Forniceal deep brain stimulation in a mouse model of Rett syndrome increases neurogenesis and hippocampal memory beyond the treatment period.

BACKGROUND: Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT. OBJECTIVES: To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice. METHODS: Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual and cued fear memory at different time points after DBS. We then examined neurogenesis, DGC apoptosis, and the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after DBS by immunohistochemistry. RESULTS: After two weeks of forniceal DBS, memory improvements lasted between 6 and 9 weeks. Repeating DBS every 6 weeks was sufficient to maintain the improvement. Forniceal DBS stimulated the birth of more MeCP2-positive than MeCP2-negative DGCs and had no effect on DGC survival. It also increased the expression of BDNF but not VEGF in the RTT mouse dentate gyrus. CONCLUSION: Improvements in learning and memory from forniceal DBS in RTT mice extends well beyond the treatment period and can be maintained by repeated DBS. Stimulation of BDNF expression correlates with improvements in hippocampal neurogenesis and memory benefits.

Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model.

Many neurodegenerative proteinopathies share a common pathogenic mechanism: the abnormal accumulation of disease-related proteins. As growing evidence indicates that reducing the steady-state levels of disease-causing proteins mitigates neurodegeneration in animal models, we developed a strategy to screen for genes that decrease the levels of tau, whose accumulation contributes to the pathology of both Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Integrating parallel cell-based and Drosophila genetic screens, we discovered that tau levels are regulated by Nuak1, an AMPK-related kinase. Nuak1 stabilizes tau by phosphorylation specifically at Ser356. Inhibition of Nuak1 in fruit flies suppressed neurodegeneration in tau-expressing Drosophila, and Nuak1 haploinsufficiency rescued the phenotypes of a tauopathy mouse model. These results demonstrate that decreasing total tau levels is a valid strategy for mitigating tau-related neurodegeneration and reveal Nuak1 to be a novel therapeutic entry point for tauopathies.

Effects of gastric cancer cells on the differentiation of Treg cells.

The aim of this study was evaluated the prevalence of Treg cells in peripheral blood in patients with gastric cancer, and investigate the effect of gastric cancer cells on their differentiation. ELISA was employed to assess the concentrations of TGF-ß and IL-10 in gastric cancer patients' serum. Then, mouse gastric cancer cells were co-cultured with T lymphocytes or T lymphocytes + anti-TGF-ß. Flow cytometric analysis and RT-PCR were then performed to detect Treg cells and TGF-ß and IL-10 expression in gastric cancer cells. Our data showed that the expression of TGF-ß and IL-10 in the patients with gastric cancer was increased compared to the case with healthy donors. The population of Treg cells and the expression levels of TGF-ß and IL-10 in the co-culture group were much higher than in the control group (18.6% vs 9.5%) (P<0.05). Moreover, the population of Treg cells and the expression levels of TGF-ß and IL-10 in the co-culture systerm were clearly decreased after addition of anti-TGF-ß (7.7% vs 19.6%) (P<0.01). In conclusion, gastric cancer cells may induce Treg cell differentiation through TGF-ß, and further promote immunosuppression.

Addictive nicotine alters local circuit inhibition during the induction of in vivo hippocampal synaptic potentiation.

The drug addiction process shares many commonalities with normal learning and memory. Addictive drugs subvert normal synaptic plasticity mechanisms, and the consequent synaptic changes underlie long-lasting modifications in behavior that accrue during the progression from drug use to addiction. Supporting this hypothesis, it was recently shown that nicotine administered to freely moving mice induces long-term synaptic potentiation of the perforant path connection to granule cells of the dentate gyrus. The perforant path carries place and spatial information that links the environment to drug taking. An example of that association is the nicotine-induced synaptic potentiation of the perforant path that was found to underlie nicotine-conditioned place preference. The present study examines the influence of nicotine over local GABAergic inhibition within the dentate gyrus during the drug-induced synaptic potentiation. In vivo recordings from freely moving mice suggested that both feedforward and feedback inhibition onto granules cells were diminished by nicotine during the induction of synaptic potentiation. In vitro brain slice studies indicated that nicotine altered local circuit inhibition within the dentate gyrus leading to disinhibition of granule cells. These changes in local inhibition contributed to nicotine-induced in vivo synaptic potentiation, thus, likely contributed to drug-associated memories. Through this learning process, environmental features become cues that motivate conditioned drug-seeking and drug-taking behaviors.

Dopamine enables in vivo synaptic plasticity associated with the addictive drug nicotine.

Addictive drugs induce a dopamine signal that contributes to the initiation of addiction, and the dopamine signal influences drug-associated memories that perpetuate drug use. The addiction process shares many commonalities with the synaptic plasticity mechanisms normally attributed to learning and memory. Environmental stimuli repeatedly linked to addictive drugs become learned associations, and those stimuli come to elicit memories or sensations that motivate continued drug use. Applying in vivo recording techniques to freely moving mice, we show that physiologically relevant concentrations of the addictive drug nicotine directly cause in vivo hippocampal synaptic potentiation of the kind that underlies learning and memory. The drug-induced long-term synaptic plasticity required a local hippocampal dopamine signal. Disrupting general dopamine signaling prevented the nicotine-induced synaptic plasticity and conditioned place preference. These results suggest that dopaminergic signaling serves as a functional label of salient events by enabling and scaling synaptic plasticity that underlies drug-induced associative memory.