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Biomedical subjects

Paul F Smith

Publications and source records attributed to Paul F Smith.

At least 19 recordsLinked to original sources
PubMed2006

Neuronal nitric oxide synthase expression in the cochlear nucleus in a salicylate model of tinnitus.

Although a number of studies suggest that the development of tinnitus is associated with hyperactive neuronal discharges in the brainstem cochlear nucleus (CN), there is relatively little evidence to indicate the neurochemical basis of this phenomenon. While some studies suggest that it may be partly due to a decrease in GABAergic inhibition, it is also possible that increased excitability is a contributing factor. In the current study, we investigated whether the salicylate animal model of tinnitus is associated with changes in the number of CN neurons expressing neuronal nitric oxide synthase (nNOS), one of the NOS isoforms that results in the production of the neurotransmitter, nitric oxide. We used a behavioral conditioning paradigm to confirm that animals receiving salicylate injections experienced tinnitus, and used immunohistochemistry with stereology to quantify the number of nNOS-expressing neurons in the dorsal and ventral CN (DCN and VCN, respectively) in salicylate- and vehicle control-treated animals. We also employed Western blotting to quantify the amount of nNOS protein expression in the total CN (i.e., the DCN and VCN together). We found a significant increase (of approximately 70%) in the number of nNOS-expressing principal neurons in the VCN of salicylate-treated animals compared to controls, with no significant differences in the DCN; nor did we find any significant difference in the overall level of nNOS protein in the total CN using Western blotting. These results suggest that changes in the number of neurons in the VCN expressing nNOS may be implicated in the mechanisms of tinnitus.

Animals↗
PubMed2006

The endocannabinoid system: A new player in the neurochemical control of vestibular function?

The results of recent clinical trials of medicinal cannabinoid drugs show that dizziness and vertigo are commonly reported adverse side-effects. Cannabinoid CB1 receptors were initially thought to be expressed in very low densities in the vestibular nucleus complex (VNC). Recent immunohistochemical studies have challenged this idea and suggested that CB1 receptors may exist in numbers similar to the granule cell layer of the cerebellum. This, together with evidence that brainstem CB1 receptors have a higher efficacy than those in many other parts of the brain and that application of cannabinoids can elicit potent electrophysiological effects in VNC neurons, suggests that CB1 receptors and their endogenous ligands may be important in central vestibular function. In this review, we consider the potential clinical significance of the endocannabinoid system for the development of vestibular disorders, the effects of recreational cannabis use and the therapeutic use of medicinal cannabinoids.

Cannabinoids↗
PubMed2006

Co-distribution of the cannabinoid CB1 receptor and the 5-HT transporter in the rat amygdale.

Cannabis sometimes causes dysphoria rather than euphoria; however, evidence relating to the interaction between the cannabinoid and 5-hydroxtryptamine (5-HT) systems is limited, especially in areas of the brain such as the amygdale. Here we report that cannabinoid CB(1) receptors and 5-HT transporter proteins are co-distributed in the amygdale, suggesting the possibility that activation of cannabinoid CB(1) receptors might cause a reduction in 5-HT release, similar to its effect on other neurotransmitters, thereby resulting in dysphoria.

Amygdala↗
PubMed2006

Impairment and recovery on a food foraging task following unilateral vestibular deafferentation in rats.

It has been suggested that the vestibular system may contribute to the development of higher cognitive function, especially spatial learning and memory that uses idiothetic cues (e.g., dead reckoning). However, few studies have been done using behavioral tasks that could potentially separate the animals' ability for dead reckoning from piloting. The food foraging task requires the animal to continuously monitor and integrate self-movement cues and generate an accurate return path. It has been shown that bilateral vestibular-lesioned rats were impaired on this task. The present study used the same task to further examine the contribution of vestibular information to spatial navigation by comparing unilateral and bilateral lesions and by testing the animals at different time points following the lesion. The results demonstrated that animals with unilateral vestibular deafferentation were impaired in performing the task in the dark at 3 months after the lesion, and this impairment disappeared at 6 months after the lesion. This supports the notion that vestibular information contributes to dead reckoning and suggests possible recovery of function over time after the lesion. Animals with bilateral vestibular deafferentation were not able to be tested on the foraging task because they exhibited behavior distinct from the unilateral-lesioned animals, with significant hesitation in leaving their home cage for as long as 6 months after the lesion.

