Biomedical subjects

G M Alexander

Publications and source records attributed to G M Alexander.

At least 19 recordsLinked to original sources

PubMed2006

Cortical feedback to the thalamus is selectively enhanced by nitric oxide.

The brain somehow merges visual information with the behavioral context in which it is being processed, a task that is often attributed to the cerebral cortex. We have identified a new role of the gaseous neurotransmitter, nitric oxide (NO), in the early selective enhancement of corticogeniculate communication that may participate in this process at the level of the thalamus. Visual information is dynamically gated through the thalamus by brainstem neurons that release acetylcholine and NO. Using in vitro electrophysiology, we characterized NO effects on excitatory postsynaptic potentials and currents (EPSCs) elicited from retinal and cortical pathways in the lateral geniculate nucleus of the ferret. NO selectively and reversibly increased cortically-evoked postsynaptic responses, and this effect was mimicked by cyclic guanosine 3',5'-monophosphate (cGMP). Conversely, NO inhibited retinally-evoked responses independently of cGMP. We demonstrated that these differential effects were specific to postsynaptic N-methyl-d-aspartate (NMDA) receptors by studying treatment effects on pharmacologically isolated EPSCs from each pathway. We propose that when brainstem activity is increased during behavioral arousal or rapid eye movement sleep, NO may increase the relative sensitivity of relay neurons to corticogeniculate feedback. The net effect of these changes in synaptic processing may be to selectively suppress peripheral information while unifying data carried by reentrant corticogeniculate loops with the behavioral context in which the visual information is processed.

Animals↗

PubMed2006

The native T-type calcium current in relay neurons of the primate thalamus.

The generation of thalamic bursts depends upon calcium currents that flow through transiently open (T)-type calcium channels. In this study, we characterized the native T-type calcium current underlying thalamic burst responses in the macaque monkey. Current clamp recordings from lateral geniculate nucleus (LGN) slices showed characteristic burst responses when relay cells were depolarized from relatively hyperpolarized membrane potentials. These bursts could also be elicited by stimulation of excitatory synaptic inputs to LGN cells. Under voltage clamp conditions, the inactivation kinetics of native currents recorded from primate LGN neurons showed consistency with T-type currents recorded in other mammals and in expression systems. Real-time reverse transcriptase PCR performed on RNA isolated from the LGN (including tissues isolated from magnocellular and parvocellular laminae) detected voltage-dependent calcium channel (Ca(v)) 3.1, Ca(v) 3.2, and Ca(v) 3.3 channel transcripts. Ca(v) 3.1 occurred at relatively higher expression than other isoforms, consistent with in situ hybridization studies in rats, indicating that the molecular basis for burst firing in thalamocortical systems is an important conserved property of primate physiology. Since thalamic bursts have been observed during visual processing as well as in a number of CNS disorders, studies of the expression and modulation of these currents at multiple levels are critical for understanding their role in vision and for the discovery of new treatments for disruptions of thalamic rhythms.

Animals↗

PubMed2006

Unique presynaptic and postsynaptic roles of Group II metabotropic glutamate receptors in the modulation of thalamic network activity.

The thalamic reticular nucleus (TRN) is a sheet of GABAergic neurons that project to other TRN neurons and to associated thalamocortical relay nuclei. The TRN receives glutamatergic synaptic inputs from cortex as well as reciprocal inputs from the collaterals of thalamocortical neurons. In addition to ionotropic glutamate receptors, metabotropic glutamate receptors (mGluRs) are present in the TRN circuitry. Using whole cell voltage clamp recordings, we pharmacologically characterized unique pre- and postsynaptic functions for Group II mGluRs (mGluR 2 and mGluR 3) within the TRN circuitry in ferrets. mGluR 2 was found on presynaptic cortical axon terminals in the TRN, where it reduced glutamate release, while mGluR 3 acted postsynaptically on TRN cells to increase membrane conductance. Using miniature inhibitory postsynaptic current analysis, we also found that picrotoxin-sensitive intra-TRN GABA-mediated neurotransmission was not affected by administration of a Group II mGluR agonist, indicating that neither mGluR 2 nor 3 acts on presynaptic GABA-containing terminals within the TRN. Because strong corticothalamic activation is implicated in abnormal thalamic rhythms, we used extracellular recordings in the lateral geniculate nucleus to study the effect of Group II mGluR agonists upon these slow oscillations. We induced approximately 3 Hz spike-and-wave discharge activity through corticothalamic stimulation, and found that such activity was reduced in the presence of the Group II mGluR agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268). These data indicate that Group II mGluR reduce the impact of corticothalamic excitation, and that they may be a useful target in the reduction of absence-like rhythms.

