Biomedical subjects

M Fleshner

Publications and source records attributed to M Fleshner.

At least 37 records · Page 2Linked to original sources

PubMed2000

Effects of vagotomy on serum endotoxin, cytokines, and corticosterone after intraperitoneal lipopolysaccharide.

The vagus nerve appears to play a role in communicating cytokine signals to the central nervous system, but the exact extent of its involvement in cytokine-to-brain communication remains controversial. Recently, subdiaphragmatic vagotomy was shown to increase bacterial translocation across the gut barrier and thus may cause endotoxin tolerance. The current experiment tested whether or not vagotomized animals have similar systemic responses to endotoxin challenge as do sham-operated animals. Subdiaphragmatically vagotomized and sham-operated animals were injected intraperitoneally with one of three doses (10, 50, 100 microg/kg) of lipopolysaccharide (LPS) or vehicle, and blood samples were taken at 15, 30, 60, 90, and 120 min after the injection. The intraperitoneal injection of LPS increased circulating LPS levels at all time points examined. In addition, all three doses of LPS significantly increased serum interleukin (IL)-1beta, IL-6, and corticosterone in both control and vagotomized rats. In conclusion, vagotomy itself has no marked effect on circulating endotoxin levels or the production of IL-1beta, IL-6, or corticosterone in blood after an intraperitoneal injection of LPS.

Animals↗

PubMed2000

Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats.

Exercise training produces a vast array of physiological adaptations, ranging from changes in metabolism to muscle mitochondrial biogenesis. Researchers studying the physiological effects of exercise often use animal models that employ forced exercise regimens that include aversive motivation, which could activate the stress response. This study examined the effect of forced treadmill running (8 wk) on several physiological systems that are sensitive to training and stress. Forced treadmill running produced both positive and negative physiological adaptations. Indicative of positive training adaptations, exercised male Sprague-Dawley rats had a decrease in body weight gain and an increase in muscle citrate synthase activity compared with sedentary controls. In contrast, treadmill running also resulted in the potentially negative adaptations of adrenal hypertrophy, thymic involution, decreased serum corticosteroid binding globulin, elevated lymphocyte nitrite concentrations, suppressed lymphocyte proliferation, and suppressed antigen-specific IgM. Such alterations in neuroendocrine tissues and immune responses are commonly associated with chronic stress. Thus treadmill running produces both positive training adaptations and potentially negative adaptations that are indicative of chronic stress. Researchers employing forced activity need to be aware that this type of exercise procedure also produces physiological adaptations indicative of chronic stress and that these changes could potentially impact other measures of interest.

Adaptation, Physiological↗

PubMed2000

Spaceflight induces changes in splenocyte subpopulations: effectiveness of ground-based models.

Spaceflight produces changes in the immune system. The mechanisms for the alterations in immune function after spaceflight remain unclear due in part to the difficulties associated with conducting spaceflight research. The purpose of the following studies, therefore, was to create a ground-based protocol that can reproduce the immunological changes found after spaceflight, i.e., changes in splenic lymphocyte populations. Rats were exposed to either flight aboard the Space Shuttle Endeavor (STS-77) or ground-based simulations of various components of the spaceflight experience. The ground-based mock spaceflight was comprised of exposure to launch and landing loads and unloading of the hindlimbs. In addition, each component of this ground-based mock spaceflight was tested separately. The results were that spaceflight reduced splenic CD4(+) T (helper/inducer) cells and CD11b(+) (neutrophils/macrophages) cells. The ground-based simulations of spaceflight did not reproduce the same pattern of splenocyte changes. In fact, exposure to landing loads alone increased splenic CD4(+) T (helper/inducer) cells. These findings support the conclusion that the ground models tested did not induce similar changes in the immune system as did spaceflight. It is possible, therefore, that stressors/factors unique to the spaceflight experience impact the immune system in ways that cannot be currently, fully modeled on the ground.

Animals↗

PubMed2000

TNF-alpha blockade by a dimeric TNF type I receptor molecule selectively inhibits adaptive immune responses.