Animals↗
PubMed2006

Lesions of the vestibular system disrupt hippocampal theta rhythm in the rat.

The hippocampus has a major role in memory for spatial location. Theta is a rhythmic hippocampal EEG oscillation that occurs at approximately 8 Hz during voluntary movement and that may have some role in encoding spatial information. We investigated whether, as part of this process, theta might be influenced by self-movement signals provided by the vestibular system. The effects of bilateral peripheral vestibular lesions, made > or = 60 days prior to recording, were assessed in freely moving rats. Power spectral analysis revealed that theta in the lesioned animals had a lower power and frequency compared with that recorded in the control animals. When the electroencephalography (EEG) was compared in epochs matched for speed of movement and acceleration, theta was less rhythmic in the lesioned group, indicating that the effect was not a result of between-group differences in this behavior. Blood measurements of corticosterone were also similar in the two groups indicating that the results could not be attributed to changes in stress levels. Despite the changes in theta EEG, individual neurons in the CA1 region of lesioned animals continued to fire with a periodicity of approximately 8 Hz. The positive correlation between cell firing rate and movement velocity that is observed in CA1 neurons of normal animals was also maintained in cells recorded from lesion group animals. These findings indicate that although vestibular signals may contribute to theta rhythm generation, velocity-related firing in hippocampal neurons is dependent on nonvestibular signals such as sensory flow, proprioception, or motor efference copy.

Animals↗
PubMed2005

Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study.

Reports of cannabinoid CB2 receptor protein in the brain have been ambiguous. We therefore tested for CB2 immunoreactivity in the rat brain using immunofluorescence. We detected CB2 labeling in fine fibers in the granule layer. This CB2 labeling did not co-localise with the astrocyte marker glial fibrillary acidic protein (GFAP) and, therefore, the CB2-positive fibers were not astrocytes and were possibly microglial or neuronal. Additionally, strong CB2 labeling was detected in capillary endothelia in the granule, Purkinje cell, and molecular layers. Our results suggest that the role of CB2 receptors in the brain may have been previously underestimated.

Animals↗
PubMed2005

Mitochondrial ultrastructure and apoptotic protein expression in the vestibular nucleus complex following unilateral labyrinthectomy.

We hypothesized that peripheral vestibular disorders might affect mitochondria in the vestibular nucleus complex (VNC). We tested this using unilateral labyrinthectomy (UL) as a model for the effects of vestibular damage on the VNC and used Western blotting and electron microscopy to analyze mitochondria. In rats receiving UL we did not find any changes in mitochondrial ultrastructure in the medial vestibular nucleus following UL, and there was no change in the expression or activation of the apoptosis effector caspase-3 in the whole VNC following UL. However, we did detect a small but statistically significant upregulation of the anti-apoptotic protein Bcl-2 in the contralateral VNC at 10 h post-UL.

Animals↗
PubMed2005

Ginkgo biloba extracts for tinnitus: More hype than hope?

The investigation into the effects of Ginkgo biloba extracts on tinnitus has suffered from a dearth of effective animal models as well as systematic clinical trials employing double-blind and placebo-controlled designs. Some clinical trials have yielded positive results, however, these studies are few and have been limited either by design flaws, the small size of the significant effects, or else the results have not been published in peer-reviewed journals and therefore the quality of the research is not assured. By contrast, the two most systematic clinical trials, both double-blind and placebo controlled, and published in respected peer-reviewed journals, have yielded negative results and suggest that Ginkgo biloba extracts are of little more use in the treatment of tinnitus than a placebo. Treatments for tinnitus that do not have therapeutic efficacy not only waste money but can potentially prevent patients from seeking therapy that is efficacious. Furthermore, the unsupervised use of Ginkgo biloba extracts with other medications could lead to adverse side effects which are unnecessary and not justified in terms of therapeutic benefit.

