Biomedical subjects
Publications and source records attributed to L L Brown.
Recent studies have found that the basal ganglia are involved in diverse behavioral activities and suggest that they have executive functions. Highlights from the past year include anatomical and clinical studies that have used sophisticated, novel methods to confirm a role for the basal ganglia in somatosensory discrimination, visual perception, spatial working memory and habit learning.
The effect of estradiol on opioid receptor density in the hypothalamus of female rats was examined by in vitro receptor autoradiography using [3H]naloxone as the ligand. Exposure of ovariectomized rats to estradiol for 48 h markedly increased the density of [3H]naloxone binding in both the ventral and dorsal premammillary nuclei but not in other regions of the hypothalamus or amygdala. Thus, estrogen selectively modulates opioid receptor binding in posterior hypothalamic regions involved in gonadotropin secretion and temperature regulation.
Although it is well known that there are sex differences in stress-induced activation of the hypothalamic-pituitary-adrenal axis, it is not known if there are also gender-related differences in stress-induced neural activity. In this study, restraint and formalin injections into a forelimb were used as stressors and 2-[14C]-deoxyglucose (2DG) autoradiography was used to evaluate regional brain glucose metabolism, an index of neural activity. Analysis of blood samples collected during the 2DG procedure confirmed that stress elevates plasma glucose levels signficantly more in females than in males. Moreover, females show higher brain glucose utilization in all regions examined, including sex hormone-responsive regions such as the medial amygdala, medial preoptic nucleus, ventromedial nucleus, and arcuate nucleus, as well as the CA1 layer and dentate region of the hippocampus, the posterior parietal (sensorimotor) cortex, medial and lateral habenula, and splenium of the corpus callosum. The sex differences are apparent regardless of whether animals were injected with saline or formalin. Interestingly, the medial preoptic area, which shows robust neuroanatomical sex differences, demonstrates greater activation in response to formalin than to saline only in females. In some regions of both males and females, glucose utilization was higher on the side of the brain contralateral to the saline or formalin injection site. These findings suggest that there are widespread, gender-related differences in neuronal as well as endocrine activation in response to highly stressful conditions.
In unanaesthetized rats, mechanical stimulation of a single vibrissa increased glucose utilization in one cortical column of the somatosensory area and in several spots in the dorsolateral neostriatum, predominantly on the side contralateral to the stimulation. Two or three peaks of glucose utilization unique to the stimulated animals were seen in cross sections throughout a 1.8 mm anteroposterior extent in the dorsolateral striatum. These observations suggest that one cortical column is functionally related to several neostriatal regions. The distributed modularity may be an important characteristic of the basal ganglia system.
Prior studies assessing the relation between negative affective traits and cortisol have yielded inconsistent results. Two studies assessed the relation between individual differences in repressive-defensiveness and basal salivary cortisol levels. Experiment 1 assessed midafternoon salivary cortisol levels in men classified as repressors, high-anxious, or low-anxious. In Experiment 2, more rigorous controls were applied as salivary cortisol levels in women and men were assessed at 3 times of day on 3 separate days. In both studies, as hypothesized, repressors and high-anxious participants demonstrated higher basal cortisol levels than low-anxious participants. These findings suggest that both heightened distress and the inhibition of distress may be independently linked to relative elevations in cortisol. Also discussed is the possible mediational role of individual differences in responsivity to, or mobilization for, uncertainty or change.
