TrkB-dependent regulation of molecular signaling across septal cell types.

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning, and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.

TrkB-dependent regulation of molecular signaling across septal cell types.

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.

A randomized controlled trial of cognitive remediation and d-cycloserine for individuals with bipolar disorder.

BACKGROUND: Cognitive remediation (CR) has shown significant promise in addressing the cognitive deficits that accompany serious mental illness. However, this intervention does not appear to completely ameliorate the cognitive deficits that accompany these illnesses. D-cycloserine (DCS), an NMDA receptor partial agonist, has been shown to enhance the therapeutic benefits of learning-based psychosocial interventions for psychiatric disorders. Thus, the goal of this study is to examine the utility of combining cognitive remediation and d-cycloserine in the treatment of cognitive deficits among individuals with bipolar disorder. METHODS/DESIGN: Approximately forty individuals with bipolar disorder will be recruited to participate in this study. Participants will be randomized to one of two study arms: CR + DCS or CR + placebo. The primary outcome for this study is change in cognitive functioning. We will also examine several secondary outcomes, including the rate of change of cognitive functioning, social functioning, and symptomatology. DISCUSSION: Cognitive deficits are a rate-limiting factor in functional recovery among individuals with bipolar disorder. Unfortunately, treatment options for these deficits are limited. The results of the proposed study may reveal a valuable intervention strategy (i.e., CR with concurrent DCS) to improve cognitive functioning among individuals with bipolar disorder. Ultimately, this treatment strategy may prove useful in addressing the cognitive deficits that are ubiquitous across serious mental illnesses. TRIAL REGISTRATION: ClinicalTrials.gov NCT01934972.