Showing papers in "Brain Behavior and Immunity in 1998"
TL;DR: It emerges that 5-HT may mediate interactions of these two systems by four different pathways, which include T cell and natural killer cell activation, delayed-type hypersensitivity responses, production of chemotactic factors, and natural immunity delivered by macrophages.
Abstract: Serotonin (5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. 5-HT is, however, also present in a variety of peripheral tissues including in constituents of the immune system. The function of 5-HT in the immune system has received increasing attention since about 1984, but has been reviewed only once, in 1985. In recent years, modern techniques of molecular biology such as reverse-transcriptase polymerase chain reaction and targeted gene disruption have made it possible to study new important aspects of 5-HT in the immune system. In the first part of the review, we explore whether 5-HT is involved in interactions between the central nervous and immune systems. It emerges that 5-HT may mediate interactions of these two systems by four different pathways. In the second part, we dissect the functional roles of 5-HT in the immune system. We describe the distribution of 5-HT receptors and the 5-HT transporter on immune cells and estimate which levels 5-HT may attain in the extracellular space in physiological conditions and under pathological circumstances such as inflammation, thrombosis, and ischemia. At these 5-HT concentrations, four major functions for 5-HT emerge. These include T cell and natural killer cell activation, delayed-type hypersensitivity responses, production of chemotactic factors, and natural immunity delivered by macrophages. Finally, we discuss promising future avenues to further advance knowledge of the role of 5-HT in the immune system and in neuroimmune interactions.
423 citations
TL;DR: The reduction in inflammation and delayed healing correlated with serum corticosterone levels and suggest that disruption of neuroendocrine homeostasis modulates wound healing.
Abstract: The impact of stress on cutaneous wound healing was assessed in a murine model. Female, hairless SKH-1 mice, 6-8 weeks of age were subjected to restraint stress (RST) 3 days before and for 5 days following dorsal application of a 3.5-mm sterile punch wound. Control mice were wounded, but not restrained. Using photography and image analysis, the rate of wound healing was compared between the two groups. Wounds on control mice healed on average 3.10 days sooner than RST-treated mice. In addition, cross-sectional, morphometric analysis of the dermal and epidermal layers revealed reduced inflammation surrounding wounds from RST mice at 1, 3, and 5 days after wounding. In the RST group, serum corticosterone levels averaged 162.5 ng/ml compared to 35.7 ng/ml in the controls. Treatment of RST-stressed animals with the glucocorticoid receptor antagonist RU40555 resulted in healing rates comparable to those of control animals. Thus, the reduction in inflammation and delayed healing correlated with serum corticosterone levels and suggest that disruption of neuroendocrine homeostasis modulates wound healing.
288 citations
TL;DR: The results suggest that LPS disrupts posttrial memory consolidation processes, and provide evidence for a role of immune activation and cytokine activity in learning and memory processes.
Abstract: 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.
276 citations
TL;DR: Data suggest that psychologically stressful situations shift type-1/type-2 cytokine balance toward type-2 and result in an immune dysregulation rather than overall immunosuppression, which may partially explain the increased incidence ofType-2-mediated conditions such as increased viral infections, latent viral expression, allergic/asthmatic reactions, and autoimmunity reported during periods of high stress.
Abstract: The mechanisms of stress-related immune alterations have not been fully elucidated. Cell-mediated immune responses as well as antibody and certain cytokines are reported as being suppressed during times of high stress. However, the role of suppression vs dysregulation has not been established in human stress models. The effect of exam stress on regulatory cytokines in 16 healthy medical students was assessed by measuring type-1 (IFN-gamma) and type-2 (IL-10) cytokines from 72-h PHA/PMA-stimulated PBMC 4 weeks before and 48 h after exams. Results demonstrated decreased IFN-gamma accompanied by increased IL-10 during exam stress that resulted in a decreased IFN-gamma:IL-10 ratio. There was a significant correlation between the cytokine response to PHA/PMA and number and subjective adjustment to daily hassles. Additionally, students who reported greater levels of loneliness also reported greater numbers of and poorer subjective adjustment to hassles. The differences were consistent in both males and females but did not correlate with AM cortisol levels. Additionally, when individuals were grouped into high vs low preexam hassle levels, the type-1/type-2 shift in the IFN-gamma:IL-10 ratio occurred in the low hassles group only. These data suggest that psychologically stressful situations shift type-1/type-2 cytokine balance toward type-2 and result in an immune dysregulation rather than overall immunosuppression. This may partially explain the increased incidence of type-2-mediated conditions such as increased viral infections, latent viral expression, allergic/asthmatic reactions, and autoimmunity reported during periods of high stress.
