Neuroscience
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Previous neuroimaging studies of response inhibition have examined correlations between behavioral efficiency and brain activity, but the temporal stability of the correlations has largely been ignored. The present functional magnetic resonance imaging (fMRI) study demonstrates the temporal changes of the brain activity associated with performance efficiency that led to more robust brain-behavior correlations in a later part of the experimental sessions. Participants performed a stop-signal task requiring inhibition of inappropriate responses, where more efficient behavioral performance is reflected in a shorter stop-signal reaction time (SSRT). ⋯ In the cerebellar region that showed the greatest difference in correlations between the second and the first halves, the brain activity increased in efficient performers, whereas the brain activity decreased in poor performers. These results suggest the existence of multiple brain mechanisms that increase and decrease the brain activity depending on the behavioral efficiency of the performers. More practically, these results indicate that robust brain-behavior correlations can more effectively be detected in a later part of the experimental sessions.
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β-Site amyloid precursor protein cleaving enzyme (BACE1) is the rate-limiting enzyme for production of Aβ peptides, proposed to drive the pathological changes found in Alzheimer's disease (AD). Reticulon 3 (RTN3) is a negative modulator of BACE1 (β-secretase) proteolytic activity, while peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2) positively regulated BACE1 gene expression in a cell-based assay. This study aimed to analyze RTN3 and PPIL2 mRNA levels in four brain regions from individuals with AD and controls. ⋯ Both RTN3 and PPIL2 mRNA levels correlated significantly with BACE1 mRNA and all three showed similar disease stage-dependent changes with respect to NSE and GFAP. These findings indicated that the in vitro data demonstrating an effect of PPIL2 on BACE1 expression have functional relevance in vivo. Further research into BACE1-interacting proteins could provide a fruitful approach to the modulation of this protease and consequently Aβ production.
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Zellweger syndrome (ZS) is a severe peroxisomal disorder caused by mutations in peroxisome biogenesis, or PEX, genes. A central hallmark of ZS is abnormal neuronal migration and neurodegeneration, which manifests as widespread neurological dysfunction. The molecular basis of ZS neuropathology is not well understood. ⋯ We demonstrate that PEX13 brain mutants display changes that reflect an abnormal serotonergic system - decreased levels of tryptophan hydroxylase-2, the rate-limiting enzyme of serotonin (5-hydroxytryptamine, 5-HT) synthesis, dysmorphic 5-HT-positive neurons, abnormal distribution of 5-HT neurons, and dystrophic serotonergic axons. The raphe nuclei region of PEX13 brain mutants also display increased levels of apoptotic cells and reactive, inflammatory gliosis. Given the role of the serotonergic system in brain development and motor control, dysfunction of this system would account in part for the observed neurological changes of PEX13 brain mutants.
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Glial cell line-derived neurotrophic factor (GDNF) exerts neurotrophic and neuroprotective effects on substantia nigra (SN) dopamine neurons and has great therapeutic potential for Parkinson's disease (PD). Hindering this potential is the fact that GDNF cannot cross the blood-brain barrier. The aim of this study was to assess the effects of GDNF administered by the intranasal route in normal rats, and in the unilateral 6-hydroxydopamine (6-OHDA) model of PD. ⋯ Three 50-μg doses given at daily intervals (1 day before, 1h before, and 1 day after 6-OHDA) provided even greater protection than single 150-μg doses. Multiple doses at short intervals may therefore provide greater neuroprotection than single bolus doses. These results demonstrate both a neurotrophic effect of intranasal GDNF in the intact SN as well as neuroprotective efficacy in the unilateral 6-OHDA model, supporting pursuit of this approach as a potential treatment for PD.
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Brain injury causes dysfunction of the blood-brain barrier (BBB). The BBB is comprised of perivascular astrocytes whose end-feet ensheath brain microvascular endothelial cells. We investigated trauma-induced morphological changes of human astrocytes (HA) and human cerebral microvascular endothelial cells (hCMEC/D3) in vitro, including the potential role of mitogen-activated protein kinase (MAPK) signal-transduction pathways. ⋯ In summary, traumatic injury induces JNK-mediated HA retraction in vitro, while sparing morphological changes in cerebral microvascular endothelial cells. Astrocyte retraction from microvascular endothelial cells in vivo may occur after brain trauma, resulting in cellular uncoupling and BBB dysfunction. JNK may represent a potential therapeutic target for traumatic brain injuries.