Ginkgo biloba↗
PubMed2005

GABA(A) receptor subunit expression in the guinea pig vestibular nucleus complex during the development of vestibular compensation.

The aim of this experiment was to investigate whether vestibular compensation following unilateral vestibular deafferentation (UVD) is associated with changes in the expression of GABA(A) receptor subunits in the guinea pig vestibular nuclear complex (VNC) at 2, 10, and 30 h post-surgery. Using Western blotting, the alpha1 and gamma2 subunits (but not the beta2 subunit) were detected in the VNC of labyrinthine-intact animals. However, there were no significant differences in the protein expression of the alpha1 and gamma2 subunits within the ipsilateral or contralateral VNC at any time post-UVD compared to sham and anesthetic controls. Furthermore, UVD did not induce the expression of the beta2 protein. These results suggest that vestibular compensation in guinea pig, as in the rat, is not associated with changes in the protein levels of the GABA(A) receptor subunits alpha1, beta2, and gamma2 in the VNC. However, a limitation of this study is that the Western blotting technique can detect only changes that are larger than 30% and therefore small changes cannot be excluded.

Adaptation, Physiological↗
PubMed2005

Immunocytochemical and stereological analysis of GABA(B) receptor subunit expression in the rat vestibular nucleus following unilateral vestibular deafferentation.

The process of behavioral recovery that occurs following damage to one vestibular labyrinth, vestibular compensation, has been attributed in part to a down-regulation of GABA(B) receptors in the vestibular nucleus complex (VNC) ipsilateral to the lesion, which could potentially reduce commissural inhibition from the contralateral VNC. In this study, we tested the possibility that this occurs through a decrease in the expression of either the GABA(B1) or GABA(B2) subunits of the GABA(B) receptor. We used Western blotting to quantify the expression of these subunits in the VNC at 10 h and 50 h following unilateral vestibular deafferentation (UVD) or sham surgery in rats. We then used immunocytochemistry and stereological counting methods to estimate the number of neurons expressing these subunits in the MVN at 10 h and 2 weeks following UVD or sham surgery. Compared to sham controls, we found no significant changes in either the expression of the two GABA(B) receptor subunits in the VNC or in the number of MVN neurons expressing these GABA(B) receptor subunits post-UVD. These results suggest that GABA(B) receptor expression does not change substantially in the VNC during the process of vestibular compensation.

Afferent Pathways↗
PubMed2005

Effects of chronic infusion of a GABAA receptor agonist or antagonist into the vestibular nuclear complex on vestibular compensation in the guinea pig.

The aim of this study was to determine the effects of chronic infusion of a GABA(A) receptor agonist/antagonist into the ipsilateral or contralateral vestibular nuclear complex (VNC) on vestibular compensation, the process of behavioral recovery that occurs after unilateral vestibular deafferentation (UVD). This was achieved by a mini-osmotic pump that infused, over 30 h, muscimol or gabazine into the ipsilateral or contralateral VNC. Spontaneous nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT) were measured. Infusion of muscimol or gabazine into either the ipsilateral or the contralateral VNC had little effect on SN compensation. In contrast, infusion of muscimol (250, 500, and 750 ng) into the contralateral VNC and gabazine (31.25, 62.5, and 125 ng) into the ipsilateral VNC significantly affected YHT and RHT (p < 0.05), but not their rate of compensation (p > 0.05). Interestingly, the effects of muscimol and gabazine on YHT and RHT were consistent throughout the first 30 h post-UVD. Infusion of muscimol (62.5, 125, and 250 ng) into the ipsilateral VNC and gabazine (125, 375, and 750 ng) into the contralateral VNC had little effect on YHT and RHT or their rate of compensation. These results suggest that the ipsilateral gabazine and contralateral muscimol infusions are modifying the expression of the symptoms without altering the mechanism of compensation. Furthermore, the neurochemical mechanism responsible for vestibular compensation can cope with the both the GABA(A) receptor-mediated and the UVD-induced decrease in resting activity.