Tumor necrosis factor-alpha (TNF-alpha) is a mediator of severe inflammatory processes, including rheumatoid arthritis. Suppression of TNF with a soluble type I or type II receptor molecule (TNF-RI or TNF-RII) has the potential to decrease cytokine levels and modulate inflammatory diseases in humans. However, it has recently been reported that treatment of mice with a TNF-RI:Fc immunoadhesin protein augmented Gram positive infections and subsequent mortality. To determine if TNF-alpha blockade with soluble TNF-alpha receptors might alter immune system function, assays were assessed in rodents treated with a dimeric form of the p55 TNF-RI, Tumor Necrosis Factor-binding protein (TNFbp). Administration of TNFbp resulted in suppression of primary and secondary IgG antibody responses and cell-mediated immune function. No treatment-related differences were detected in immune-enhancing assays or non-specific immune function parameters. Bacterial host resistance assays with Listeria monocytogenes, Staphylococcus aureus or Escherichia coli showed an increase in tissue colony counts only with L. monocytogenes challenged animals following TNFbp administration. These results suggest that TNFbp has the capacity to inhibit adaptive immune function in experimental animal models. Studies suggest that while reducing TNF-alpha is important in controlling cytokine-dependent disease states, maintenance of a threshold level may be critical for normal immune function.

Animals↗

PubMed1999

Combined effects of space flight factors and radiation on humans.

The probability that a dose of ionizing radiation kills a cell is about 10,000 times the probability that the cell will be transformed to malignancy. On the other hand, the number of cells killed required to significantly impact health is about 10,000 times the number that must be transformed to cause a late malignancy. If these two risks, cell killing and malignant transformation, are about equal, then the risk that occurs during a mission is more significant than the risk that occurs after a mission. The latent period for acute irradiation effects (cell killing) is about 2-4 weeks; the latent period for malignancy is 10-20 years. If these statements are approximately true, then the impact of cell killing on health in the low-gravity environment of space flight should be examined to establish an estimate of risk. The objective of this study is to synthesize data and conclusions from three areas of space biology and environmental health to arrive at rational risk assessment for radiations received by spacecraft crews: (1) the increased physiological demands of the space flight environment; (2) the effects of the space flight environment on physiological systems; and (3) the effects of radiation on physiological systems. One physiological system has been chosen: the immune response and its components, consisting of myeloid and lymphoid proliferative cell compartments. Best-case and worst-case scenarios are considered. In the worst case, a doubling of immune-function demand, accompanied by a halving of immune capacity, would reduce the endangering dose to a crew member to around 1 Gy.

Animals↗

PubMed1999

Long-term changes in mineralocorticoid and glucocorticoid receptor occupancy following exposure to an acute stressor.

Stressors produce rapid activation of the hypothalamic-pituitary-adrenal axis, which typically resolves within 60-90 min following termination of the stressor. In addition, some stressors such as inescapable tailshock (IS) also produce elevated basal levels of corticosterone (CORT), and reduced serum levels of corticosteroid binding globulin (CBG). The elevated basal levels of CORT produced by IS are only observed at the trough of the circadian rhythm of CORT secretion, and are sustained for 2-3 days following stressor termination. The goal of the following experiments was to determine the extent to which the elevated basal levels of CORT observed following IS exposure produced greater corticosteroid receptor occupancy in the brain and pituitary. To do so, rats (n=8-10 per group) received either sham or bilateral adrenalectomy (with CORT replacement in their drinking water; 25 microg/ml) and were given 3 days to recover. Rats were then exposed to 100 ISs (1.6 mA, 5 s each) administered on a 60 s variable intertrial interval, or remained in their home cages. As seen previously, IS produced an increase in basal CORT (5 microg/dl) and a decrease in CBG (30% decrease). Rats were sacrificed 24 h following IS for trunk blood samples and brain dissections. IS exposure had very little effect on corticosteroid receptor protein expression as determined by mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) binding levels in ADX rats. In addition, no changes in whole cell GR levels (as detected by Western blot) were observed in sham rats exposed to IS. On the other hand, IS exposure led to greater occupancy of MR (ranging from 25%-50%) in hippocampus, hypothalamus, pituitary, and posterior cortex. IS also produced greater occupancy of GR (approximately 20%) in hypothalamus and posterior cortex. These long-term changes in corticosteroid receptor activation, evident 24 h after IS exposure, may be responsible for some of the long-term neural, behavioral and immune changes observed following this acute stress procedure.

