Biomedical subjects

T J McCown

Publications and source records attributed to T J McCown.

11 recordsLinked to original sources

PubMed2016

Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism.

No adeno-associated virus (AAV) capsid has been described in the literature to exhibit a primary oligodendrocyte tropism when a constitutive promoter drives gene expression, which is a significant barrier for efficient in vivo oligodendrocyte gene transfer. The vast majority of AAV vectors, such as AAV1, 2, 5, 6, 8 or 9, exhibit a dominant neuronal tropism in the central nervous system. However, a novel AAV capsid (Olig001) generated using capsid shuffling and directed evolution was recovered after rat intravenous delivery and subsequent capsid clone rescue, which exhibited a >95% tropism for striatal oligodendrocytes after rat intracranial infusion where a constitutive promoter drove gene expression. Olig001 contains a chimeric mixture of AAV1, 2, 6, 8 and 9, but unlike these parental serotypes after intravenous administration Olig001 has very low affinity for peripheral organs, especially the liver. Furthermore, in mixed glial cell cultures, Olig001 exhibits a 9-fold greater binding when compared with AAV8. This novel oligodendrocyte-preferring AAV vector exhibits characteristics that are a marked departure from previously described AAV serotypes.

Animals↗

PubMed1991

Neuroanatomical characterization of inferior collicular seizure genesis: 2-deoxyglucose and stimulation mapping.

Previous work has demonstrated that the cortical sub-division of the inferior colliculus is capable of seizure genesis, so the present studies delineated the neuroanatomical extent of this seizure genesis using two mapping techniques, [14C]2-deoxyglucose (2-DG) uptake and electrical stimulation. When 4 inferior collicular seizures were elicited over a 5 min period, the stimulated side of the brain showed highly selective increases in the [14C]2-DG uptake in comparison to the unstimulated side. Although the substantial change in [14C]2-DG uptake occurred over the entire inferior collicular cortex, electrical stimulation mapping delineated a specific area capable of seizure genesis within the inferior collicular cortex. The electrical stimulation also identified a number of regions that would support electrically dependent seizure behaviors: the cuneiform nucleus, the ventrolateral inferior colliculus, portions of the dorsal central gray, and the peripeduncular nucleus. In concert, marked unilateral increases in [14C]2-DG uptake were found on the stimulated side in the peripeduncular/substantia nigra lateralis area, the medial geniculate and a specific region of the dorsal central gray. These studies verify the asymmetric nature of inferior collicular seizure genesis, identify areas of seizure modulation, and delineate a region in the inferior collicular cortex that modulates sensory-motor integration.

Animals↗

PubMed1991

The role of the inferior collicular cortex in the neonatal rat: sensorimotor modulation.

A tail pinch in rats up to 10 days of age produces a spectrum of motor behaviors characterized by forelimb paddling, hindlimb treading and occasional curling and rolling of the torso, a behavioral pattern similar to the seizure behaviors electrically-elicited from the inferior collicular cortex of 5- or 10-day-old rats. In 5-day-old rats, these tail pinch-induced paddling and treading behaviors coincided with afterdischarge-like EEG activity recorded from the seizure-sensitive site in the inferior collicular cortex. In contrast, no change in the EEG activity occurred in an adjacent seizure-insensitive site during these tail pinch-induced behaviors. Similar electrographic-behavioral synchrony was found in 10-day-old rats, but by 16 days of age, as in the adult rat, a tail pinch stimulus did not induce post-stimulus behavioral changes or afterdischarge-like EEG activity. Since auditory function does not develop until 12-14 days of age in the rat, we propose that the inferior collicular cortex modulates sensorimotor integration in the neonatal rat, prior to assumption of this function by the cerebral cortex.

Animals↗

PubMed1991

Unilateral kindling of the inferior collicular cortex does not transfer to the contralateral seizure sensitive site or alter [3H]flunitrazepam and [35S]TBPS binding.

Acute electrical stimulation of a specific area in the inferior collicular cortex produced bilateral collicular afterdischarge and symmetrical wild running seizures. However, generalized seizures induced by kindling the inferior collicular cortex did not alter the kindling rate in the contralateral side. Furthermore, after both sides of the inferior collicular cortex have been kindled unilateral electrolytic lesions did not alter the seizure initiation or generalization elicited from the contralateral side. Since GABAergic function has been implicated in inferior collicular seizures, potential seizure-induced changes were measured for the chloride channel ([35S]TBPS) and the benzodiazepine receptor ([3H]flunitrazepam). Prior kindling did not alter [35S]TBPS or [3H]flunitrazepam binding in the central nucleus or cortex of the inferior colliculus, the medial geniculate, or the deep prepiriform cortex. Thus, the permanent neural change that subserves seizure generalization from the inferior collicular cortex is unilateral, but this change is not reflected by altered binding characteristics of the GABAA receptor complex.

