Biomedical subjects

R J Nelson

Publications and source records attributed to R J Nelson.

At least 109 records · Page 6Linked to original sources

PubMed1997

Aggressive behavior in male mice lacking the gene for neuronal nitric oxide synthase requires testosterone.

Nitric oxide acts as a neural messenger in both the central and peripheral nervous systems. Mice with targeted disruption of the neuronal isoform of nitric oxide synthase (nNOS - / -) are extremely aggressive relative to wild-type (WT) mice. Male nNOS - / - mice exhibit an increase in the number and duration of aggressive encounters compared to WT animals when tested in a variety of paradigms used to test rodent aggression. This inappropriate aggressive behavior has only been observed in male nNOS - /- mice; nNOS - /- females, like female WT mice, exhibit little or no aggression. The present study sought to test the dependence of increased aggressive behavior in nNOS - / - males on testosterone. Intact nNOS - / - males exhibited elevated levels of aggression relative to intact WT males. Castration reduced aggression in both WT and nNOS - /- males to equivalent low levels. Testosterone replacement restored aggression to precastration levels in both genotypes. These data provide evidence that increased aggressive behavior of nNOS - /- mice, like aggression in WT mice, is testosterone-dependent.

Aggression↗

PubMed1997

Microchannel electrophoretic separations of DNA in injection-molded plastic substrates.

Microfabricated electrophoretic separation devices have been produced by an injection-molding process. The strategy for producing the devices involved solution-phase etching of a master template on a silicon wafer, followed by electroforming more durable injection-molding masters in nickel from the silicon master. One of the nickel electroforms was then used to prepare an injection mold insert, from which microchannel chips in an acrylic substrate were mass-produced. The microchannel devices were used to demonstrate high-resolution separations of double-stranded DNA fragments with total run times of less than 3 min. Run-to-run and chip-to-chip reproducibility was good, with relative standard deviation values below 1% for the run-to-run data and in the range of 2-3% for the chip-to-chip comparisons. Such devices could lead to the production of low-cost, single-use electrophoretic chips suitable for a variety of separation applications, including DNA sizing, DNA sequencing, random primary library screening, and rapid immunoassay testing.

Bacteriophage phi X 174↗

PubMed1997

Effects of nitric oxide on neuroendocrine function and behavior.

Nitric oxide (NO) is an unusual chemical messenger. NO mediates blood vessel relaxation when produced by endothelial cells. When produced by macrophages, NO contributes to the cytotoxic function of these immune cells. NO also functions as a neurotransmitter and neuromodulator in the central and peripheral nervous systems. The effects on blood vessel tone and neuronal function form the basis for an important role of NO on neuroendocrine function and behavior. NO mediates hypothalamic portal blood flow and, thus, affects oxytocin and vasopression secretion; furthermore, NO mediates neuroendocrine function in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. NO influences several motivated behaviors including sexual, aggressive, and ingestive behaviors. Learning and memory are also influenced by NO. Taken together, NO is emerging as an important chemical mediator of neuroendocrine function and behavior.

Animals↗

PubMed1997

The hypothalamic-pituitary-adrenal axis of prairie voles (Microtus ochrogaster): evidence for target tissue glucocorticoid resistance.

Basal plasma corticosterone levels in prairie voles (Microtus ochrogaster) are extremely high, in the absence of any apparent negative consequences of glucocorticoid excess. We tested the hypothesis that prairie voles are a novel rodent model of target tissue resistance to glucocorticoids. Prairie voles had a significantly higher adrenal-to-body weight ratio, 5- to 10-fold greater basal plasma corticosterone, and 2- to 3-fold greater basal plasma ACTH concentrations than montane voles (Microtus montanus) and rats. While plasma corticosterone binding globulin (CBG) was 2-fold higher in prairie voles than in rats, both estimated and directly measured plasma free corticosterone were significantly higher in prairie voles than in rats. Plasma corticosterone levels in prairie voles were responsive to both circadian cues and a stressor, but were resistant to suppression by the synthetic glucocorticoid, dexamethasone (DEX). Western blots of brain and liver protein extracts, using a glucocorticoid receptor (GR) antibody, revealed the presence of a approximately 97 kDa immunoreactive band, the expected size for GR. Binding assays revealed significantly lower DEX affinity of corticosteroid receptors (CR) in cytosol of prairie vole brain and liver than that in the same tissues in rats. We conclude that prairie voles are a novel rodent model of glucocorticoid resistance, and that decreased affinity of CR for ligand might be partially responsible for this phenomenon.

