD, mostly in the cortex compared to amygdala. PTSD-specific DEGs were preferentially enriched in cortistatin-expressing cells, a subpopulation of somatostatin interneurons. These PTSD DEGs also showed strong enrichment for gene sets associated with immune-related pathways and microglia, largely driven by decreased expression of these genes in PTSD donors. While we identified a greater number of DEGs for MDD, there were only a few that were specific to MDD as they showed high overlap with PTSD DEGs. Finally, we used weighted gene co-expression network analysis (WGCNA) as an orthogonal approach to confirm the observed cellular and molecular associations. These findings highlight the sub-population of cortistatin-expressing interneurons as having potential functional significance in PTSD and provide supporting evidence for dysregulated neuroinflammation and immune signaling in MDD and PTSD pathophysiology.