Amino Acids↗

PubMed2005

Differential response dynamics of corticothalamic glutamatergic synapses in the lateral geniculate nucleus and thalamic reticular nucleus.

The corticothalamic feedback pathway provides excitatory synaptic input to both the thalamic reticular nucleus and the lateral geniculate nucleus. We studied excitatory postsynaptic currents elicited from corticothalamic stimulation in the visual sector of the thalamic reticular nucleus and the lateral geniculate nucleus to compare the response of these neurons to stimulation of their common input pathway. Using whole cell patch clamp recordings in ferret thalamic slices, we compared single excitatory postsynaptic current decay kinetics, presynaptic glutamate release dynamics through paired pulse facilitation and responses to corticothalamic train stimulation. We found that single thalamic reticular nucleus excitatory postsynaptic currents were significantly sharper than lateral geniculate nucleus responses. The mean thalamic reticular nucleus excitatory postsynaptic current decay constant (tau) was 4.9+/-0.5 ms, while the mean lateral geniculate nucleus excitatory postsynaptic current tau value was 11.8+/-0.8 ms. Presynaptic release dynamics as measured by responses to paired stimuli were conserved between the thalamic reticular nucleus and lateral geniculate nucleus. However, facilitating responses to train stimulation were markedly different between nuclei. Lateral geniculate nucleus responses showed proportionately larger facilitation (reaching 842.9 +/- 76.4% of excitatory postsynaptic current 1 amplitude) than thalamic reticular nucleus responses (reaching 223.1 +/- 44.0% of excitatory postsynaptic current 1 amplitude). These data indicate that while the corticothalamic pathway produces excitatory postsynaptic currents in both the thalamic reticular nucleus and lateral geniculate nucleus, other factors uniquely affect the functional integration of the inputs in each nucleus.

Action Potentials↗

PubMed2005

Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder. While most cases of ALS are sporadic, 10-15% are familial, and of these 15-20% possess a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1). In families of ALS patients with specific SOD1 mutations, affected members demonstrate significant heterogeneity of disease and a large variation in age of onset and severity, suggesting that there are genetic modifiers of disease expression. Transgenic mice expressing mutant forms of SOD1 demonstrate symptoms similar to those seen in patients with ALS. We have observed in our colony of G93A SOD1 transgenic mice a milder phenotype in mice in a C57BL/6J background than the C57BL/6JxSJL/J hybrid background used by Jackson Laboratories to maintain their colony. To investigate the effect of genetic background on phenotype, we have constructed congenic lines on two genetic backgrounds, C57BL/6J (B6) and SJL/J (SJL). We report the influence of background and gender on the survival of these congenic lines compared to the hybrid C57BL/6JxSJL/J background. The mean survival of G93A SOD1 mice in the hybrid B6/SJL background was 130 days, with females surviving significantly longer than males. When compared to the hybrid B6/SJL background, the survival of mice in the SJL background significantly decreased, and the gender difference in survival was maintained. On the other hand, mean survival in the B6 background significantly increased, and in contrast to the B6/SJL and SJL backgrounds, there was no difference in survival between males and females. Transgene copy numbers were verified in all animals to ensure that any phenotypic differences observed were not due to alterations in copy number. This is the first report of a shortened lifespan when the G93A SOD1 transgene is placed on the SJL/J background and an increased survival with the loss of gender influences when the transgene is placed on the C57BL/6J background.

Age Factors↗

PubMed2001

Sex steroids and human behavior: implications for developmental psychopathology.