Adrenalectomy↗

PubMed1999

Exposing rats to a predator blocks primed burst potentiation in the hippocampus in vitro.

This study evaluated the effects of acute psychological stress (cat exposure) in adult male rats on electrophysiological plasticity subsequently assessed in the hippocampus in vitro. Two physiological models of memory were studied in CA1 in each recording session: (1) primed burst potentiation (PBP), a low-threshold form of plasticity produced by a total of five physiologically patterned pulses; and (2) long-term potentiation (LTP), a suprathreshold form of plasticity produced by a train of 100 pulses. Three groups of rats were studied: (1) undisturbed rats in their home cage (home cage); (2) rats placed in a chamber for 75 min (chamber); and (3) rats placed in a chamber for 75 min in close proximity to a cat (chamber/stress). At the end of the chamber exposure period, blood samples were obtained, and the hippocampus was prepared for in vitro recordings. Only the chamber/stress group had elevated (stress) levels of corticosterone. The major finding was that PBP, but not LTP, was blocked in the chamber/stress group. Thus, the psychological stress experienced by the rats in response to cat exposure resulted in an inhibition of plasticity, which was localized to the intrinsic circuitry of the hippocampus. This work provides novel observations on the effects of an ethologically relevant stressor on PBP in vitro and of the relative insensitivity of LTP to being modulated by psychological stress. We discuss the relevance of these electrophysiological findings to our behavioral work showing that predator stress impairs spatial memory.

Action Potentials↗

PubMed1999

Role of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation.

Isolating rats immediately after conditioning impairs contextual but not auditory-cue fear conditioning. The reported experiments examine the involvement of brain interleukin-1beta (IL-1beta) in the impairment in contextual fear conditioning caused by social isolation. As measured by the conditioned freezing response, 5 h of social isolation after conditioning, impaired contextual but not auditory-cue fear conditioning in adult male Sprague-Dawley rats. Social isolation for 1 or 3 h after conditioning also increased IL-1beta protein in the hippocampus and cerebral cortex. No differences in IL-1beta protein levels were found in the pituitary or the hypothalamus. Intracerebroventricular (ICV) IL-1 receptor antagonist (IL-1ra) given after conditioning prevented the impairment in contextual fear conditioning caused by isolation. ICV IL-1ra had no effect on auditory-cue fear conditioning in these same animals, nor did it affect the level of contextual fear conditioning displayed by home cage controls. Like isolation, ICV IL-1beta (10 or 20 ng) after conditioning also impaired contextual but not auditory-cue fear conditioning. These results suggest that increased levels of brain IL-1beta play a role in producing the impairment in contextual fear conditioning produced by social isolation. These findings also add to the generality of the idea that stressors induce IL-1beta activity in the brain and that IL-1beta may play physiological roles in the uninjured brain.

Acoustic Stimulation↗

PubMed1999

Differential expression of stress proteins in rat myocardium after free wheel or treadmill run training.

