Neuroscience
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Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the CNS and peripheral nervous system and play an important role in modulating the cell activity and function. We have shown that the cholinergic agonist carbachol reduces the pigeon's inwardly rectifying potassium channel (pKir2.1) ionic currents in native vestibular hair cells. We have cloned and sequenced pigeon mAChR subtypes M2-M5 and we have studied the expression of all five mAChR subtypes (M1-M5) in the pigeon vestibular end organs (semicircular canal ampullary cristae and utricular maculae), vestibular nerve fibers and the vestibular (Scarpa's) ganglion using tissue immunohistochemistry (IH), dissociated single cell immunocytochemistry (IC) and Western blotting (WB). ⋯ Results from WB of the dissociated vestibular epithelia, nerve fibers and vestibular ganglia were consistent with the results from IH and IC. Our findings suggest that there is considerable co-expression of the subtypes on the neural elements of the labyrinth. Further electrophysiological and pharmacological studies should delineate the mechanisms of action of muscarinic acetylcholine receptors on structures in the labyrinth.
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Aristaless-related homeobox gene (ARX) is an important paired-type homeobox gene involved in the development of human brain. The ARX gene mutations are a significant contributor to various forms of X-chromosome-linked mental retardation with and without additional features including epilepsy, lissencephaly with abnormal genitalia, hand dystonia or autism. Here we demonstrate that the human ARX protein is a potent transcriptional repressor, which binds to Groucho/transducin-like enhancer of split (TLE) co-factor proteins and the TLE1 in particular through its octapeptide (Engrailed homology repressor domain (eh-1) homology) domain. ⋯ The introduction of the two most frequent ARX polyalanine tract expansion mutations increases the repression activity in a manner dependent on the number of extra alanines. Interestingly, deletions of alanine residues within polyalanine tracts 1 and 2 show low or no effect. In summary we demonstrate that the ARX protein is a strong transcription repressor, we identify novel ARX interacting proteins (TLE) and offer an explanation of a molecular pathogenesis of some ARX mutations, including the most frequent ARX mutations, the polyalanine tract expansion mutations, c.304ins(GCG)7 and c.428_451dup.
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Serotonin 2C receptors (5-HT2CR) appear to exert tonic inhibitory influence over dopamine (DA) neurotransmission in the ventral tegmental area (VTA), the origin of the mesolimbic DA system, thought to be important in psychiatric disorders including addiction and schizophrenia. Current literature suggests that the inhibitory influence of 5-HT2CR on DA neurotransmission occurs via indirect activation of GABA inhibitory neurons, rather than via a direct action of 5-HT2CR on DA neurons. The present experiments were performed to establish the distribution of 5-HT2CR protein on DA and GABA neurons in the VTA of male rats via double-label immunofluorescence techniques. ⋯ The 5-HT2CR immunoreactivity was also present in cells that contained immunoreactivity for tyrosine hydroxylase (TH), the DA synthetic enzyme, validating the localization of 5-HT2CR to DA neurons in the VTA. While the degree of 5-HT2CR+GAD co-localization was similar across the rostro-caudal levels of VTA subnuclei, 5-HT2CR+TH co-localization was highest in the middle relative to rostral and caudal levels of the VTA, particularly in the paranigral, parabrachial, and interfascicular subnuclei. The present results suggest that the inhibitory influence of the 5-HT2CR over DA neurotransmission in the VTA is a multifaceted and complex interplay of 5-HT2CR control of the output of both GABA and DA neurons within this region.
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Many chronic pain conditions are more prevalent in women than men and both fundamental and clinical research supports the implication of endogenous pain inhibitory mechanisms. The goal of this study was to verify if sex differences on endogenous pain inhibitory mechanisms during the formalin test are opioidergic and modulated by sex hormones. Formalin tests were performed with naloxone hydrochloride, a non-selective opioid antagonist in intact and gonadectomized Sprague-Dawley rats of both sexes. ⋯ Finally, intrathecal administration permitted us to support that the action of naloxone is primarily at the spinal level, even if a supraspinal action cannot be ruled out. These results are of particular interest in showing sexual dimorphisms in endogenous pain modulation mechanisms during the interphase of the formalin test. A clearer understanding of the difference between male and female endogenous pain inhibitory pathways should lead to a better understanding of the role of endogenous pain modulation deficits in certain chronic pain conditions.
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Reaching for food, or skilled reaching, is used as a test of basal ganglia function in preclinical studies as well as studies of human neurological conditions. Although changes in the end-point measure of success document the effects of neurotoxic cellular damage to the caudate-putamen and its treatment in rodents, there has been no examination of the cause of change in success after neurotoxic lesions of the striatum. This objective was addressed in the present study, in which rats trained to reach for single food pellets with one forelimb, received contralateral quinolinic acid or ibotenic acid lesions of the medial and lateral caudate-putamen. ⋯ After recovery of the withdrawal movement, the rats displayed chronic qualitative impairments in the rotatory movements of aiming, pronating, and supinating the forepaw. Medial quinolinic lesions improved success relative to control rats and did not change qualitative aspects of limb movement. The acute dissociation between transport and withdrawal, the chronic qualitative changes in movement elements, and the differential effect of medial and lateral injury on success, support a complex contribution of the caudate-putamen to skilled reaching that includes sensorimotor neglect, and quantitative and qualitative motoric changes.