Neuroscience
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Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). ⋯ By contrast, maintaining pregnancy levels of estradiol and progesterone during 'postpartum' stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated 'postpartum' females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging 'synaptogenic hypothesis' of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness.
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Adolescence is a period of major brain white matter (WM) changes, and membrane lipid metabolism likely plays a critical role in brain WM myelination. Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential components of cell membranes including oligodendrocytes, and LC-PUFA release and turnover in membranes is regulated by phospholipase A2 enzymes. To investigate the role of membrane lipid metabolism in healthy WM myelination across adolescence, the present study examined the relationship between membrane LC-PUFA biostatus, phospholipase A2 activity, and brain WM microstructure in healthy subjects aged 9-20years (n=30). ⋯ These findings suggest that there may be optimal physiological inPLA2 activity levels associated with healthy WM myelination in late childhood and adolescence. Myelination may be mediated by cleavage of docosahexaenoic acid from membrane phospholipids by inPLA2. These findings have implications for our understanding of the role of LC-PUFA homeostasis in myelin-related neurodevelopmental disorders.
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Lipopolysaccharide (LPS) might affect the central nervous system by causing neuroinflammation, which subsequently leads to brain damage and dysfunction. In this study, we evaluated the role of nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation in long-term behavioral alterations of 8-week-old male C57BL/6 mice injected intraperitoneally with LPS (5mg/kg). At different time points after injection, we assessed locomotor function with a 24-point neurologic deficit scoring system and the rotarod test; assessed recognition memory with the novel object recognition test; and assessed emotional abnormality (anhedonia and behavioral despair) with the tail suspension test, forced swim test, and sucrose preference test. ⋯ We found that LPS-injected mice displayed long-term depression-like behaviors and recognition memory deficit; elevated expression of NLRP3, ASC, and caspase-1 p10; increased levels of IL-1β, IL-18, and TNFα; decreased levels of IL-10; and increased microglial activation. These effects were blocked by the NLRP3 inflammasome inhibitor Ac-Tyr-Val-Ala-Asp-chloromethylketone. The results demonstrate proof of concept that NLRP3 inflammasome activation contributes to long-term behavioral alterations in LPS-exposed mice, probably through enhanced inflammation, and that NLRP3 inflammasome inhibition might alleviate peripheral and brain inflammation and thereby ameliorate long-term behavioral alterations in LPS-exposed mice.
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The CNTNAP2 (contactin-associated protein-like 2) gene, highly expressed in the human prefrontal cortex, has been linked with autism and language impairment. Potential relationships between CNTNAP2, dorsolateral prefrontal cortex (DLPFC), and cognition have been suggested by previous clinical studies, but have not been directly examined in the same study. The current study collected structural MRI, genetic, and behavioral data in 317 healthy Chinese adults, and examined associations between CNTNAP2 variants, DLPFC, and cognitive performance (measured by the Stroop task). ⋯ Subjects with greater left DLPFC surface area had better cognitive performance. Importantly, the left DLPFC surface area mediated the association between the CNTNAP2 rs4726946 genotype and cognitive performance. This study provides the first evidence for associations among the CNTNAP2 gene, left DLPFC structure, and cognitive control.
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Adult mammalian CNS axons generally do not regenerate, creating an obstacle to effective repair and recovery after neuronal injury. The canonical Wnt/β-catenin signaling pathway is an essential signal transduction cascade that regulates axon growth and neurite extension in the developing mammalian embryo. In this study, we investigated whether a Wnt/β-catenin signaling activator could be repurposed to induce regeneration in the adult CNS after axonal injury. ⋯ Furthermore, Wnt3a-injected eyes showed increased survival of RGCs and significantly higher pattern electroretinography (PERG) amplitudes compared to the control. Additionally, Wnt3a-induced axonal regeneration and RGC survival were associated with elevated activation of the transcription factor Stat3, and reducing expression of Stat3 using a conditional Stat3 knock-out mouse line led to diminished Wnt3a-dependent axonal regeneration and RGC survival. Therefore, these findings reveal a novel role for retinal Wnt signaling in axonal regrowth and RGC survival following axonal injury, which may lead to the development of novel therapies for axonal regeneration.