High-intensity treadmill exercise increases the expression of a cardioprotective, inducible 72-kDa stress protein (SP72) in cardiac muscle. This investigation examined whether voluntary free wheel exercise training would be sufficient to confer a similar response. Male Sprague-Dawley rats were randomly assigned to either treadmill (TM-Tr) or free wheel (FW-Tr) training groups. By the end of the 8-wk training period, TM-Tr animals ran 1 h/day, 5 days/wk up a 10% grade, covering a distance of 8,282 m/wk. FW-Tr rats ran, on average, 5,300 m/wk, with one-third of the animals covering distances similar to those for the TM-Tr group. At the time of death, hearts of trained and caged sedentary control (Sed) animals were divided into left (LV) and right (RV) ventricles. Citrate synthase activity and the relative immunoblot contents of SP72, SP73 (the constitutive isoform of the SP70 family), and a 75-kDa mitochondrial chaperone (SP75) were subsequently determined. LV and RV did not differ on any measure, and SP73, SP75, and citrate synthase were not affected by training. Cardiac SP72 levels were elevated over fourfold in both ventricles of TM-Tr compared with RV of FW-Sed rats. Despite the animals having run a similar total distance, cardiac SP72 content in FW-Tr rats was not different from that in Sed animals. These data indicate that voluntary exercise training is insufficient to elicit an elevation of SP72 in rat heart and suggest that exercise intensity may be a critical factor in evoking the cardioprotective SP72 response.

Animals↗

PubMed1999

The enhancement of hippocampal primed burst potentiation by dehydroepiandrosterone sulfate (DHEAS) is blocked by psychological stress.

This series of studies investigated the effects of psychological stress and the neurosteroid dehydroepiandrosterone sulfate (DHEAS) on hippocampal primed burst (PB) and long-term (LTP) potentiation, two electrophysiological models of memory. The DHEAS and stress manipulations were performed on awake rats, and then PB and LTP were recorded while the rats were anesthetized. DHEAS enhanced PB potentiation when administered to rats under non-stress conditions, but had no effect when given to stressed rats. Further study showed that DHEAS enhanced PB potentiation only when it was administered before, but not after, the rats were stressed. The DHEAS and stress manipulations had no effect on LTP. This study provides three major findings regarding stress, neurosteroids and hippocampal plasticity. First, DHEAS enhanced a threshold form of plasticity (PB potentiation), but had no effect on a supra-threshold form of plasticity (LTP). Second, stress blocked the DHEAS-induced enhancement of PB potentiation. Third, stress and DHEAS effects on the hippocampus were so durable they could be performed on awake animals and then be studied while the animals were anesthetized. That DHEAS enhanced a subset of forms of hippocampal plasticity under restricted behavioral conditions may help to resolve conflicting observations of DHEAS effects on cognition and mood in people.

Animals↗

PubMed1998

The long term acute phase-like responses that follow acute stressor exposure are blocked by alpha-melanocyte stimulating hormone.

Both intracerebroventricular (i.c.v.) IL-1beta and exposure to inescapable tail shock (IS) activate acute phase responses (APRs) that include increases in core body temperature (CBT), increases in hypothalamic-pituitary-adrenal activity, decreases in carrier proteins such as corticosterone binding globulin (CBG), aphagia and adipsia. A variety of data suggested that stressors produce APRs by inducing brain IL-1beta. The current series of studies further explored this possibility by determining whether the functional IL-1beta antagonist, alpha-melanocyte-stimulating hormone (alpha-MSH(1-13)), would block IS-induced APRs. Immediately following i.c.v. alpha-MSH(1-13) administration, rats were exposed to a single session of 100, 5 s, 1.6 mA ISs, or control treatment (home cage control). alpha-MSH(1-13) blocked IS-induced increased CBT, increased plasma corticosterone (CORT), decreased CBG, aphagia and adipsia 24 h after IS. The inhibitory effects of alpha-MSH(1-13) were shown not to be a consequence of alpha-MSH(1-13) producing its actions 24 h after its administration because alpha-MSH(1-13) given 24 h before IS did not block IS-induced increased CBT and CORT during IS. Additionally, alpha-MSH(1-13), given 24 h before IS, had no effect on increased CBT, increased CORT, decreased CBG, adipsia, or aphagia 24 h after IS. These data provide support for a specific mode of action for i.c.v. alpha-MSH(1-13), namely blockade of APRs with no impact on acute hyperthermia or increased levels of CORT produced during IS.