In a variety of mammalian species, prenatal androgens organize brain structures and functions that are later activated by steroid hormones in postnatal life. In humans, studies of individuals with typical and atypical development suggest that sex differences in reproductive and nonreproductive behavior derive in part from similar prenatal and postnatal steroid effects on brain development. This paper provides a summary of research investigating hormonal influences on human behavior and describes how sex differences in the prevalences and natural histories of developmental psychopathologies may be consistent with these steroid effects. An association between patterns of sexual differentiation and specific forms of psychopathology suggests novel avenues for assessing the effects of sex steroids on brain structure and function, which may in turn improve our understanding of typical and atypical development in women and men.

Journal Article↗

PubMed2001

Rat marrow stromal cells rapidly transduced with a self-inactivating retrovirus synthesize L-DOPA in vitro.

Autologous bone marrow stromal cells engineered to produce 3,4,-dihydroxyphenylalanine (L-DOPA) can potentially be used as donor cells for neural transplantation in Parkinson's disease. Here, we examined the possibility of using several different promoters and either a self-inactivating retrovirus (pSIR) or standard retroviruses to introduce into marrow stromal cells (MSCs), the two genes necessary for the cells to synthesize L-DOPA. pSIR vectors were constructed using the mouse phosphoglycerate kinase-1 (PGK) promoter or the cytomegalovirus (CMV) promoter to drive expression of either a GFP reporter gene or a bicistronic sequence containing the genes for human tyrosine hydroxylase type I (TH) and rat GTP cyclohydrolase I (GC) separated by an internal ribosome entry site (IRES). rMSCs were successfully transduced with both standard retroviral vectors and pSIR containing the PGK promoter. Transduced rMSCs expressed GFP (90.4--94.4% of cells) or were able to synthesize and secrete L-DOPA (89.0--283 pmols/10(6) cells/h). After transduced rMSCs were plated at low density (3--6 cells/cm(2)), the cells expanded over 1000-fold in 3--4 weeks, and the rMSCs continued to either express GFP or produce L-DOPA. Furthermore, two high-expressing clones were isolated and expanded at low-density from rMSCs transduced with pSIR driven by the PGK promoter (97.0% GFP+ or 1096.0 pmols L-DOPA/10(6) cells/h).

Animals↗

PubMed2001

Preoperative anxiolysis and postoperative recovery in women undergoing abdominal hysterectomy.

BACKGROUND: Every year, millions of patients receive sedatives for reduction of anxiety before surgery, but there is little objective data on the effect of this treatment on postoperative outcomes. To address this issue, the effects of benzodiazepine administration were evaluated in women undergoing abdominal surgery. METHODS: Patients were randomized to receive 1 mg of oral lorazepam the night before surgery and 5 mg of intramuscular midazolam on the morning of surgery (n = 34), or to receive a placebo the night before surgery and on the morning of surgery (n = 36). Postoperative pain (Visual Analogue Scale for pain, McGill Pain Questionnaire) and analgesic consumption (patient-controlled analgesia), and clinical recovery parameters such as time to discharge from hospital were evaluated after surgery. RESULTS: Patient-controlled analgesia use showed a marginal main effect of treatment group (F(1,51) = 2.8; P = 0.047). Post boc analysis demonstrated that patient-controlled analgesia consumption was significantly lower in the treatment group only during the first 4 h of patient-controlled analgesia use after surgery (P = 0.027). There were no significant group differences at any later postoperative time points (P = not significant). There were no group differences in the cumulative Percocet (Pfizer, New York, NY) consumption in the postoperative period (P = not significant). Further, self-reported postoperative pain did not differ significantly between groups at any of the time points (P = not significant). There were also no group differences with regard to any postoperative clinical recovery parameters. CONCLUSIONS: Benzodiazepines administered before surgery have minimal beneficial effects on the postoperative clinical course of women undergoing abdominal hysterectomy.

Adult↗

PubMed2000

Patch clamp studies of the thr1313met mutant sodium channel causing paramyotonia congenita.

