Neuroscience
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The neuronal adaptor X11alpha interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Abeta40 and Abeta42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11alpha-mediated effects on APP trafficking and metabolism, and that X11alpha modulates APP metabolism in both secretory and endocytic pathways. X11alpha failed to interact with the endocytic-defective APPswe mutants Y738A, N740A, or P741A, and thus did not modulate their trafficking or metabolism. ⋯ In contrast to endocytic-defective mutants, X11alpha interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11alpha with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Abeta40, and Abeta42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11alpha modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Abeta generated in either pathway.
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Hypocretin/orexin modulates sleep-wake state via actions across multiple terminal fields. Within waking, hypocretin may also participate in high-arousal processes, including those associated with stress. The current studies examined the extent to which alterations in neuronal activity, as measured by Fos immunoreactivity, occur within both hypocretin-synthesizing and hypocretin-1 receptor-expressing neurons across varying behavioral state/environmental conditions associated with varying levels of waking and arousal. ⋯ Additionally, these data suggest that waking per se may not be associated with increased hypocretin neurotransmission. In contrast, high-arousal states, including stress, appear to be associated with substantially higher rates of hypocretin neurotransmission. Finally, these studies provide further evidence indicating coordinated actions of hypocretin across a variety of arousal-related basal forebrain and brainstem regions in the behavioral state modulatory actions of this peptide system.
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Comparative Study
Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection.
Previous studies in a mouse model of neonatal excitotoxic brain damage mimicking the brain lesions in human cerebral palsy showed microglial activation within 24 h after intracerebral injection of the glutamatergic analog ibotenate. Using this model, we studied the expression of CD-45 antigen, a marker of blood-derived cells, by these activated microglial cells labeled by Griffonia simplicifolia I isolectin B4. ⋯ Repeated i.p. administrations of chloroquine, chloroquine+colchicine, minocycline, or an anti-MAC1 antibody coupled to the toxin saporin before and/or after ibotenate injection induced a significant reduction in the density of isolectin B4-positive cells. This inhibition of resident microglial and/or blood-derived monocytes activation was accompanied by a significant reduction in the severity of ibotenate-induced brain lesions (up to 79% lesion size reduction with the highest minocycline dose) as well as of ibotenate-induced cortical caspase-3 activation (49% reduction).
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Comparative Study
Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury.
Pain and allodynia following spinal cord injury are poorly understood and difficult to treat. Since there is evidence that supraspinal mechanisms are important in such pain, we have studied the role of the thalamus in an experimental model of spinal injury. Extracellular recordings were obtained from neurones of the thalamic nucleus ventralis postero-lateralis (VPL) in normal rats and those which had sustained a contusive spinal cord injury to the thoraco-lumbar junction 7 days previously. ⋯ We have previously reported that a proportion of spinal neurones in allodynic spinally injured rats show increased evoked responses and afterdischarges following brushing the skin and hence the enhanced thalamic responses may reflect a greater spinal input. In view of the increasing evidence that thalamo-cortical rhythmical firing is linked to sensorimotor and cognitive brain functions, we propose that pain following brushing the skin results from an exaggerated spinal input being processed by a dysrhythmic thalamus. Thus both spinal and thalamic mechanisms may be important in the genesis of pain and allodynia following spinal cord injury.
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Electroencephalographic activity at the transition from wakefulness to sleep is characterized by the appearance of spindles (12-15 Hz) and slow wave rhythms including delta activity (1-4 Hz) and slow oscillations (0.2-1 Hz). While these rhythms originate within neocortico-thalamic circuitry, their emergence during the passage into slow wave sleep (SWS) critically depends on the activity of neuromodulatory systems. Here, we examined the temporal relationships between these electroencephalogram rhythms and the direct current (DC) potential recorded from the scalp in healthy men (n=10) using cross-correlation analyses. ⋯ Data indicate close links between increasing spindle, delta and slow oscillatory activity and the occurrence of a steep surface negative cortical DC potential shift during the transition from wake to SWS. Likewise, a DC potential shift toward surface positivity accompanies the disappearance of these oscillatory phenomena at the end of the non-REM sleep period. The DC potential shifts may reflect gradual changes in extracellular ionic (Ca2+) concentration resulting from the generation of spindle and slow wave rhythms, or influences of neuromodulating systems on cortical excitability thereby controlling the emergence of cortical spindle and slow wave rhythms at SWS transitions.