Adrenocorticotropic Hormone↗

PubMed1997

The use of genetic "knockout" mice in behavioral endocrinology research.

The production of mice with specific deletion of targeted genes (knockouts) has provided a useful tool in understanding the mechanisms underlying behavior. There are many opportunities with this new tool for behavioral neuroendocrinology, specifically, and behavioral biology, generally. Although this genetic technique offers new opportunities to study the mechanisms of behavior, as with all behavioral techniques there are some potential limitations. For example, the products of many genes are essential to normal function, and inactivating the gene may prove lethal or induce gross morphological or physiological abnormalities that can complicate interpretation of discrete behavioral effects. Unexpected compensatory or redundancy mechanisms might be activated when a gene is missing and cloud interpretation of the normal contribution of the gene to behavior. Behavioral tests study the effects of the missing gene (and gene product), not the effects of the gene directly. This conceptual shortcoming can be overcome in the same way that it is overcome in other types of ablation studies, by collecting converging evidence using a variety of pharmacological, lesion, and genetic manipulations. Finally, because mammalian genome mapping is currently focused on mice (Mus musculus), standardized behavioral testing of mice should be adopted. Against those disadvantages are several important advantages to using knockout mice in behavioral research: (1) disabling a gene is often a very precise and "clean" ablation, (2) the effects of the gene product can be abolished without the side-effects of drugs, and (3) genetic manipulations may be the only way to determine the precise role of many endogenous factors on behavior. The use of new inducible knockouts, in which the timing and placement of the targeted gene disruption can be controlled, will be an extremely important tool in behavioral endocrinology research.

Animals↗

PubMed1997

Social environment and steroid hormones affect species and sex differences in immune function among voles.

Testosterone has bipotential effects on male fitness; that is, it both suppresses immune function and maintains characteristics important for reproductive success. Presumably, these effects of testosterone may be more pronounced among polygynous species because testosterone concentrations are generally higher among polygynous than monogamous males. The present study examined sex and species differences in cell-mediated immunity among four arvicoline rodents. The role of mating system and sex steroids in sex differences in immune function was examined in individually housed polygynous meadow (Microtus pennsylvanicus) and montane (M. montanus) voles and monogamous prairie (M. ochrogaster) and pine (M. pinetorum) voles in Experiment 1. No sex differences in splenocyte proliferation were observed among the four species and circulating testosterone concentrations did not correlate with immune function of individuals within each species. The contribution of social isolation to these results was examined in Experiment 2, in which meadow and prairie voles were housed individually, or with same- or opposite-sex conspecifics in either pairs or groups of four per cage for 28 days. Overall, prairie voles exhibited more robust immune responses than meadow voles when housed in pairs or in same-sex groups. Sex differences in immune function were also apparent; male meadow voles had higher immune responses than female conspecifics when housed in pairs, whereas female prairie voles had higher responses than male conspecifics when housed in same-sex pairs. Circulating sex steroid hormones and corticosterone appear to mediate some, but not all, of the changes in immune function evoked by differential housing conditions. Taken together, these results suggest that social factors have significant effects on immunity and should be considered in studies of sex differences in immunity at both proximate and ultimate levels.

Animals↗

PubMed1997

The effects of photoperiod and food intake on reproductive development in male deer mice (Peromyscus maniculatus).