Animals↗

PubMed1990

Effects of apamin and nicotinic acetylcholine receptor antagonists on inferior collicular seizures.

These studies compared the actions of apamin and nicotinic acetylcholine antagonists on seizure genesis within the inferior collicular cortex. In vitro alpha-bungarotoxin, d-tubocurarine and gallamine all competitively displaced [125I]apamin binding to brain sections through the inferior colliculus, while intracollicular microinjection of intermediate doses of apamin (21 pmol), alpha-bungarotoxin (0.3 nmol), d-tubocurarine (0.22 nmol) or gallamine (1.7 nmol) all significantly reduced the seizure initiation threshold current. However, higher doses of apamin did not cause spontaneous seizure activity, while higher doses of the nicotinic acetylcholine antagonists caused spontaneous seizures. Carbamylcholine also produced spontaneous seizures, but did not alter the seizure threshold current. N-Methyl-atropine caused a dose-related elevation of the seizure threshold current, yet microinjection of N-methyl-atropine (10 nmol) into the inferior collicular cortex reversed the effects of alpha-bungarotoxin on seizure threshold, partially opposed the effects of gallamine and d-tubocurarine, and had no effect on the ability of apamin to reduce the seizure threshold current. Thus, both the apamin-sensitive potassium channel and a variety of distinct cholinergic mechanisms contribute in vivo to seizure genesis within the inferior collicular cortex, but not through the same mechanisms.

Animals↗

PubMed1990

Opposite alterations in cerebrospinal fluid uridine after severe cerebral ischemia or intrathecal blood injection.

1. Rats which survived hypoglycemia by insulin, hypoxia by 10% O2, or ischemia by carotid ligation and hypotension to 40 mm Hg, evidenced no changes in cerebrospinal fluid (CSF) uridine. Animals which died soon after the above interventions or as a result of KCl-induced cardiac arrest had elevated CSF uridine concentrations. 2. Injection of whole blood or the soluble contents of lysed blood cells into the lateral ventricle of rats reduced CSF uridine to less than one-half normal at 24 hrs but values returned to normal 3 days later. Changes in hypoxanthine resembled those of uridine, but were less dramatic, whereas xanthine concentrations were largely unaltered. Intraventricular injection of plasma or saline did not alter CSF uridine. 3. It seems most likely that low CSF uridine concentrations previously reported in head injury patients may be secondary to the effects of blood cell contents in the cerebrospinal fluid, rather than responses to altered metabolism in neurons or glia cells.

Animals↗

PubMed1990

Multiple withdrawals from chronic ethanol "kindles" inferior collicular seizure activity: evidence for kindling of seizures associated with alcoholism.

The present investigation tested the hypothesis that multiple withdrawals from chronic ethanol treatment "kindles" seizure activity. Two animal models of kindled seizure activity--electrical stimulation of the inferior collicular cortex or the amygdala--were used to evaluate this hypothesis. Four withdrawals from a 12-day ethanol-liquid diet regimen facilitated the seizure kindling rate in the inferior collicular cortex, when the stimulation was initiated 7 days after the last withdrawal. In contrast, four withdrawals from this chronic ethanol regimen significantly attenuated the rate of amygdaloid kindling. When the withdrawals were increased to six or 10 using a 5-day chronic ethanol treatment schedule, the kindling rate in the inferior collicular cortex proved directly proportional to the withdrawal number. Continuous ethanol exposure over the same period as the 10 withdrawal group also facilitated the inferior collicular kindling rate, but not to the extent found in the 10 withdrawal group. A before, 10 withdrawals from the 5-day chronic ethanol liquid diet treatment attenuated the rate of amygdaloid kindling. Thus, this kindling action of repeated ethanol withdrawals appears specific to seizures originating from the inferior collicular cortex, not the limbic system. These findings support a previous hypothesis for a kindling etiology of alcoholism related seizures.

Alcohol Withdrawal Delirium↗

PubMed1989

Mechanistic and functional divergence between thyrotropin-releasing hormone and RO 15-4513 interactions with ethanol.

