ProBDNF Dependence of LTD and Fear Extinction Learning in the Amygdala of Adult Mice.

Neurotrophins are secreted proteins that control survival, differentiation, and synaptic plasticity. While mature neurotrophins regulate these functions via tyrosine kinase signaling (Trk), uncleaved pro-neurotrophins bind preferentially to the p75 neurotrophin receptor (p75NTR) and often exert opposite effects to those of mature neurotrophins. In the amygdala, brain-derived neurotrophic factor (BDNF) enables long-term potentiation as well as fear and fear extinction learning. In the present study, we focused on the impact of mature BDNF and proBDNF signaling on long-term depression (LTD) in the lateral amygdala (LA). Hence, we conducted extracellular field potential recordings in an in vitro slice preparation and recorded LTD in cortical and thalamic afferents to the LA. LTD was unchanged by acute block of BDNF/TrkB signaling. In contrast, LTD was inhibited by blocking p75NTR signaling, by disinhibition of the proteolytic cleavage of proBDNF into mature BDNF, and by preincubation with a function-blocking anti-proBDNF antibody. Since LTD-like processes in the amygdala are supposed to be related to fear extinction learning, we locally inhibited p75NTR signaling in the amygdala during or after fear extinction training, resulting in impaired fear extinction memory. Overall, these results suggest that in the amygdala proBDNF/p75NTR signaling plays a pivotal role in LTD and fear extinction learning.

Moderate differences in common feeding diets change lipid composition in the hippocampal dentate gyrus and affect spatial cognitive flexibility in male rats.

There is growing evidence that lipids play a fundamental role in neuronal plasticity and learning and memory. Effects of nutrition on brain lipid composition and neuronal functioning are known, but the feeding interventions are often severe and may not reflect nutritional effects below clinical relevance. Therefore, we tested two commercially available rat feeding diets with only moderate differences in the food compositions, a standard diet (gross energy metabolizable 12.8 MJ/kg) and a energy reduced diet (gross energy metabolizable 8.9 MJ/kg) on possible effects upon dentate gyrus lipid composition, spatial learning and memory in a water maze and corticosterone release (blood serum concentrations) in adult male rats. Rats were fed with the standard diet up to an age of 8 weeks. One group was further fed with the standard and another with the energy reduced diet until an age of 5 months. We did not found differences in serum corticosterone levels. We found group differences in a variety of lipids in the hippocampal dentate gyrus.. Most of the lipid levels were lower in energy reduced diets, namely glycerophosphoethanolamines, sphingomyelins and hexosyceramides, whereas some ceramides (Cer18:0 and Cer24:1) and glycerophosphocholines (PC34:3 and PC36:2) were upregulated compared to the standard diet group. The performance in a common reference memory water maze task was not different between groups, however during reversal learning (platform in a different position) after the initial training, the standard diet fed rats learned better and spatial memory was improved compared to the energy reduced diet group. Thus, moderate differences in feeding diets have effects specifically upon spatial cognitive flexibility. Possible relations between differences in lipid composition and cognitive flexibility are discussed.

Differential Effects of Novel Dopamine Reuptake Inhibitors on Interference With Long-Term Social Memory in Mice.

In the laboratory, long-term social recognition memory (SRM) in mice is highly susceptible to proactive and retroactive interference. Here, we investigate the ability of novel designed dopamine (DA) re-uptake inhibitors (rac-CE-123 and S-CE-123) to block retroactive and proactive interference, respectively. Our data show that administration of rac-CE-123 30 min before learning blocks retroactive interference that has been experimentally induced at 3 h, but not at 6 h, post-learning. In contrast, S-CE-123 treatment 30 min before learning blocked the induction of retroactive interference at 6 h, but not 3 h, post-learning. Administration of S-CE-123 failed to interfere with proactive interference at both 3 h and 6 h. Analysis of additional behavioral parameters collected during the memory task implies that the effects of the new DA re-uptake inhibitors on retroactive and proactive interference cannot easily be explained by non-specific effects on the animals' general social behavior. Furthermore, we assessed the mechanisms of action of drugs using intracerebral in vivo-microdialysis technique. The results revealed that administration of rac-CE-123 and S-CE-123 dose-dependently increased DA release within the nucleus accumbens of freely behaving mice. Thus, the data from the present study suggests that the DA re-uptake inhibitors tested protect the consolidation of long-term social memory against interference for defined durations after learning. In addition, the data implies that DA signaling in distinct brain areas including the nucleus accumbens is involved in the consolidation of SRM in laboratory mice.

Role of the normal gut microbiota.

Relation between the gut microbiota and human health is being increasingly recognised. It is now well established that a healthy gut flora is largely responsible for overall health of the host. The normal human gut microbiota comprises of two major phyla, namely Bacteroidetes and Firmicutes. Though the gut microbiota in an infant appears haphazard, it starts resembling the adult flora by the age of 3 years. Nevertheless, there exist temporal and spatial variations in the microbial distribution from esophagus to the rectum all along the individual's life span. Developments in genome sequencing technologies and bioinformatics have now enabled scientists to study these microorganisms and their function and microbe-host interactions in an elaborate manner both in health and disease. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Several factors play a role in shaping the normal gut microbiota. They include (1) the mode of delivery (vaginal or caesarean); (2) diet during infancy (breast milk or formula feeds) and adulthood (vegan based or meat based); and (3) use of antibiotics or antibiotic like molecules that are derived from the environment or the gut commensal community. A major concern of antibiotic use is the long-term alteration of the normal healthy gut microbiota and horizontal transfer of resistance genes that could result in reservoir of organisms with a multidrug resistant gene pool.

CTR1 silencing inhibits angiogenesis by limiting copper entry into endothelial cells.

Increased levels of intracellular copper stimulate angiogenesis in human umbilical vein endothelial cells (HUVECs). Copper transporter 1 (CTR1) is a copper importer present in the cell membrane and plays a major role in copper transport. In this study, three siRNAs targeting CTR1 mRNA were designed and screened for gene silencing. HUVECs when exposed to 100 µM copper showed 3 fold increased proliferation, migration by 1.8-fold and tube formation by 1.8-fold. One of the designed CTR1 siRNA (si 1) at 10 nM concentration decreased proliferation by 2.5-fold, migration by 4-fold and tube formation by 2.8-fold. Rabbit corneal packet assay also showed considerable decrease in matrigel induced blood vessel formation by si 1 when compared to untreated control. The designed si 1 when topically applied inhibited angiogenesis. This can be further developed for therapeutic application.