Seasonal breeding is a tactic that has evolved in rodents that limits reproduction to specific times of the year to increase reproductive success. In order to time breeding accurately, many animals respond to changes in daily photoperiod. Short day lengths inhibit breeding in many nontropical rodent species. Restricted food availability can also inhibit reproductive function among some individuals in these so-called "photoperiodic" populations. Rodents born at the end of the breeding season typically delay sexual maturation until the following spring. Prepubertal rodents exposed to day lengths that are < 12 h light/day will not undergo puberty for 4-7 months in the laboratory. Food restriction can also affect the timing of puberty onset. Reproductive function of food-restricted juvenile mice may remain inhibited until food availability improves. Alternatively, reproductive function of food-restricted juvenile mice might eventually develop despite restricted food intake. This study examined the effects of chronic food restriction and photoperiod on reproductive development in male deer mice (Peromyscus maniculatus bairdii). Short-day mice fed ad lib delayed gonadal development for 5-7 months, but eventually achieved reproductive maturity. The reproductive function of short-day mice fed ad lib was indistinguishable from long-day control animals when assessed at week 32. Long-day food-restricted mice exhibited an intermediate level of gonadal development and function. Short-day food-restricted deer mice also inhibited reproductive growth, but failed to demonstrate reproductive maturity by week 32 of the study. Taken together, these results suggest that retardation of reproductive development by food restriction is only superficially similar to the delay in reproductive maturation imposed by short day exposure. It does not appear that male deer mice escape from the inhibitory effects of food restriction to attain sexual development.

Animals↗

PubMed1997

Stress affects corticosteroid and immunoglobulin concentrations in male house mice (Mus musculus) and prairie voles (Microtus ochrogaster).

Glucocorticoids, secreted in response to perceived stress, can suppress immunoglobulin (Ig) levels and compromise immune function in mice and rats. Prairie voles (Microtus ochrogaster) have been reported to exhibit basal corticosterone concentrations that would cause pathological changes in the immune function of most other rodents. The goals of the present study were to verify that serum corticosterone concentrations are high in prairie voles, as compared with house mice (Mus musculus), by measuring serum corticosterone with the same RIA; to examine the effects of mild stressors on corticosterone response in both species and to examine the effects of elevated corticosterone levels on IgM and IgG levels in prairie voles and house mice. After 2 weeks of randomly timed 15-min daily restraint or cold-water swim sessions, animals were injected with sheep red blood cells. The data confirmed that basal blood concentrations of corticosterone were higher in prairie voles than house mice, but these high levels doubled after the first swim session in prairie voles, indicating that the adrenals can respond to stressors by producing increased corticosterone. After stress, antibody production (both IgM and IgG) was reduced in house mice but not in prairie voles, despite higher blood concentrations of glucocorticoids in prairie voles. Although body mass was statistically equivalent between species, prairie voles and mice differed dramatically in adrenal and splenic masses. Average adrenal mass of prairie voles was approximately three times the average mass of these organs in house mice; in contrast, the average splenic mass of house mice was approximately three times that of prairie voles. These data may be relevant to seasonal changes in immune function and survival.

Adrenal Cortex Hormones↗

PubMed1997

Role of melatonin in mediating seasonal energetic and immunologic adaptations.

Winter is energetically demanding and stressful; thermoregulatory demands increase when food availability usually decreases. Physiological and behavioral adaptations, including termination of breeding, have evolved among nontropical animals to cope with the energy shortages during winter. Presumably, selection for the mechanisms that permit physiological and behavioral anticipation of seasonal ambient changes have led to current seasonal breeding patterns for many populations. In addition to the well-studied seasonal cycles of mating and birth, there are also significant seasonal cycles of illness and death among field populations of mammals and birds. Energetically challenging winter conditions can directly induce death via hypothermia, starvation, or shock; surviving these demanding conditions likely puts individuals under great physiological stress. The stress of coping with energetically demanding conditions may increase adrenocortical steroid levels that could indirectly cause illness and death by compromising immune function. Individuals would enjoy a survival advantage if seasonally recurring stressors could be anticipated and countered by bolstering immune function. The primary environmental cue that permits physiological anticipation of season is daily photoperiod, a cue that is mediated by melatonin. However, other environmental factors may interact with photoperiod to affect immune function and disease processes. Immune function is compromised during the winter in field studies of birds and mammals. However, laboratory studies of seasonal changes in mammalian immunity consistently report that immune function is enhanced in short day lengths. To resolve this apparent discrepancy, we hypothesize that winter stressors present in field studies counteract short-day enhancement of immune function. Prolonged melatonin treatment mimics short days, and also enhances rodent immune function. Reproductive responsiveness to melatonin appears to affect immune function. In sum, melatonin may be part of an integrative system to coordinate reproductive, immunologic, and other physiological processes to cope successfully with energetic stressors during winter.