Acute-Phase Reaction↗

PubMed1998

Thermogenic and corticosterone responses to intravenous cytokines (IL-1beta and TNF-alpha) are attenuated by subdiaphragmatic vagotomy.

The brain orchestrates changes in behavior and physiology as a consequence of peripheral immune activation and infection. These changes require that the brain receives signals from the periphery that an immunological challenge has occurred. Previous research has established that cytokines play a role in signalling the brain. What remains unclear, however, is how peripheral cytokines signal the central nervous system. A recent proposal is that cytokines signal the brain by stimulating peripheral nerves. The hypothesis states that following infection and the release of cytokines such as IL-1beta into local tissue or microvasculature, IL-1beta stimulates IL-1 receptors on vagal afferent terminals, or more likely on cells of vagal paraganglia. Vagal afferents, in turn, signal the brain. Previous work has demonstrated that transection of the vagus below the level of the diaphragm blocks or attenuates many illness consequences of intraperitoneally (i.p.) administered lipopolysaccharide (LPS) or IL-1beta. The present studies extend these findings by examining the effect of subdiaphragmatic vagotomy on illness consequences following intravenously (i.v.) administered IL-1beta and TNF-alpha. Subdiaphragmatic vagotomy attenuated both the fever response and corticosterone response produced by i.v. administered cytokines. This effect was dose dependent. The results add support to the hypothesis that vagal afferents are involved in peripheral cytokine-to-brain communication.

Animals↗

PubMed1998

The role of the vagus nerve in cytokine-to-brain communication.

Peripheral interleukin-1 beta (IL-beta) and inflammatory stimuli that induce the synthesis and release of IL-1 beta produce a variety of central nervous system responses. Most proposals designed to explain how peripheral IL-1 beta influences the CNS have focused on blood-borne routes of communication. We will review data that indicate that at least some of the CNS response to peripheral IL-1 beta are instead mediated by a neural route of communication between the periphery and the CNS. IL-1 beta activates afferent vagal fibers that terminate in the nucleus tractus solitarius, and communication via the vagus is responsible for much of the hyperalgesia, fever, anorexia, taste aversions, increased levels of plasma corticosteroid, and brain norepinephrine changes produced by intraperitoneal injections of IL-1 beta and LPS. Data extending this analysis to TNF-alpha and intravenous routes will be described.

Afferent Pathways↗

PubMed1998

Exposure to acute stress induces brain interleukin-1beta protein in the rat.

Peripheral immune stimulation such as that provided by lipopolysaccharide (LPS) has been reported to increase brain levels of IL-1beta mRNA, immunoreactivity, and bioactivity. Stressors produce many of the same neural and endocrine responses as those that follow LPS, but the impact of stressors on brain interleukin-1beta (IL-1beta) has not been systematically explored. An ELISA designed to detect IL-1beta was used to measure levels of IL-1beta protein in rat brain. Brain IL-1beta was explored after exposure to inescapable shock (IS; 100 1.6 mA tail shocks for 5 sec each) and LPS (1 mg/kg) as a positive control. Rats were killed either immediately or 2, 7, 24, or 48 hr after IS. Brains were dissected into hypothalamus, hippocampus, cerebellum, posterior cortex, and nucleus tractus solitarius regions. LPS produced widespread increases in brain IL-1beta, but IS did not. Adrenal glucocorticoids are known to suppress IL-1beta production in both the periphery and brain. Thus, it was possible that the stressor did provide stimulus input to the brain IL-1beta system(s), but that the production of IL-1beta protein was suppressed by the rapid and prolonged high levels of glucocorticoids produced by IS. To test this possibility rats were adrenalectomized or given sham surgery, with half of the adrenalectomized rats receiving corticosterone replacement to maintain basal corticosterone levels. IS produced large increases in brain IL-1beta protein in the adrenalectomized subjects 2 hr after stress, whether basal corticosterone levels had been maintained. Thus elimination of the stress-induced rise in corticosterone unmasked a robust and widespread increase in brain IL-1beta.

Acute Disease↗

PubMed1998

Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning.