256 citations
TL;DR: In contrast to previous observations in depressed populations, depression (indicated by elevated Beck scores), comorbid with PTSD, was associated with increased natural cytotoxicity, and NK activity was higher in the PTSD population than in the controls.
Abstract: Resting immune [WBC and differential cell counts, lymphocyte phenotyping (CD2, CD4, CD8, CD16, CD20, and CD56), and NK activity] and endocrine (cortisol, prolactin, growth hormone, and DHEA-SO 4 ) parameters were measured in 10 male, Vietnam combat veterans diagnosed with long-term post-traumatic stress disorder (PTSD) and 9 control Vietnam combat veterans without a PTSD diagnosis but with a comparable history of alcohol abuse. Subjects completed a battery of psychological questionnaires. We report on preliminary observations of the relationship between PTSD and physiological and psychological parameters. With some important exceptions, PTSD patients did not differ from the age-matched control group with regard to hormone levels or lymphocyte phenotypes. However, NK activity was higher in the PTSD population than in the controls. Beck, Mississippi, and Combat Exposure scores were significantly elevated in the PTSD population. In contrast to previous observations in depressed populations, depression (indicated by elevated Beck scores), comorbid with PTSD, was associated with increased natural cytotoxicity.
85 citations
TL;DR: Results show that previous defeat stress increases the number of MCs in the thalamus, habenula, and hypothalamus of subjects exposed to a fighting opponent or to a clean cage, compared to subjects placed in a cage with the bedding of the opponent or a group-housed, nondefeated control.
Abstract: Mast cells (MCs) are amine-storing cells with heterogeneous histological, biochemical, and functional properties. They are found in connective tissue as well as in the peripheral and central nervous system (CNS) of many mammalian species. In this study we investigated whether the distribution of MCs in the CNS of adult male CD-1 mice was modified following repeated defeat stress. Experimental subjects underwent a 3-week period of fighting encounters with a highly aggressive resident. On the test day they were divided into three groups: (a) paired with the resident for 20 min; (b) placed in a cage containing the soiled bedding of the resident for 20 min; (c) placed in a cage with clean sawdust for 20 min. Results show that previous defeat stress increases the number of MCs in the thalamus, habenula, and hypothalamus of subjects exposed to a fighting opponent or to a clean cage, compared to subjects placed in a cage with the bedding of the opponent or to a group-housed, nondefeated control. These results, together with previous reports in birds and rodents, suggest that MCs have a wider role than previously expected and might be involved in the behavioral response to highly relevant psychosocial stimuli.
62 citations
TL;DR: The findings underline the Rapidity with which physiological changes may transpire in the course of a brief and acute period of psychological stress, and the rapidity of their reversal upon relief from the stressor.
Abstract: The present research investigated the effects of controlled experimental manipulations of stress on biological and psychological reactions. Fifty young adult male volunteers were exposed to a 12-min period of stress induced by the threat of an unavoidable, painful electric shock. A 12-min period without this threat preceded or followed the stress period. Blood was drawn during the 4th and the 12th minute of each period. Anticipatory threat led to significant elevations in the proportions and cytotoxic activity of natural killer (NK) lymphocytes, plasma epinephrine levels, pulse rate, and reported level of tension, and to a reduction in the CD4/CD8 ratios. The no-threat period induced a return to baseline values for epinephrine, pulse rate, and tension, and lower than baseline levels for cytotoxic activity of NK lymphocytes, within a similarly short time span. The findings underline the rapidity with which physiological changes may transpire in the course of a brief and acute period of psychological stress, and the rapidity of their reversal upon relief from the stressor.
49 citations
46 citations
TL;DR: The lack of IFNγ appears to contribute to increased emotionality, but the basal behaviors of the parental strain (e.g., BALBc) may overshadow the expression of this emotionality.