Animals↗
PubMed2005

GABAergic systems in the vestibular nucleus and their contribution to vestibular compensation.

GABA and the GABAA and GABAB receptors play a pivotal role in the coordination of the central vestibular pathways. The commissural inhibition, which exists between the two vestibular nucleus complexes (VNCs) and which is responsible for enhancing the dynamic sensitivity of VNC neurons to head acceleration, is known to be substantially mediated by GABA acting on GABAA and GABAB receptors. After unilateral vestibular deafferentation (UVD), the large asymmetry in spontaneous resting activity between the two VNCs is reinforced and exacerbated by the GABAergic interaction between the ipsilateral and contralateral sides. Although it has been suggested that reduced GABAergic inhibition of the ipsilateral VNC may be partially responsible for the recovery of resting activity that underlies vestibular compensation of the static symptoms of UVD, at present there are few data available to test this hypothesis systematically. There is some evidence that GABA concentrations change in the ipsilateral VNC during the development of compensation; however, it is unclear whether these changes relate to GABA release or to metabolic pools of GABA. Most biochemical studies of GABA receptors have been conducted at the gene expression level. Therefore, it is unclear whether changes in the receptor protein also occur, although the most recent data suggest that changes in GABAA and GABAB receptor density in the VNC are unlikely. The few radioligand binding data relate to GABAA receptors with benzodiazepine binding sites only. A decrease in the sensitivity of ipsilateral VNC neurons from compensated animals to GABA receptor agonists has been reported; however, these studies have employed brainstem slices and therefore the functional identity of the neurons involved has been unclear. Although it seems likely that some changes in central GABAergic systems accompany the recovery of resting activity in the ipsilateral VNC during the development of vestibular compensation, at the present stage there is no compelling evidence that these changes have a causal role in the compensation process.

Adaptation, Physiological↗
PubMed2005

Hippocampal nitric oxide synthase and arginase and age-associated behavioral deficits.

The present study investigated age-related changes in nitric oxide synthase (NOS) and arginase in the subregions of the hippocampus and their correlations with animals' performance in the open field, T-maze, and water maze tasks. Aged rats (24 months old) showed reduced exploratory activity and poorer spatial learning relative to the young adults (4 months old). Significant increases in total NOS activity were found in the aged dentate gyrus and a dramatic decrease in endothelial NOS expression was observed in the aged CA2/3. Activity or protein expression of inducible NOS was not detected in any subregion of the hippocampus. There were no age-related changes in total arginase activity or arginase I and arginase II protein expression. Correlation analysis revealed that animals' motor ability was associated with CA1 NOS and arginase, as well as hippocampal function. The present findings provide further support for the involvement of NOS/NO and arginase in the normal aging process. A strong positive correlation between CA1 eNOS protein expression and swimming speed in the water maze task may reflect a relationship between the local cerebral blood flow and neuronal activity.

Aging↗
PubMed2005

The effects of vestibular lesions on hippocampal function in rats.

