Neuroscience
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Exposure to ethanol in utero is associated with a myriad of sequelae for the offspring. Some of these effects are morphological in nature and noticeable from birth, while others involve more subtle changes to the brain that only become apparent later in life when the individuals are challenged cognitively. One brain structure that shows both functional and structural deficits following prenatal ethanol exposure is the hippocampus. ⋯ Deficits in hippocampal neurogenesis were not apparent in younger animals. Surprisingly, even when ethanol exposure occurred in conjunction with maternal stress, deficits in neurogenesis did not occur at this young age, suggesting that the capacity for neurogenesis is highly conserved early in life. These findings are unique in that they demonstrate for the first time that deficits in neurogenesis associated with prenatal ethanol consumption appear later in life.
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Aspirin-triggered Lipoxin A4 (ATL), as a Lipoxin A4 (LXA4) epimer, is endogenously produced by aspirin-acetylated cycloxygenase-2 (COX-2) and plays a vital role in endogenous anti-inflammation via the LXA4 receptor (ALX). Recent investigations have indicated that spinal neuroinflammation and the activation of the Janus Kinase 2 (JAK2)/Signal Transducers and Transcription Activators 3 (STAT3) signaling pathway are involved in neuropathic pain states. However, the effect of ATL on neuroinflammation and JAK2/STAT3 signaling in chronic constriction injury (CCI)-induced neuropathic pain in rats has not been well-studied. ⋯ Blockade of JAK2-STAT3 signaling with intrathecal administration of the JAK2 inhibitor AG490 or the STAT3 inhibitor S3I-201 clearly reduced mechanical allodynia and the upregulation of pro-inflammatory cytokines in CCI rats. Interestingly, inhibition of JAK2/STAT3 signaling via ATL or the specific signaling inhibitor (AG49, S3I-201) further promoted the increased expression of suppressor of cytokine signaling 3 (SOCS3) mRNA in the spinal cord induced by CCI surgery. Taken together, our results suggested that the analgesic effect of ATL was mediated by inhibiting spinal JAK2/STAT3 signaling and hence the spinal neuroinflammation in CCI rats.
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We previously demonstrated that mice which overexpress human renin and angiotensinogen (R+A+) show enhanced cerebral damage in both in vivo and in vitro experimental ischemia models. Angiotensin-converting enzyme 2 (ACE2) counteracts the effects of angiotensin (Ang-II) by transforming it into Ang-(1-7), thus reducing the ligand for the AT1 receptor and increasing stimulation of the Mas receptor. Triple transgenic mice, SARA, which specifically overexpress ACE2 in neurons of R+A+ mice were used to study the role of ACE2 in ischemic stroke using oxygen and glucose deprivation (OGD) of brain slices as an in vitro model. ⋯ Finally, western blots revealed less Nox2 and Nox4 expression in SARA mice compared with R+A+ mice both before and after OGD. We suggest that reduced brain swelling and cell death observed in SARA animals exposed to OGD result from diminished ROS production coupled with lower expression of Nox isoforms. Thus, the ACE2/Ang-(1-7)/Mas receptor pathway plays a protective role in brain ischemic damage by counteracting the detrimental effects of Ang-II-induced ROS production.
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Fragile X mental retardation protein (FMRP) binds select mRNAs, functions in intracellular transport of these mRNAs and represses their translation. FMRP is highly expressed in neurons and lack of FMRP has been shown to result in dendritic dysmorphology and altered synaptic function. FMRP is known to interact with mRNAs for the Kv3.1b potassium channel which is required for neurons to fire action potentials at high rates with remarkable temporal precision. ⋯ To examine this hypothesis, we have studied normal human brainstem tissue with immunohistochemical techniques and confocal microscopy. Our results demonstrate that FMRP is widely expressed in cell bodies and dendritic arbors of neurons in the human cochlear nucleus and superior olivary complex and also that coincidence detector neurons of the medial superior olive colocalization of FMRP and Kv3.1b. We interpret these observations to suggest that the lower auditory brainstem is a potential site of dysfunction in FXS.
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Physical activity influences inflammation, and both affect brain structure and Alzheimer's disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans. In 43 cognitively intact older adults (79.3±4.8 years) and 39 patients with AD (81.9±5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. ⋯ When considered together, more intense physical activity intensity and lower serum TNFα were both associated with greater total brain volume on follow-up MRI scans. TNFα, but not physical activity, was associated with regional volumes of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFα may independently influence brain structure in older adults.