Neuroscience
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The kinetics of neurotransmitter release was recognized recently as an important contributor to synaptic efficiency. Since adenosine is the ubiquitous modulator of presynaptic release in peripheral and central synapses, in the current project we studied the action of this purine on the timing of acetylcholine quantal release from motor nerve terminals in the skeletal muscle. Using extracellular recording from frog neuromuscular junction we tested the action of adenosine on the latencies of single quantal events in the pro-oxidant and antioxidant conditions. ⋯ Thus, adenosine which is generated at the neuromuscular junction from the breakdown of the co-transmitter ATP induces the synchronization of quantal events. The effect of adenosine on release timing should preserve the fidelity of synaptic transmission via "cost-effective" use of less transmitter quanta. Our findings also revealed important crosstalk between purinergic and redox modulation of synaptic processes which could take place in the elderly or in neuromuscular diseases associated with oxidative stress like lateral amyotrophic sclerosis.
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The velocity of impact between an object and the human head is a critical factor influencing brain injury outcomes but has not been explored in any detail in animal models. Here we provide a comprehensive overview of the interplay between impact velocity and injury severity in a well-established weight-drop impact acceleration (WDIA) model of diffuse brain injury in rodents. ⋯ There were impact velocity-dependent reductions in sensorimotor performance and in cortical depth-related depression of sensory cortex responses; however axonal injury (demonstrated by immunohistochemistry for β-amyloid precursor protein and neurofilament heavy-chain) was discernible only at the highest impact velocity. We conclude that the WDIA model is capable of producing graded axonal injury in a repeatable manner, and as such will prove useful in the study of the biomechanics, pathophysiology and potential treatment of diffuse axonal injury.
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Neuronal losses have been shown to occur in the brainstem following a neonatal hypoxic-ischaemic (HI) insult. In particular serotonergic neurons, situated in the dorsal raphé nuclei, appear to be vulnerable to HI injury. Nonetheless the mechanisms contributing to losses of serotonergic neurons in the brainstem remain to be elucidated. ⋯ On the other hand, after tracer deposit in the DR ventral nucleus, we found significant reductions in numbers of retrogradely labelled neurons in the hypothalamus, preoptic area and medial amygdala in P3 HI animals compared to controls. Since losses of descending inputs are associated with decreases in serotonergic neurons in the brainstem raphé nuclei, we propose that disruption of certain descending neural inputs from the forebrain to the DR dorsal and the DR ventral nuclei may contribute to losses of serotonergic neurons after P3 HI. It is important to delineate the phenotypes of different neuronal networks affected by neonatal HI, and the mechanisms underpinning this damage, so that interventions can be devised to target and protect axons from the harmful effects of neonatal HI.
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Cognitive dysfunction is relatively frequent in multiple sclerosis (MS) and it happens from the early stages of the disease. There is increasing evidence that the grey matter may be involved in autoimmune inflammation during relapses of MS. The purpose of this study was to evaluate if a single transfer of encephalitogenic T cells, mimicking a relapse of MS, may cause hippocampal damage and memory disturbances in rats. ⋯ The water maze test, however, did not reveal memory deficits. The present data indicate that a single transfer of autoimmune T cells results in preserved inflammation and probable on-going neuronal injury in the hippocampus, long after recovery from motor disturbances. These findings suggest that any relapse of the MS may start the neurodegenerative process in the hippocampus, which is not necessarily connected with memory deficits.
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γ-Hydroxybutyric acid (GHB) is used as an effective therapeutic for reducing the hypersomnolence and cataplexy (loss of motor control) of the sleeping disorder, narcolepsy, with an immediate pharmacologic behavioral action of inducing a natural sleep-like state. Despite its clinical use, few studies have examined the cellular actions of this drug on behavioral state-related neurons. Therefore, we monitored GHB-induced responses using calcium imaging within the laterodorsal tegmentum (LDT) and the dorsal raphe (DR), two pontine nuclei important in state and motor control. ⋯ Given the roles played by these nuclei, these actions are consistent with acute pharmacologic effects of GHB: hypotonia and promotion of sleep, including presence of REM, a sub-state of sleep. Differences in GHB-mediated calcium suggest differential regulation of calcium-dependent processes, which may also contribute to functioning of the LDT and DR in state and motor control and the therapeutic pharmacologic actions of GHB, which develop following chronic administration. These findings add to knowledge of cellular actions of GHB and it is hoped that, combined with findings from other studies examining GHB neurotransmission, these data can contribute to development of highly targeted therapeutics at the GABAB receptor for management of human disorders presenting with alterations in motor and arousal control.