Abstract: Evidence suggests that interferon-gamma (IFNγ) plays an important role in CNS function and development. While the paucity of agents that selectively modify IFNγ production or interaction with its receptors makes analyses of its potential behavioral relevance difficult, mice with null mutations of the IFNγ gene have been used to investigate the potential role of IFNγ in emotional behaviors. C57Bl/6 (B6) mice with null mutations of the IFNγ gene (IFNγ (−/−)) showed significantly increased emotionality compared to the wild-type (IFNγ (+/+)) B6 mice. This was manifested in performance in the elevated plus maze as well as increased defecation scores and decreased locomotor activity both in novel environments and following a sonic stimulus. In contrast, the general level of emotionality of both IFNγ (+/+) and (−/−) BALB/c (C) mice was substantially greater than that of either of the B6 mouse groups. While C IFNγ (−/−) showed increased immobility in response to novelty, other indices of emotionality of C IFNγ (−/−) mice were not significantly different from those of the C IFNγ (+/+) mice. In summary, the lack of IFNγ appears to contribute to increased emotionality, but the basal behaviors of the parental strain (e.g., BALBc) may overshadow the expression of this emotionality. While mice with null mutations of the IFNγ gene may be useful tools for investigating the role of IFNγ in brain function and behavior, the influence of the parent strain genome(s) on the behaviors in question must be taken into account.
46 citations
TL;DR: While footshock reduced mitogen-stimulated B-cell proliferation in BALB/cByJ mice, it had the opposite effect in the CD-1 strain, andMacrophage activity and NK cytotoxicity were reduced in response to both stressors in a strain-dependent fashion.
Abstract: It is demonstrated that cell proliferation in response to mitogens, natural killer cell (NK) activity, and macrophage functioning of mice may be influenced by either a neurogenic stressor (footshock) or a psychogenic stressor (exposing the mouse to a predator, namely a rat). The nature and magnitude of the immune changes, however, varied across three strains of mice (BALB/cByJ, C57BL/6ByJ, and CD-1), differing in reactivity to stressors and also as a function of the type of stressor employed. While footshock reduced mitogen-stimulated B-cell proliferation in BALB/cByJ mice, it had the opposite effect in the CD-1 strain. Exposure to the predator, however, had little effect in any of the strains. Macrophage activity and NK cytotoxicity were reduced in response to both stressors in a strain-dependent fashion. Plasma corticosterone in response to footshock was greater in BALB/cByJ than in C57BL/6ByJ mice; however, the strain difference was not evident in response to the psychogenic stressor. It is suggested that analyses of stressor effects on immune functioning need to consider the specific strain/species employed, the particular immune parameters being examined, and the nature of the stressor employed.
41 citations
TL;DR: The persistence of denervation-induced changes even when the effect of corticosterone is blocked with RU-486 or diminished with chronic denervation indicates that the changes are driven mainly by a glucocorticoid-independent mechanism.
Abstract: Removal of sympathetic noradrenergic input to the immune system by injection of 6-hydroxydopamine (6-OHDA) triggers increases in antigen-specificin vitrosplenocyte proliferation and cytokine production in BALB/cJ and C57B1/6J mice. This examines the possible role of glucocorticoids in these previously reported changes. In both strains, chemical sympathectomy triggers an elevation of glucocorticoid levels immediately following injection of 6-OHDA, returning to normal within one to two days. In the BALB/cJ strain, glucocorticoid elevation is seen only after the initial 6-OHDA injection; levels in chronically denervated animals are not different from controls. In the C57B1/6J strain, the increase is seen even with chronically denervated animals. Prior implantation of mice with pellets containing the glucocorticoid receptor antagonist RU-486 does not abrogate denervation-induced increases in cytokine production or proliferation in either strain. In addition to the previously reported increased interleukin (IL)-2 and IL-4 production, there is an increase in IFN-γ production in the C57B1/6J strain following either acute or chronic denervation. The persistence of denervation-induced changes even when the effect of corticosterone is blocked with RU-486 or diminished with chronic denervation indicates that the changes are driven mainly by a glucocorticoid-independent mechanism.
TL;DR: The findings suggest that specific subsets of lymphoid cells can produce and respond to peptides previously thought to be principally neural mediators, and suggest that CRF+ cells in the spleen and thymus are macrophages.