Interest in interaction between the vestibular system and the hippocampus was stimulated by evidence that peripheral vestibular lesions could impair performance in learning and memory tasks requiring spatial information processing. By the 1990s, electrophysiological data were emerging that the brainstem vestibular nucleus complex (VNC) and the hippocampus were connected polysynaptically and that hippocampal place cells could respond to vestibular stimulation. The aim of this review is to summarise and critically evaluate research published in the last 5 years that has seen major progress in understanding the effects of vestibular damage on the hippocampus. In addition to new behavioural studies demonstrating that animals with vestibular lesions exhibit impairments in spatial memory tasks, electrophysiological studies have confirmed long-latency, polysynaptic pathways between the VNC and the hippocampus. Peripheral vestibular lesions have been shown to cause long-term changes in place cell function, hippocampal EEG activity and even CA1 field potentials in brain slices maintained in vitro. During the same period, neurochemical investigations have shown that some hippocampal subregions exhibit long-term changes in the expression of neuronal nitric oxide synthase, arginase I and II, and the NR1 and NR2A N-methyl-D-aspartate (NMDA) receptor subunits following peripheral vestibular damage. Despite the progress, a number of important issues remain to be resolved, such as the possible contribution of auditory damage associated with vestibular lesions, to the hippocampal effects observed. Furthermore, although these studies demonstrate that damage to the vestibular system does have a long-term impact on the electrophysiological and neurochemical function of the hippocampus, they do not indicate precisely how vestibular information might be used in hippocampal functions such as developing spatial representations of the environment. Understanding this will require detailed electrical stimulation and lesion studies to elucidate the way in which different kinds of vestibular information are transmitted to various hippocampal subregions.

Animals↗
PubMed2005

Characterization of mitochondrial respiratory chain energetics in the vestibular nucleus complex.

CONCLUSIONS: Despite having very high neuronal firing rates, the VNC does not have unusually high mitochondrial activity in vitro. This study is the first in which functionally active mitochondria from the hindbrain have been isolated and characterized. OBJECTIVE: Neurons in the vestibular nucleus complex (VNC) have exceptionally high spontaneous firing rates. Neuronal mitochondria generate adenosine triphosphate critical for maintaining the membrane potentials required for axon firing. We therefore hypothesized a high rate of mitochondrial activity in the VNC. MATERIAL AND METHODS: To test this hypothesis, we compared mitochondrial activity in the VNC with mitochondrial activity from another area of the hindbrain, the cerebellum. Mitochondrial respiratory activity was assessed by measuring oxidative phosphorylation and mitochondrial respiratory enzyme complex activity. RESULTS: Assay results were not significantly different in the VNC compared to those obtained with the cerebellum or with rat brain mitochondria in previous studies.

Adenosine Triphosphate↗
PubMed2005

Immunocytochemical and stereological study of glucocorticoid receptors in rat medial vestibular nucleus neurons and the effects of unilateral vestibular deafferentation.

CONCLUSION: The results of this study suggest that neither the number of medial vestibular nucleus (MVN) neurons expressing cytosolic glucocorticoid receptors nor blood corticosterone levels change significantly during the development of vestibular compensation. OBJECTIVE: Vestibular compensation is a process of partial behavioral recovery that occurs following damage to the vestibular labyrinth. It has been suggested that this compensation process might be dependent on the release of glucocorticoids such as corticosterone at the time of unilateral vestibular deafferentation (UVD) and that changes in glucocorticoid receptors in the MVN might contribute to the initiation of the compensation process. MATERIAL AND METHODS: We compared the number of MVN neurons expressing cytosolic glucocorticoid receptors in rats at 10 h and 2 weeks following UVD, and in sham and anesthetic control animals; we also measured blood corticosterone levels. RESULTS: Using immunocytochemistry and stereology, we found that the majority of MVN neurons expressed glucocorticoid receptors, but there were no significant differences in the number of glucocorticoid receptor-expressing neurons in the ipsilateral or contralateral MVNs at 10 h or 2 weeks post-UVD; furthermore, corticosterone levels did not vary significantly between the UVD and control groups.

Adaptation, Physiological↗
PubMed2005

Strain distribution of alfalfa weevil (Coleoptera: Curculionidae) in an intergrade zone.

Strain distribution for the alfalfa weevil, Hypera postica (Gyllenhal), was determined for the five major alfalfa-growing regions of New Mexico. Mitochondrial DNA from field-collected weevils at each location was digested and sequenced to differentiate among strains. Eastern, Egyptian, and western strains were recovered, along with a population not matching any known strain. The majority of sites examined had populations of two strains intermingled within a field. This is the first confirmation of the presence of all three strains within the same geographic region. Possible implications for alfalfa weevil management are discussed.

Animals↗