Curcuma longa Linn extract suppresses neuronal apoptosis induction by sevoflurane via activation of the ERK1/2 pathway

Purpose: To investigate Curcuma longa Linn against neuronal damage induced by exposure to sevoflurane during surgical procedures. Methods: A sealed box made of transparent glass was used for anaesthetic exposure of neurons. The neurons were exposed to Curcuma longa Linn at doses of 1.5, 3, 6 and 12 μM prior to viability assessment using MTT assay. The effect of Curcuma longa Linn treatment on protein expression was determined using western blotting. Results: Sevoflurane exposure led to significant and time-dependent reductions in neuronal proliferation, when compared to unexposed cells (p < 0.05). Curcuma longa Linn at doses of 1.5, 3, 6 and 12 μM significantly decreased sevoflurane-mediated neuronal apoptosis. It reduced cleaved caspase-3 and Bax levels in neurons. However, the Curcuma longa Linn-mediated inhibition of sevoflurane-induced neuronal apoptosis was significantly suppressed by VPC23019 (p < 0.05). The p- ERK1/2 level was dose-dependently up-regulated in neurons exposed to sevoflurane on treatment with Curcuma longa Linn. Moreover, VPC23019 reversed the upregulatory effect of Curcuma longa Linn on p-ERK1/2 expression in sevoflurane-exposed neurons (p < 0.05). Conclusion: Curcuma longa Linn reversed sevoflurane-induced neuronal apoptosis by elevating p- ERK1/2 expression. Therefore, Curcuma longa Linn exerts inhibitory effect on anaesthesia-induced apoptosis in neurons, and may be useful for the treatment of this condition.

Semaphorins in Adult Nervous System Plasticity and Disease

Semaphorins, originally discovered as guidance cues for developing axons, are involved in many processes that shape the nervous system during development, from neuronal proliferation and migration to neuritogenesis and synapse formation. Interestingly, the expression of many Semaphorins persists after development. For instance, Semaphorin 3A is a component of perineuronal nets, the extracellular matrix structures enwrapping certain types of neurons in the adult CNS, which contribute to the closure of the critical period for plasticity. Semaphorin 3G and 4C play a crucial role in the control of adult hippocampal connectivity and memory processes, and Semaphorin 5A and 7A regulate adult neurogenesis. This evidence points to a role of Semaphorins in the regulation of adult neuronal plasticity. In this review, we address the distribution of Semaphorins in the adult nervous system and we discuss their function in physiological and pathological processes.

Disrupted-in-schizophrenia 1 enhances the quality of circadian rhythm by stabilizing BMAL1

Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that has been implicated in multiple mental disorders. DISC1 is known to regulate neuronal proliferation, signaling, and intracellular calcium homeostasis, as well as neurodevelopment. Although DISC1 was linked to sleep-associated behaviors, whether DISC1 functions in the circadian rhythm has not been determined yet. In this work, we revealed that Disc1 expression exhibits daily oscillating pattern and is regulated by binding of circadian locomotor output cycles kaput (CLOCK) and Brain and muscle Arnt-like protein-1 (BMAL1) heterodimer to E-box sequences in its promoter. Interestingly, Disc1 deficiency increases the ubiquitination of BMAL1 and de-stabilizes it, thereby reducing its protein levels. DISC1 inhibits the activity of GSK3β, which promotes BMAL1 ubiquitination, suggesting that DISC1 regulates BMAL1 stability by inhibiting its ubiquitination. Moreover, Disc1-deficient cells and mice show reduced expression of other circadian genes. Finally, Disc1-LI (Disc1 knockout) mice exhibit damped circadian physiology and behaviors. Collectively, these findings demonstrate that the oscillation of DISC1 expression is under the control of CLOCK and BMAL1, and that DISC1 contributes to the core circadian system by regulating BMAL1 stability.

Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration

Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells play key roles in maintaining brain homeostasis and regulating brain immune responses. They continuously scan and sense the brain environment to detect any occurring changes. Upon detection of a signal related to physiological or pathological processes, the cells are activated and transform to an amoeboid-like phenotype, mounting adequate responses that range from phagocytosis to secretion of inflammatory and trophic factors. The overwhelming evidence suggests that microglia are crucially implicated in influencing neuronal proliferation and differentiation, as well as synaptic connections, and thereby cognitive and behavioral functions. Here, we review the role of microglia in adult neurogenesis under physiological conditions, and how this role is affected in neurodegenerative diseases.

Optical activation of TrkB receptors

Brain-derived neurotrophic factor (BDNF), via activation of tropomyosin receptor kinase B (TrkB), plays a critical role in neuronal proliferation, differentiation, survival, and death. Dysregulation of TrkB signaling is implicated in neurodegenerative disorders and cancers. Precise activation of TrkB receptors with spatial and temporal resolution is greatly desired to study the dynamic nature of TrkB signaling and its role in related diseases. Here we develop different optogenetic approaches that use light to activate TrkB receptors. Utilizing the photosensitive protein Arabidopsis thaliana cryptochrome 2 (CRY2), the light-inducible homo-interaction of the intracellular domain of TrkB (iTrkB) in the cytosol or on the plasma membrane is able to induce the activation of downstream MAPK/ERK and PI3K/Akt signaling as well as the neurite outgrowth of PC12 cells. Moreover, we prove that such strategies are generalizable to other optical homo-dimerizers by demonstrating the optical TrkB activation based on the light-oxygen-voltage domain of aureochrome 1 from Vaucheria frigida. The results open up new possibilities of many other optical platforms to activate TrkB receptors to fulfill customized needs. By comparing all the different strategies, we find that the CRY2-integrated approach to achieve light-induced cell membrane recruitment and homo-interaction of iTrkB is most efficient in activating TrkB receptors. The optogenetic strategies presented are promising tools to investigate BDNF/TrkB signaling with tight spatial and temporal control.

Long-lasting effects of transient, perinatal fluoxetine exposure on cell proliferation in the dentate gyrus of mice

In the adult mammalian brain, up-regulation of serotonin via the selective serotonin reuptake inhibitor fluoxetine increases hippocampal neurogenesis. However, research assessing the long-term effects of modulating serotonin during the developmental period on hippocampal neurogenesis, is sparse. Here we evaluated hippocampal neurogenesis early (postnatal day 12), and later in life (postnatal day 60), in the offspring of mouse dams that were administered fluoxetine in their drinking water from embryonic day 15 (E15) through postnatal day 12 (P12). Fluoxetine-exposed mice had significantly higher levels of neuronal proliferation at P12, and P60, despite cessation of fluoxetine on P12. These effects were limited to proliferation, as survival of postnatal-born hippocampal neurons was unaltered. Mice exposed to fluoxetine also showed significantly higher levels of cell death, suggesting that homeostatic mechanisms present within the hippocampus may limit integration of adult-born neurons into the existing neuronal network. These findings demonstrate modulation of serotonin during development may be sufficient to induce long-lasting changes in hippocampal neurogenesis.