Diseases that affect the striatum produce movement disorders, for which rats have been a useful model. To determine the organization of functional, neural activity in the rat striatum related to motor activity, we used electrical stimulation of the motor cortex and [14C]deoxyglucose autoradiography. The stimulation produced movements of each of three body regions. Both the motor and somatosensory cortex were activated. Image analysis was used to objectively localize peak activation and to provide a map for further stereotaxic and localization studies. In the anterior striatum, in the dorsolateral sector, regions of peak activation were well separated for each body region: the hindlimb peak activation was dorsomedial, the forelimb ventrolateral and vibrissae medial. Also, the activation fields were larger in anterior than in posterior striatum. Furthermore, activation ipsilateral to movement was present and the peak localization was offset from peaks contralateral to movement. In addition, there were activation regions in lateral striatum where body region representations may overlap. This is the first demonstration of a global striatal somatotopy that separates the limbs and vibrissae in rats. The functional average revealed by the deoxyglucose autoradiography showed a predominant isotropic or rod-like representation of sensorimotor activity for the limbs in striatum during movement and confirms aspects of the anatomy known for the corticostriate system in primates: metabolism was 'patchy,' and extended throughout long anteroposterior domains in striatum. These extensive and patchy arrangements suggest integrative, combinational and/or associative networks.
The substantia nigra pars reticulata (SNR) is a structure involved in the control of seizures, and its effects on seizures are age-dependent. GABAergic transmission in the SNR, mediated by GABAA receptors, influences seizure susceptibility. We have found that in the adult SNR there may be at least two segregated GABAA-sensitive SNR projection networks involved in regulating the SNR effects on seizures, perhaps reflecting the existence of an anticonvulsant and a proconvulsant network. The two networks with opposing effects on seizures originate from two topographically distinct regions. The anterior-medial region of the SNR is associated with anticonvulsant effects, whereas the posterior-dorsal region of the SNR is associated with proconvulsant effects. To explain ontogenic differences in the SNR effects on seizures, we hypothesize that the two functionally segregated networks which influence the expression of seizures may become segregated with maturation. The increased seizure susceptibility of rat pups may be due, in part, to delayed development of this anterior-medial SNR anticonvulsant network.
The mature brain is less susceptible to seizures than the immature brain. We demonstrate that in the mature substantia nigra (SN) there are two topographically discrete GABAA-sensitive regions which differ in the amount of mRNA expression of the GABAA receptor alpha 1 subunit. These two regions mediate separate anticonvulsant and proconvulsant effects and use divergent projection networks. By contrast, in the immature SN there is no special topography of mRNA expression of the alpha 1 subunit and only the proconvulsant network is present. The decreased seizure susceptibility of the mature brain may be related to postnatal segregation of GABAA-sensitive networks.
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2-Deoxy-D-[14C]glucose autoradiography was used in awake rats to map neural activity in the sensorimotor sector of striatum. Stimulation of hindlimb, trunk, or forelimb activated primary sensory cortex in a localized columnar pattern, indicating activation of somatosensory receptors and a discrete cortical functional unit. In sensorimotor striatum, an image analysis detection technique revealed regions of maximal activity, or features, that formed a patchy pattern of activation reminiscent of the known anatomic patterns of cortico-striate terminals. Ipsilateral as well as contralateral activation was observed. The activated areas revealed a body map in striatum that was organized in a manner consistent with cortical topography (dorsoventrally: hindlimb, trunk, forelimb) at most anteroposterior levels, similar to that found in other species. However, at other levels, a different organization (e.g., trunk, hindlimb, forelimb) was observed. Furthermore, the arrangements of body region and side were also unique at different anteroposterior levels. Thus, functional activity showed multiple, different juxtapositions of body elements--i.e., a combinational map. The data suggest that striatum may provide an anatomic substrate for different combinations of inputs necessary to select and integrate movement.
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Commonly used methods for the measurement of leucine-specific activity use either high-performance liquid chromatography (HPLC) and pre-column derivatization or conventional ion-exchange chromatography. These are time-consuming, labor-intensive, relatively costly procedures, requiring high concentrations of radioactivity for accuracy. The present paper describes a method for the measurement of plasma leucine-specific activity using HPLC equipment, a large-bore ion-exchange column and post-column ninhydrin detection. With this method, determination of leucine concentration and leucine radioactivity was found to be linear (r2 greater than 0.999) over physiological ranges for both standards and deproteinized plasma. The intra- and inter-assay coefficients of variation for leucine concentrations were 1.4 and 2.7%, respectively. The intra- and inter-assay coefficients of variation for leucine-specific activities were 1.5 and 1.9%, respectively. The automated method is relatively fast (injection to injection time approximately 45 min), economical and capable of accurately assessing relatively small amounts of radioactivity.
