Neuroscience
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The spinal cord is rarely transected after spinal cord injury. Dysfunction of surviving axons, which traverse the site of spinal cord injury, appears to contribute to post-traumatic neurological deficits, although the underlying mechanisms remain unclear. The subpial rim frequently contains thinly myelinated axons which appear to conduct signals abnormally, although it is uncertain whether this truly reflects maladaptive alterations in conduction properties of injured axons during the chronic phase of spinal cord injury or whether this is merely the result of the selective survival of a subpopulation of axons. ⋯ In conclusion, chronically injured dorsal column axons show physiological evidence of dysfunction and morphological changes in axonal diameter and reduced myelination ratio. These maladaptive alterations to injured axons, including decrease in myelin thickness and the appearance of axonal swellings, contribute to the decreased excitability of chronically injured axons. These results further clarify the mechanisms underlying neurological dysfunction after chronic neurotrauma and have significant implications regarding approaches to augment neural repair and regeneration.
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Cation-chloride cotransporters have been considered to play pivotal roles in controlling intracellular and extracellular ionic environments of neurons and hence controlling neuronal function. We investigated the total distributions of K-Cl cotransporter 1 (KCC1), KCC2 (KCC2), and Na-K-2Cl cotransporter 1 (NKCC1) messenger RNAs in the adult rat nervous system using in situ hybridization histochemistry. KCC2 messenger RNA was abundantly expressed in most neurons throughout the nervous system. ⋯ The expression levels of KCC1 and NKCC1 messenger RNAs were relatively low, however, positive neurons were observed in several regions, including the olfactory bulb, hippocampus, and in the granular layer of the cerebellum. In addition, positive signals were seen in the non-neuronal cells, such as choroid plexus epithelial cells, glial cells, and ependymal cells, suggesting that KCC1 and NKCC1 messenger RNAs were widely expressed in both neuronal and non-neuronal cells in the nervous system. These results clearly indicate a wide area- and cell-specific variation of cation chloride cotransporters, emphasizing the central role of anionic homeostasis in neuronal function and communication.
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The selective 5-HT(1A) receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 microg/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle=10, Injury/MK-801=10, Injury/Repinotan HCl=10, Sham/Vehicle=10), then tested for vestibulomotor function on post-operative days 1-5 and for spatial learning on days 14-18. ⋯ No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups. These findings extend the therapeutic efficacy of Repinotan HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT(1A) receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury.
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The role of Orphanin-FQ/nociceptin in synaptic plasticity was assessed by its potency in modulating kindling epileptogenesis in vivo, and feed-forward inhibition in hippocampal recordings in vitro. In addition, a specific rabbit antiserum against this peptide was obtained and the immunohistochemical distribution of nociceptin was determined in rat brain slices. After the establishment of kindling epilepsy, by daily electrical stimulation of the piriform cortex, the i.c.v. injection of nociceptin, 20 min before the kindling stimulation, was not able to block the generation of the generalized seizures, nor to alter their duration. ⋯ By single pulses applied over the Schaffer collaterals, we found that synaptic transmission was facilitated onto CA1, but using a paired-pulse protocol, we found that nociceptin potentiated feed-forward inhibition. The immunohistochemical data show that nociceptin is expressed in limbic cortical regions, including the piriform cortex and the hippocampus. Our results demonstrate that nociceptin exerts a modulatory role in limbic excitability and suggest that it provides an inhibitory control in the development of epilepsy by possibly inhibiting the spread of excitation through the system, by favoring feed-forward inhibition.
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Hippocampal cholinergic neurostimulating peptide, an undecapeptide originally isolated from the hippocampus of young rats, enhances acetylcholine synthesis in rat medial septal nucleus in vitro. Hippocampal cholinergic neurostimulating peptide is derived from the N-terminal region of its 21-kmol.wt precursor protein. ⋯ Selective inhibition with pharmacological agents revealed that the constitutive hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA level can be up-regulated by D-(-)-2-amino-5-phosphono-valeric acid, and that activity-dependent transcription can be inhibited by tetrodotoxin, nifedipine, 6-cyano-7-nitroquinoxaline-2,3-dione, and scopolamine, but not by mecamylamine. These results indicate that septal cholinergic neurons and hippocampal glutamatergic neurons exert a reciprocal influence over the expression of hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA in the hippocampus, and that the activity-dependent and constitutive expressions of hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA may be regulated by different routes, involving calcium influx via L-type Ca(2+) channels and N-methyl-D-aspartate receptors.