Paramyotonia congenita (PC) is an autosomal-dominant disorder due to a point mutation in the adult skeletal muscle Na channel gene. Muscle fibers from PC patients have normal membrane properties at 32 degrees C. At 27 degrees C, they are inexcitable, have increased Na conductance, and have a reduced resting membrane potential of -40 mV. To define the biophysical basis for the muscle membrane abnormalities, we performed patch clamp whole-cell and outside-out single Na channel studies at 22 degrees C on cultured human muscle cells from 4 control patients and 2 sisters with PC and the thr1313met mutant Na channel. The whole-cell studies showed no difference in window currents. Unlike cells transfected with the thr1313met mutant Na channel, the inactivation time constant, tau(h), for PC cells was similar to control cells. For PC recordings containing long-duration single Na channel openings, mean open time was prolonged at -60, -40, and -20 mV. The long-duration Na channel openings occurred randomly with no evidence of modal gating. The number of channel openings, occurrence of late openings, and the prolonged mean open time resulted in a sustained inward Na current at -40 mV. We suggest that the biophysical marker of the thr1313met mutant Na channel is a voltage- and temperature-dependent abnormality in mutant single Na channel behavior.

Adult↗

PubMed2000

Preoperative anxiety and postoperative pain in women undergoing hysterectomy. A repeated-measures design.

OBJECTIVES: To determine whether psychological variables such as preoperative anxiety can serve as predictors for the postoperative pain response. METHODS: The study sample included women who underwent elective abdominal hysterectomy (n=53). Two weeks prior to surgery, characteristics such as trait anxiety, coping style, and perceived stress were evaluated. Throughout the perioperative period, state anxiety, pain, as well as analgesic consumption were assessed at multiple time points. The anesthetic and surgical management were carefully controlled for and postoperative pain management was standardized. RESULTS: Path analysis demonstrated that there are both direct and indirect effects of preoperative state anxiety on postoperative pain. Preoperative state anxiety is a significant positive predictor of the immediate postoperative pain (beta=0.30), which, in turn, is a positive predictor of pain on the wards (beta=0.54). Pain on the ward, in turn, is predictive for pain at home (beta=0.30). CONCLUSION: The results of this study indicate that preoperative anxiety may have a critical role in the chain-of-events that controls the postoperative pain response.

Adult↗

PubMed2000

Pain sensitivity and individual differences in self-reported sexual behavior.

The relationship between sexual behavior and pain sensitivity was assessed in 27 heterosexual men and 20 heterosexual women. Sexual behavior measures included sexual motivation and ratings of subjective sexual arousal to and enjoyment of an auditory stimulus. Pain sensitivity measures were pain threshold and pain tolerance in a cold pressor task. Participants were tested after exposure to a neutral or a sexual audio stimulus. Exposure to the sexual stimulus increased pain sensitivity in women but not in men. However, sexual behavior measures were correlated with pain threshold for both men and women. Specifically, higher pain thresholds were associated with weaker sexual motivation, lower enjoyment potential for sexual interaction, and increased inhibition during intercourse. These results are consistent with findings in laboratory animals, suggesting that differences in sexual behavior may reflect differences in responsiveness to a variety of stimuli.

Adolescent↗

PubMed2000

Elevated cortical extracellular fluid glutamate in transgenic mice expressing human mutant (G93A) Cu/Zn superoxide dismutase.

Transgenic mice expressing a mutated (G93A) human Cu/Zn superoxide dismutase (SOD1) develop motor neuron pathology and clinical symptoms similar to those seen in patients with amyotrophic lateral sclerosis. Loss of motor neurons is most prominent in lumbar, followed by cervical cord and then brainstem. No significant cell death has been reported in motor cortex. The integrity of the cortical glutamate reuptake systems was evaluated using intracerebral microdialysis and western immunoblot assays for the glutamate transporters GLT-1, GLAST, and EAAC1. The basal extracellular fluid levels of aspartate, glutamate, glutamine, 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindole-3-acetic acid were evaluated by HPLC. The extraction fraction of L-3H]glutamate, corrected with [14C]mannitol, was also evaluated. GLT-1, EAAC1, and GLAST protein levels were determined by semiquantitative chemiluminescence immunoblot of proteins from membrane-enriched fractions. The relative optical density of film was translated into relative protein level by comparison with a standard control mouse. The SOD1 mutant mice demonstrated a significant (p < 0.05) increase in basal levels of extracellular aspartate and glutamate. In addition, when the glutamate extraction fraction was challenged with exogenous unlabeled glutamate (500 microM) by reversed microdialysis, the glutamate extraction fraction in the mutant SOD1 mice was decreased significantly from control levels. The SOD1 mutant mice demonstrated no difference in the cortical protein levels of the glutamate transporter subtypes. This study demonstrates that in areas of no visible pathology and no loss of glutamate transporter proteins, SOD1 mutant mice have elevated extracellular fluid aspartate and glutamate levels and a decreased capacity to clear glutamate from the extracellular space.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Attenuation of the preoperative stress response with midazolam: effects on postoperative outcomes.