To assess the interaction of exercise and insulin action, healthy males were studied with saline infusion (n = 5) or with a hyperinsulinemic euglycemic clamp (0.5, 1.0, 2.0, or 15.0 mU.kg-1.min-1; n = 5 at each dose) during rest (40 min), moderate-intensity cycle exercise (100 min), and recovery (100 min). Metabolism was assessed using isotopic methods and indirect calorimetry. During rest, exercise, and recovery with saline infusion, plasma glucose was unchanged, total glucose utilization (Rd) was 2.4 +/- 0.4, 4.9 +/- 0.2, and 2.6 +/- 0.2 mg.kg-1.min-1, and carbohydrate (CHO) oxidation (OX) was 1.4 +/- 0.3, 10.6 +/- 1.1, and 0.5 +/- 0.2 mg.kg-1.min-1. The glucose infusion, insulin-dependent Rd, and CHO OX increased synergistically when exercise and insulin clamps were combined. Exercise decreased (P less than 0.05) the half-maximal doses (ED50) and increased the maximal responses (Vmax) for insulin-dependent Rd and CHO OX. Estimates of insulin-independent Rd were 1.3 +/- 0.7, 4.1 +/- 1.3, and 1.9 +/- 0.7 mg.kg-1.min-1 and insulin-independent CHO OX were 1.2 +/- 0.9, 10.4 +/- 1.3, and 0.6 +/- 0.3 mg.kg-1.min-1 during rest, exercise, and recovery. Estimates during exercise were greater than those at rest (P less than 0.05). The total suppression of free fatty acids (FFA) and fat OX by insulin were elevated by exercise (P less than 0.05). In summary, exercise and insulin interact synergistically in stimulating Rd and CHO OX.(ABSTRACT TRUNCATED AT 250 WORDS)
Determination of amino acids by reversed-phase chromatography of the adduct with orthophthalaldehyde and a thiol is rapid and sensitive. The major recognized adverse feature of this method is the instability of the reaction product, which requires precise control of reaction timing and chromatographic parameters for reliable quantitative application. We report another source of major variability: reagent instability. Deterioration of reagent was noted as low peak heights and peak broadening and was predictable if the premixed reagent was left at room temperature. Restoration of sharp chromatograms was accomplished by addition of mercaptoethanol or sodium metabisulfite. Reagent which was chromatographically inert contained minimal free thiol by direct assay. Free thiol disappearance was markedly slowed by addition of a chelating agent. Excess mercaptoethanol was deleterious. We conclude that reagent deterioration represents oxidation of the thiol, may be reversed by rereduction with minimal thiol or bisulfite, and may be minimized by inclusion of a metal chelator in the reagent.
Local cerebral glucose utilization (LCGU), estimated by the quantitative autoradiographic 2-deoxyglucose technique, was studied in rats with bilateral 6-hydroxydopamine lesions of the locus coeruleus (LC) and in vehicle-injected controls. Unanesthetized animals were studied during exposure to stressful levels of white noise (95 dB) or in relative silence (50 dB). Results indicated that noise caused greater and more widespread increases in LCGU in animals with LC lesions than in vehicle-injected controls. Lesions alone had little or no effect in animals not subjected to noise. Analyses of variance revealed significant treatment interaction effects (intact/lesion x silence/noise) for 37 of 109 regions measured. The pattern of results suggests that the LC acts during stress to limit unnecessary cerebral activity that might interfere with efficient sensory processing and/or the organization of appropriate behavioral responses. In this respect LC function may be similar to those actions of the peripheral sympathetic nervous system that suppress vegetative functions during stress to allow for the performance of coping responses.