The reported experiments explore the effects of peripheral LPS administration on learning and memory processes. As measured by the conditioned freezing response, intraperitoneal LPS administration given after conditioning impaired contextual but not auditory-cue fear conditioning in both juvenile (hooded Long Evans) and adult rats (albino Sprague Dawley) of two different strains. This impairment in contextual fear conditioning was not dependent on the presence of the tone. Preexposure to the context eliminated the effect of LPS on contextual fear conditioning, and in addition, LPS given after context preexposure negated the beneficial effects of preexposure on contextual fear. These results suggest that LPS disrupts posttrial memory consolidation processes. In support of the hypothesis that LPS-induced proinflammatory cytokine release is involved in producing the impairment in contextual fear caused by LPS, peripheral interleukin-1 receptor antagonist (IL-1ra) administered subcutaneously at a dose of 100 mg/kg prevented the impairment in contextual fear caused by LPS. These experiments provide evidence for a role of immune activation and cytokine activity in learning and memory processes.

Acoustic Stimulation↗

PubMed1998

Acute stressor exposure both suppresses acquired immunity and potentiates innate immunity.

Acute stressor exposure alters immune function. Rats exposed to inescapable tail shock stress (IS) generate less antibody to a benign, antigenic protein, keyhole limpet hemocyanin (KLH). The following studies examined the effect of IS on peritoneal cavity, spleen, and mesenteric lymph node cell number, interferon-gamma (IFN-gamma) production, and nitrite production. Rats were injected intraperitoneally with KLH (200 microg) or saline immediately before IS exposure and killed 0, 48, and 96 h after IS termination. KLH immunization resulted in elevated cell numbers and IFN-gamma levels 2-4 days later in nonstressed control rats. In contrast, rats exposed to IS failed to increase cell number and IFN-gamma levels in response to KLH. The T cell subpopulations affected were CD4 T cells, specifically the Th1-like subset. In addition, in rats exposed to IS + KLH, nitrite production was potentiated 2-4 days after stressor termination. IS had little effect on these measures in saline-injected rats. These data support the conclusion that exposure to IS suppresses the expansion of anti-KLH lymphocytes, possibly anti-KLH Th1 cells. In addition, stressor exposure potentiates the production of nitrite. Importantly, this potentiated response occurred only in KLH-immunized animals, suggesting that macrophages may be primed by stressor exposure and thus respond more vigorously to antigen. The potential links between these changes are discussed.

Animals↗

PubMed1997

Subdiaphragmatic vagotomy does not prevent fever following intracerebroventricular prostaglandin E2: further evidence for the importance of vagal afferents in immune-to-brain communication.

Brain-mediated sickness responses can be blocked by subdiaphragmatic vagotomy, suggesting that vagal afferents signal peripheral inflammation or infection. This study tested whether subdiaphragmatic vagotomy disrupts sickness responses by interrupting effector pathways. If this explanation is correct, intracerebroventricular prostaglandin E2-induced fever should be blocked by this procedure. Fever was unaffected by subdiaphragmatic vagotomy, thus these data provide support for the conclusion that vagal afferents signal the brain during immune activation.

Animals↗

PubMed1997

Type II glucocorticoid receptor antagonists impair contextual but not auditory-cue fear conditioning in juvenile rats.

There is evidence that glucocorticoids may play a role in learning and memory. To further explore this possibility, we examined the effect of the Type II glucocorticoid antagonists on contextual fear conditioning. This conditioning task is dependent on the hippocampal formation, a brain structure known to be rich in glucocorticoid receptors. Rats systemically injected with a Type II antagonist either 1 h prior to conditioning (RU 38486 and RU 40555) or immediately after conditioning displayed less contextual fear conditioning than rats injected with vehicle. Although RU impaired contextual fear conditioning, it had no effect on auditory fear conditioning. These data are consistent with other reports that contextual fear conditioning and auditory-cue fear conditioning depend on different processes and with the hypothesis that glucocorticoid activity contributes to the processes involved in the consolidation of some forms of memory.

Animals↗