BACKGROUND: Previously, effects of preoperative sedatives were assessed mainly with respect to preoperative outcomes such as anxiety and compliance. The purpose of this investigation was to evaluate the effects of preoperative sedatives on postoperative psychological and clinical recovery. METHODS: Patients undergoing general anesthesia and outpatient surgery were enrolled in a double-blind, randomized, placebo-controlled trial. Subjects (n = 55) were randomly assigned to receive either 5 mg intramuscular midazolam (n = 26) or a placebo injection (n = 29) at least 30 min before surgery. The anesthetic technique was controlled. Postoperative anxiety, pain, analgesic consumption, clinical recovery parameters, and global health (SF-36) were evaluated up to 1 month after surgery. RESULTS: Surgery length did not differ significantly between the treatment and placebo groups (118 +/- 45 min vs 129 +/- 53 min; P = NS). Throughout the first postoperative week, subjects in the treatment group reported a greater reduction in postoperative pain compared with subjects in the placebo group (F1,50= 3.5; P = 0.035). Moreover, at 1 week, ibuprofen use was reported by less subjects in the treatment group than in the placebo group (0% vs 17.2%; P = 0.026). Subjects in the treatment group also reported a greater reduction in postoperative anxiety throughout the follow-up period (F1,53 = 9.2; P = 0.04). However, global health indexes (SF-36) did not detect any significant differences between the two experimental groups (multivariate F1,45 = 0.44; P = 0.51). CONCLUSION: Subjects treated with midazolam preoperatively self-report improved postoperative psychological and pain recovery. However, the clinical significance of these findings is unclear at the present time.

Adult↗

PubMed1999

Multipotential marrow stromal cells transduced to produce L-DOPA: engraftment in a rat model of Parkinson disease.

Bone marrow stromal cells can be used as an alternative source of cells for neural transplantation and repair. Here, the efficacy of genetically modified marrow stromal cells was examined in a rat model of Parkinson disease. Rat marrow stromal cells (rMSCs) and human marrow stromal cells (hMSCs) were genetically engineered by transduction with retroviruses encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase I, the enzyme necessary for production of the tetrahydrobiopterin cofactor for TH (BH4). Transduced cells synthesized 3,4-dihydroxyphenylalanine (L-DOPA) in vitro and maintained their multipotentiality after retroviral transduction. To examine the cells in vivo, transduced rMSCs were injected into the striatum of 6-hydroxydopamine-lesioned rats. L-DOPA and metabolites were detected by microdialysis in the denervated striatum of rats that received doubly transduced rMSCs. Also, there was a significant reduction in apomorphine-induced rotation when compared with controls. The cells engrafted and survived for at least 87 days. However, expression of the transgenes ceased at about 9 days, an observation consistent with reports from other laboratories in which similar retroviruses were used to express transgenes in the brain.

Animals↗

PubMed1999

Affective properties of intra-medial preoptic area injections of testosterone in male rats.

On alternating days, adult male Long-Evans rats implanted with unilateral cannulae in the medial preoptic area (MPOA) received intracerebral injections of testosterone (0.05, 0.1 or 0.2 microg/0.5 microl), or saline immediately prior to confinement for 30 min to one of two compartments of a place preference apparatus. All rats received 8 days of pairings (4 hormone and 4 saline). On day 9, the rats were given a hormone-free 20-min test session during which they had access to all compartments of the apparatus. Intra-MPOA injections of testosterone (0.1 microg) produced a conditioned place preference, while injections of a higher dose (0.2 microg) produced a conditioned place aversion. The rewarding effects of intra-MPOA testosterone may in part mediate the facilatory effects of testosterone on motivational aspects of sexual behavior.

