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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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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Comparative Study
Direct comparison of microglial dynamics and inflammatory profile in photothrombotic and arterial occlusion evoked stroke.
Many focal cerebral ischemia models utilize the middle cerebral artery occlusion (MCAO) evoked by coagulation to induce ischemic damage in the cortex and mimic the pathology observed in human patients. A second, increasingly popular model, the photothrombotic stroke, uses a laser beam to irradiate the MCA after administration of a photosensitizing dye. This widely used procedure is slowly replacing the MCAO model because of the easiness of the surgical protocol and the reproducibility of the damage. ⋯ It also elicited higher levels of inflammatory cytokines/chemokines and increased infiltration from the periphery. In addition, only the neurons in the MCAO stroke showed phenotype plasticity by downregulating the transcription factor NeuN. These data provide a better understanding of the exact temporal and spatial dynamics of the inflammatory response in these two animal models of stroke and identify more relevant targets for human therapy.
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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.
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In the spinal cord high extracellular glutamate evokes excitotoxic damage with neuronal loss and severe locomotor impairment. During the cell dysfunction process, extracellular pH becomes acid and may activate acid-sensing ion channels (ASICs) which could be important contributors to neurodegenerative pathologies. Our previous studies have shown that transient application of the glutamate analog kainate (KA) evokes delayed excitotoxic death of spinal neurons, while white matter is mainly spared. ⋯ Likewise, immunohistochemistry indicated significant neuronal loss when KA was followed by the ASIC inhibitors DAPI or amiloride. Electrophysiological recording from ventral roots of isolated spinal cords showed that alternating oscillatory cycles were slowed down by 0.01mMKA, and intensely inhibited by subsequently applied DAPI or amiloride. Our data suggest that early rise in ASIC expression and function counteracted deleterious effects on spinal networks by raising the excitotoxicity threshold, a result with potential implications for improving neuroprotection.