Investigating the interplay between early life stress, acute secondary pathogenesis, and chronic hippocampal impairments in young mice with traumatic brain injury

While Traumatic brain injury (TBI) is the leading cause of disability in children, it is unclear how early life stress (ELS) may act as a determinant of long-term recovery in brain-injured children. A murine model of ELS preceding TBI at postnatal day (P)21 addressed the following: regionally specific acute pathogenesis of the hippocampus after ELS+TBI, are these early changes predictive of hippocampal damage and impairment at adulthood. Males and females were exposed to ELS (P2-9) with the limited bedding nestlet (LBN) model, randomized to TBI or sham, and euthanized at P22 or adulthood. At P22, ELISAs revealed an upregulation of IL1B, IL-6, TNFα, and IFNγ in both sexes after injury. ELS+TBI elevated IL-1B, IL-10, TNFα, and IFNγ in males compared to TBI. Iba-1 and caspase-3 were evaluated in hippocampal subregions. While TBI increased microglial density in both sexes, ELS+TBI increased microglial density in male CA2 and CA3 but only in the CA3 in females compared to TBI. Quantification of caspase-3 revealed apoptosis in males and females after TBI. ELS + TBI increased apoptosis in CA1 and CA3 in males and females compared to TBI. Adulthood learning and memory were assessed with the NOR and Barnes Maze. Compared to TBI, ELS+TBI reduced novelty preference in females and increased path length to target in both sexes. Hippocampal neuron loss after ELS+TBI was evaluated at adulthood. TBI significantly reduced neurons in all subregions; ELS+TBI reduced neurons in the CA1 region in females only. These findings highlight hippocampal vulnerability after ELS+TBI and ELS prior to a TBI may enhance acute pathogenesis in males. Correlation matrices determined hippocampal acute pathogenesis is predictive of neuronal loss at adulthood and is associated with learning and memory impairments. Males and females were assessed for all outcomes. Both sexes showed similar vulnerability to secondary pathogenesis following TBI and adulthood impairments in learning and memory; males showed greater vulnerability to acute pathogenesis and females showed greater vulnerability to adulthood outcomes. These findings may advocate for opportunities to tailor therapies specific to each sex. Thus, developing pre-clinical biomarkers to predict long-term recovery may continue to bolster care management.Psycholog

Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis

Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABAA receptors (GABAARs). The impact of changes in steady state Cl− gradient is relatively straightforward to understand, but how dynamic interplay between Cl− influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl− load on a fast time scale, whereas Cl−extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl− gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABAAR-mediated inhibition, but increasing GABAAR input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl−. Furthermore, if spiking persisted despite the presence of GABAAR input, Cl− accumulation became accelerated because of the large Cl− driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl− and pH regulation. Several model predictions were tested and confirmed by [Cl−]i imaging experiments. Our study has thus uncovered how Cl− regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K− accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention

Supplementary Table 1 -Supplemental material for Patient-Reported Disease-Modifying Therapy Adherence in the Clinic: A Reliable Metric?

<p>Supplemental material, Supplementary Table 1 for Patient-Reported Disease-Modifying Therapy Adherence in the Clinic: A Reliable Metric? by Devon S Conway, Maria Cecilia Vieira, Nicolas R Thompson, Kaila N Parker, Xiangyi Meng and Robert J Fox in Multiple Sclerosis Journal – Experimental, Translational and Clinical</p

Hybrid flagellin as a T cell independent vaccine scaffold

BACKGROUND: To extend the potency of vaccines against infectious diseases, vaccines should be able to exploit multiple arms of the immune system. One component of the immune system that is under-used in vaccine design is the subset of B cells known to be capable of responding to repetitive antigenic epitopes and differentiate into plasma cells even in the absence of T cell help (T-independent, TI). RESULTS: To target vaccine responses from T-independent B cells, we reengineered a bacterial Flagellin (FliC) by replacing its exposed D3 domain with a viral envelope protein from Dengue virus (DENV2). The resulting hybrid FliC protein (hFliC) was able to form stable filaments decorated with conformationally intact DENV2 envelope domains. These filaments were not only capable of inducing a T cell-dependent (TD) humoral antibody response, but also significant IgM and IgG3 antibody response in a helper T cell repertoire-restricted transgenic mouse model. CONCLUSIONS: Our results provide proof-of-principle demonstration that a reengineered hybrid FliC could be used as a platform for polymeric subunit vaccines, enhancing T cell-dependent and possibly inducing T-independent antibody responses from B-1 B cells as well. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12896-015-0194-0) contains supplementary material, which is available to authorized users