Acclimatization↗

PubMed1997

Urinary bladder-urethral sphincter dysfunction in mice with targeted disruption of neuronal nitric oxide synthase models idiopathic voiding disorders in humans.

Idiopathic voiding disorders affect up to 10-15% of men and women. We describe bladder abnormalities in mice with targeted deletion of the gene for neuronal nitric oxide synthase which model the clinical disorders. The mice possess hypertrophic dilated bladders and dysfunctional urinary outlets which do not relax in response to electrical field stimulation or L-arginine. The mice also display increased urinary frequency.

Animals↗

PubMed1997

Reduced aggressive behaviour in mice with targeted disruption of the oxytocin gene.

Oxytocin (OT) has been reported to mediate aggressive and affiliative behaviours in several species. The behavioural role of OT has been established with physiological manipulations that potentially affected blood pressure, which may have indirectly affected the behaviours under study. To provide converging evidence of the physiological role of OT in aggressive behavior, wild type (WT), heterozygous (OT-/+), and homozygous (OT-/-) mutant mice were tested in two aggression paradigms. In general, there was no significant difference in aggressiveness between WT and OT-/+ mice. However, there were significant reductions in the duration of aggressive behaviors among OT-/- animals, especially in agonistic encounters within neutral arenas. The OT-/- mice did not exhibit any sensorimotor deficits or display any altered general anxiety levels that may have accounted for the observed reduction in aggressive behavior. These data indicate that aggression is mediated in part by OT in mice and that increased aggressiveness is not an obligatory phenotypic result of targeted genetic disruption of any gene.

Aggression↗

PubMed1997

Changes in tissue oxyhaemoglobin concentration measured using multichannel near infrared spectroscopy during internal carotid angiography.

OBJECTIVE: To develop an in vivo model for testing spatially resolved spectroscopy and quantified near infrared spectroscopy (NIRS) cerebral blood flow measurements. METHOD: Multiple detector NIRS has been used to study changes in tissue oxyhaemoglobin (O2Hb) concentration during selective internal carotid angiography. A significant reduction in O2Hb occurred in tissue interrogated by detectors situated between 0.7 and 4.1 cm from the NIRS light source. RESULTS: The time course of O2Hb concentration change was consistent with displacement of oxygenated blood by the radiocontrast medium from vascular beds of differing flow and NIR light attenuation. Increasing changes in O2Hb concentration per unit photon path length--predicted to occur at greater emitter-detector separations if those changes had occurred predominantly in cerebral tissue--were found in the first four seconds after injection of radiocontrast medium. However, later changes (6-10 s) were larger and were not proportional to emitter-detector separation. CONCLUSION: The findings indicate that simple assumptions regarding the distribution of the internal carotid artery blood supply to cerebral and extracerebral tissues, the photon path length through those tissues, and their relative contributions to attenuation of NIR light may not be justified.

Brain↗

PubMed1997

Effects of photoperiod and 2-deoxy-D-glucose-induced metabolic stress on immune function in female deer mice.