Both thyrotropin-releasing hormone (TRH) and RO 15-4513 antagonize ethanol-induced depression, but this common property does not infer that both compounds share similar mechanisms of action. In the present studies, both TRH (30 mg/kg, i.p.) and RO 15-4513 (10 mg/kg, i.p.) reversed ethanol-induced depression of locomotor activity, in accord with previous reports. However, the benzodiazepine antagonist, RO 15-1788, blocked this action of RO 15-4513, while exerting no effect on the analeptic action of TRH. Using a model of seizure activity electrically elicited from the inferior colliculus, ethanol exerted a dose-related attenuation of seizure activity. This anticonvulsant action of ethanol was not altered by TRH (30 mg/kg, i.p.), but RO 15-4513 (3 mg/kg) reversed the effect of the 0.5, but not the 1.0 g/kg, dose of ethanol. In addition, pretreatment with RO 15-4513 (1 or 3 mg/kg, i.p.), but not TRH (30 mg/kg, i.p.), caused seizure generalization into the forebrain following inferior collicular stimulation, further verifying the proconvulsant properties of RO 15-4513. In conclusion, the analeptic action of TRH appears independent of benzodiazepine activity, and in contrast to RO 15-4513, TRH does not exhibit proconvulsant properties. Furthermore, because TRH did not antagonize both depressant actions of ethanol studied, it appears unlikely that TRH directly interacts with the molecular basis of ethanol action.

Animals↗

PubMedDate not supplied

Changes in cerebrospinal fluid homovanillic acid in children with Ondine's curse.

The cerebrospinal fluid (CSF) concentrations of three acid monoamine metabolites, two purines, and a group of amino acids were determined in two children with chronic central alveolar hypoventilation (Ondine's curse). The levels of all assayed neuroactive substances, metabolites, and amino acids, with one exception, were normal compared to an age-matched group of neurologically healthy children. The levels of the dopamine metabolite homovanillic acid in the children with Ondine's curse were approximately 2.4 times higher than expected for age range. The present findings may indicate a link between central nervous system dopamine activity and chronic central alveolar hypoventilation. Among other possible explanations, the changes seen might represent a primary alteration in dopamine activity or may reflect a change in dopamine turnover resulting from the chronic hypoventilation.

Adenosine↗

PubMedDate not supplied

Seizure interactions between the inferior collicular cortex and the deep prepiriform cortex.

In rats, electrographic seizure activity was recorded from both the inferior collicular cortex and the deep prepiriform after i.p. administration of 15 mumol/kg bicuculline, a dose which produced a variety of seizure behaviors. electrographic spikes recorded from the deep prepiriform cortex coincided with myoclonic jerks, while both brain areas exhibited an increase in afterdischarge frequency at the onset of forelimb tonic extension. Conversely, afterdischarge activity was recorded in both brain regions, while no seizure behaviors were apparent, providing examples of dissociation between electrographic and behavioral seizure activity. However, when functional interactions were assessed, the tonic-clonic behaviors produced by kindling stimulation of the inferior collicular cortex were prevented by microinjections of procaine into the deep prepiriform cortex. Thus, a forebrain site, that has been associated with limbic seizure activity, also can modulate seizure generalization from the inferior collicular cortex into the forebrain.

Animals↗

PubMedDate not supplied

The developmental profile of seizure genesis in the inferior collicular cortex of the rat: relevance to human neonatal seizures.

The ontogeny of seizure genesis within the inferior collicular cortex was characterized in rats ranging in age from 3 days old to adult. Brief electrical stimulation of the right inferior collicular cortex in 30-day-old rats evoked poststimulus wild running behavior that coincided with afterdischarge activity in the inferior collicular cortex but not in the adjacent occipital cortex. Similar electrical stimulation in 16-day-old rats produced poststimulus wild running and jumping behaviors, which also coincided with afterdischarge in the inferior collicular cortex. In 10- and 5-day-old rats, electrical stimulation of the inferior collicular cortex produced poststimulus locomotion and coincident afterdischarge activity, but unlike older rats the locomotor behaviors consisted of forelimb paddling, hindlimb treading, and rolling/curling movements of the torso. Identical behaviors can be electrically elicited in 3-day-old rats. Although many of the seizure characteristics appear to be similar among the different age groups, 5-day-old rats were more sensitive to low frequency stimulation than 16-day-old rats, who in turn were more sensitive than adult rats. Thus, the inferior collicular cortex is capable of generating seizure activity in rats as young as 3 days of age, providing a focal model of neonatal seizure genesis.

Age Factors↗