Affect↗

PubMed1998

Androgen-behavior correlations in hypogonadal men and eugonadal men. II. Cognitive abilities.

Sex-typed cognitive abilities were assessed in 33 hypogonadal men receiving testosterone replacement therapy, 10 eugonadal men receiving testosterone in a male contraceptive clinical trial, and 19 eugonadal men not administered testosterone. Prior to and following hormone administration, men completed four tests measuring visuospatial ability, three tests measuring verbal fluency, two tests measuring perceptual speed, and a measure of verbal memory. Group differences in testosterone levels were unrelated to performance on most cognitive measures, including visuospatial ability. Relative to other men, hypogonadal men were impaired in their verbal fluency and showed improved verbal fluency following treatment with testosterone. These data suggest that testosterone may enhance verbal fluency in hypogonadal men and support the general hypothesis that current levels of testosterone may influence some aspects of cognitive function.

Adult↗

PubMed1998

Expression of testosterone conditioned place preference is blocked by peripheral or intra-accumbens injection of alpha-flupenthixol.

Previous evidence indicates that peripheral and intranucleus accumbens injections of testosterone have rewarding effects in male rats as measured in a conditioned place preference (CPP) paradigm. The present study investigated the neurochemical bases of the rewarding properties of testosterone by examining the effect of peripheral and intranucleus accumbens injection of the dopamine receptor antagonist alpha-flupenthixol on expression of testosterone-induced CPP. On alternating days, adult male Long-Evans rats received peripheral injections of testosterone in a water-soluble hydroxypropyl-beta-cyclodextrin (HBC) inclusion complex (0.8 mg/kg) or saline-HBC immediately prior to being confined for 30 min to one of two compartments of a place preference apparatus. All rats received 8 days of pairings (four hormone pairings, four saline pairings). On day 9 the rats were given a 20-min test session during which they had access to all compartments of the apparatus. No hormone was injected prior to the test session; however, rats received a peripheral (20 min prior; 0.2, 0.3 mg/kg) or intra-accumbens (2 min prior, 5.0 micrograms) injection of alpha-flupenthixol or saline. On the test day, rats receiving saline injections spent significantly more time in the compartment previously paired with injections of testosterone than in the compartment previously paired with vehicle injections. In contrast, rats receiving peripheral or intra-accumbens alpha-flupenthixol injections did not spend significantly more time in the compartment previously paired with testosterone. The blockade of testosterone CPP was not due to an effect of alpha-flupenthixol on motor behavior. The findings provide further evidence of the rewarding affective properties of testosterone and indicate that peripheral administration and intra-accumbens administration of alpha-flupenthixol block expression of testosterone CPP. The rewarding affective properties of testosterone are mediated, at least in part, via an interaction with the mesolimbic dopamine system.

Animals↗

PubMed1997

Intracerebral microdialysis study of glutamate reuptake in awake, behaving rats.

The central nervous system has high-affinity uptake systems for the clearance of amino acid transmitters. These systems are found in both neurons and astrocytes. Previous studies have shown that the uptake of amino acid transmitters by astrocytes in culture can be modulated by adrenergic agents. The objectives of this study were to develop a methodology that evaluates the brain's reuptake capacity for glutamate in awake, behaving animals and to determine whether glutamate reuptake is under alpha-adrenergic regulation in the intact central nervous system. Male Sprague-Dawley rats weighing 250-450 g were used in this study. The extraction fraction of L-[3H]glutamate with [14C]mannitol as a reference was measured. The cortical extraction fraction of L-[3H]glutamate corrected for [14C]mannitol (EL-glu) reaches steady state rapidly and is both stable and repeatable. EL-glu is a measure of L-glutamate reuptake and not metabolism. EL-glu is decreased in a dose-dependent manner by the addition of the glutamate reuptake blocker D,L-threo-beta-hydroxyaspartic acid or unlabeled L- glutamate. In addition, EL-glu is increased in a dose-dependent manner by the alpha1-adrenergic agonist phenylephrine, and this increase is blocked by the alpha-adrenergic antagonist phentolamine.

3,4-Dihydroxyphenylacetic Acid↗