Nontropical rodents may experience large fluctuations in both food availability and energetic demands. The energy required for thermoregulation is high during the winter when energy availability is usually low. Winter conditions can induce a state of energetic stress that elevates circulating glucocorticoid levels and compromises immune function. Exposure to short days enhances immune function; the adaptive function of short-day enhancement of immune function may be to counteract the effects of stress-induced immunocompromise. To examine the role of energy availability in immune function, female deer mice were housed in either long (16:8-h light-dark cycle) or short (8:16-h light-dark cycle) days for 8 wk and then injected with either saline or 2-deoxy-D-glucose (2-DG), a glucose analog that inhibits cellular utilization of glucose and induces energetic stress. Long-day mice injected with 2-DG exhibited elevated corticosterone levels and reduced splenocyte proliferation compared with control mice. Short days buffered the animals against glucoprivation stress. Neither corticosterone levels nor splenocyte proliferation differed between 2-DG injected and control mice housed in short days. These data are consistent with the hypothesis that short days provide a buffer against metabolic stress.

Animals↗

PubMed1997

Sex differences in immunocompetence differ between two Peromyscus species.

Males generally exhibit reduced immunocompetence and greater susceptibility to disease than females. The explanations for why males may be more susceptible to disease than females fall into two categories: 1) the proximate mechanisms mediating immunity, such as hormonal mechanisms, and 2) variation in reproductive success between the sexes. The present study examined the extent to which these factors contribute to sex differences in cell-mediated immune function in polygynous Peromyscus maniculatus and monogamous Peromyscus californicus. Prevailing hypotheses suggest that, because variation in male and female reproductive success is greater among polygynous than monogamous species, sex differences in immunocompetence should be greater among polygynous than monogamous species as well. In contrast to these predictions, sex differences in cell-mediated immunity and body mass were only observed among monogamous P. californicus, in which females exhibited higher splenocyte proliferation in response to the T cell mitogen, concanavalin A, and weighed less than male conspecifics. Male P. maniculatus had higher serum testosterone concentrations than male P. californicus, but females of the two species did not differ in circulating estradiol concentrations. Sex steroid concentrations were not correlated with either immunocompetence or body mass; however, large P. californicus males exhibited reduced immune responses. Taken together, these results do not support the hypothesis that sex differences in immunocompetence are more pronounced among polygynous compared with monogamous species. Furthermore, these data suggest that circulating testosterone does not mediate sex differences in immuno-competence or body mass in P. californicus.

Animals↗

PubMed1997

Metabolic costs of mounting an antigen-stimulated immune response in adult and aged C57BL/6J mice.

Animals must balance their energy budget despite seasonal changes in both energy availability and physiological expenditures. Immunity, in addition to growth, thermoregulation, and cellular maintenance, requires substantial energy to maintain function, although few studies have directly tested the energetic cost of immunity. The present study assessed the metabolic costs of an antibody response. Adult and aged male C5BL/6J mice were implanted with either empty Silastic capsules or capsules filled with melatonin and injected with either saline or keyhole limpet hemocyanin (KLH). O2 consumption was monitored periodically throughout antibody production using indirect calorimetry. KLH-injected mice mounted significant immunoglobulin G (IgG) responses and consumed more O2 compared with animals injected with saline. Melatonin treatment increased O2 consumption in mice injected with saline but suppressed the increased metabolic rate associated with an immune response in KLH-injected animals. Melatonin had no effect on immune response to KLH. Adult and aged mice did not differ in antibody response or metabolic activity. Aged mice appear unable to maintain sufficient heat production despite comparable O2 production to adult mice. These results suggest that mounting an immune response requires significant energy and therefore requires using resources that could otherwise be allocated to other physiological processes. Energetic trade-offs are likely when energy demands are high (e.g., during winter, pregnancy, or lactation). Melatonin appears to play an adaptive role in coordinating reproductive, immunologic, and energetic processes.

Aging↗

PubMed1997

Amygdala but not hippocampal lesions impair olfactory memory for mate in prairie voles (Microtus ochrogaster).

Exposure to an unfamiliar male conspecific results in pregnancy interruption (i.e., the Bruce effect) in rodents. Unlike most laboratory rodents, female prairie voles (Microtus ochrogaster) are induced into estrus by chemosensory stimuli contained in the urine of male conspecifics while grooming the anogenital (A-G) region of unfamiliar males. Female prairie voles maintain a brief "memory" for the stud male for 8-10 days after mating. Subsequent exposure to the same mate within this 8- to 10-day window does not elicit A-G investigation by the female and pregnancy block does not result. However, exposure to the original male after 10 days evokes A-G investigation and pregnancy block. To determine the neuroanatomic area(s) involved in olfactory memory for mate, female voles received bilateral electrolytic lesions of either the amygdala or hippocampus. Females were subsequently exposed to males for 48 h, separated for 3 days, then reintroduced to their original mate for 24 h. Although pregnancy rate did not differ among the experimental groups, a greater proportion of amygdala-lesioned females displayed pregnancy block when reexposed to their previous mates compared with hippocampal- or sham-lesioned voles. Amygdala-lesioned voles also displayed a greater number of A-G investigations compared with the other groups. Performance on olfactory tests was not impaired. Taken together, these results suggest that the amygdala plays an important role in olfactory memory for mate in prairie voles.

Amygdala↗

PubMed1997

Inhibition of neuronal nitric oxide synthase increases aggressive behavior in mice.

BACKGROUND: Mice with targeted disruption of the gene for the neuronal isoform of nitric oxide synthase (nNOS) display exaggerated aggression. Behavioral studies of mice with targeted gene deletions suffer from the criticism that the gene product is missing not only during the assessment period but also throughout development when critical processes, including activation of compensatory mechanisms, may be affected. To address this criticism, we have assessed aggressive behavior in mice treated with a specific pharmacological inhibitor of nNOS. MATERIALS AND METHODS: Aggressive behavior, as well as brain citrulline levels, were monitored in adult male mice after treatment with a specific nNOS inhibitor, 7-nitroindazole (7-NI) (50 mg/kg i.p.), which is known to reduce NOS activity in brain homogenates by > 90%. As controls, animals were treated with a related indazole, 3-indazolinone (3-I) (50 mg/kg i.p.) that does not affect nNOS or with on oil vehicle. RESULTS: Mice treated with 7-NI displayed substantially increased aggression as compared with oil- or 3-I-injected animals when tested in two different models of aggression. Drug treatment did not affect nonspecific locomotor activities or body temperature. Immunohistochemical staining for citrulline in the brain revealed a dramatic reduction in 7-NI-treated animals. CONCLUSIONS: 7-NI augmented aggression in WT mice to levels displayed by nNOS- mice, strongly implying that nNOS is a major mediator of aggression. NOS inhibitors may have therapeutic roles in inflammatory, cardiovascular, and neurologic diseases. The substantial aggressive behavior soon after administration of an nNOS inhibitor raises concerns about adverse behavioral sequelae of such pharmacological agents.

Aggression↗

PubMed1996

Reproductive and immune responses to photoperiod and melatonin are linked in Peromyscus subspecies.

The effects of photoperiod and melatonin treatment on reproductive and immune function were assessed in two subspecies of Peromyscus maniculatus from different latitudes of origin. In experiment 1, P. m. bairidii (latitude = 42 degrees 51' N) and P. m. luteus (latitude = 30 degrees 37' N) were housed in either long (LD 16:8) or short days (LD 8:16) for 8 weeks. Short-day P. m. bairdii displayed reproductive regression and elevated splenocyte proliferation in response to the T-cell mitogen concanavalin A, as compared to long-day mice. In contrast, P. m. luteus did not undergo reproductive regression or exhibit any increase in lymphocyte proliferation in short days. In experiment 2, individuals of both P. m. bairdii and P. m. luteus were implanted with empty capsules or capsules that contained melatonin. Individual P. m. bairdii implanted with melatonin underwent reproductive regression. Individuals of this subspecies also displayed elevated lymphocyte proliferation compared to control mice. Conversely, P. m. luteus implanted with melatonin did not undergo reproductive regression and displayed no significant changes in lymphocyte proliferation. These results suggest that reproductive responsiveness to melatonin mediates short-day enhancement of immune function in deer mice. These data also imply that melatonin may not possess universal immunoenhancing properties. Rather, the effectiveness of melatonin to influence immune responses may be constrained by reproductive responsiveness to this indole-amine.

Animals↗