Abstract: Cells of the immune system produce a variety of neuropeptides or peptide hormones, either constitutively or upon induction, and possess specific neuropeptide receptors that display ligand-receptor interactions similar to those described in the central nervous system (CNS). These findings suggest that specific subsets of lymphoid cells can produce and respond to peptides previously thought to be principally neural mediators. Recently, corticotropin releasing factor (CRF) mRNA was detected in the rat thymus and spleen, although the cells that synthesize CRF were not identified. We examined the localization of CRF and its mRNA in the rat spleen, thymus, and mesenteric lymph nodes using immunocytochemistry (ICC) and in situ hybridization (ISH), respectively. Immunoreactive CRF was present in cells in the marginal zone and red pulp of the spleen, in connective tissue septa and the subcapsular region of the thymus, and in the medullary cords and sinuses of the mesenteric lymph nodes. Dual ICC/ISH for CRF and its mRNA, respectively, demonstrated CRF mRNA over CRF-immunoreactive cells, suggesting CRF synthesis. Double-label ICC for CRF and markers for specific immunocyte subsets suggest that CRF+ cells in the spleen and thymus are macrophages. CRF+ cells in primary and secondary lymphoid organs reside in compartments that are innervated by sympathetic nerves, and some cells appears to be contacted by noradrenergic sympathetic nerve fibers, suggesting that CRF release may be influenced by the sympathetic nervous system, as it is in the hypothalamo-pituitary-adrenal axis. The presence of CRF in organs of the immune system suggests that this neuropeptide may modulate immune functions after paracrine release.
TL;DR: The results show that, depending on the timing of the exposure of Wistar rats to the CVS, the neuroendocrine disbalance favors a more pronounced humoral or cellular profile of the response.
Abstract: Stress disturbs homeostasis by altering the equilibrium of various hormones which have a significant impact on immune responses. Few studies have examined the influence of stressors on autoimmune disease in animal models. In our work, we studied the effects of long-term exposure (14 days) to chronic varied stress (CVS) in a model of experimental autoimmune encephalomyelitis (EAE) in Wistar rats. We studied whether the exposure to CVS before or after the immune challenge would correlate with differences in the clinical course of the disease. We also examined whether the CVS would modulate the magnitude of the cellular or the humoral immune response. We observed opposite effects on the clinical signs in animals stressed before or after the immune challenge. The clinical signs of the disease were attenuated in animals stressed before but not after the immune challenge. Relationships were found in the modulation of the clinical severity related to the time of exposure to the CVS, the histological alterations and the proliferative results. Stressed animals with milder clinical signs presented an exacerbated humoral response against myelin antigens while stressed animals with more severe clinical symptoms exhibited a significantly diminished one. Besides, we detected the presence of specific IgG1 associated with the exposure to CVS before the induction of EAE. Our results show that, depending on the timing of the exposure of Wistar rats to the CVS, the neuroendocrine disbalance favors a more pronounced humoral or cellular profile of the response.
TL;DR: Results demonstrate that the peripheral sympathetic nervous system influences the migration and accumulation in vivo of both naive and memory/effector lymphocytes in mucosal lymphoid tissues.
Abstract: The effects of chemical sympathectomy on the mucosal compartments of the immune system were examined in adult rats. Ablation of the sympathetic nervous system using 6-hydroxydopamine in recipient animals reduced the migration into Peyer's patches and mesenteric lymph nodes (MLN) of adoptively transferred cells from MLN of normal donors. The mucosal immune response to ovalbumin (OVA), assessed by enumeration of anti-OVA antibody containing cells (AOCC) in the lamina propria after intestinal immunisation, was reduced in animals sympathectomized prior to immunization. In order to identify whether this reduction in AOCC response in intestinally immunized sympathectomized animals was due to a defect in migration of AOCC precursors to the intestinal lamina propria, the effect of chemical sympathectomy on the appearance of AOCC in the gut of immunized animals after adoptive transfer of AOCC precursors was investigated. The IgA-specific AOCC response was significantly reduced in sympathectomized recipients compared to the control group. Taken together these results demonstrate that the peripheral sympathetic nervous system influences the migration and accumulationin vivoof both naive and memory/effector lymphocytes in mucosal lymphoid tissues.
TL;DR: The results of this work suggest that the IC is involved in the neural mechanisms underlying the acquisition and evocation of conditioned immunosuppression, and the amygdala could be important in mediating the input of the immune information necessary for the acquisition of conditioned immunity.
Abstract: It has been established that the insular cortex (IC) mediates conditioned taste aversion, and recently we have demonstrated that lesions of this structure disrupt the acquisition of conditioned immunosuppression (CIS). The IC is functionally and reciprocally interconnected with the amygdala (AM) which has been suggested to be involved in neural-immune interactions. The aim of this work was to test the effects of NMDA-induced lesions in either the IC or AM in the acquisition (lesions made before conditioning) and evocation (lesions made after conditioning) of a conditioned immunosuppression task, obtained by one single pairing of saccharin taste and the immunosuppressive drug, cyclophosphamide. AM and IC lesioned rats were separated into four groups: the first two received lesions before and the other two were lesioned after the acquisition of conditioned immunosuppression. Twenty days after conditioning, animals were reexposed to saccharin and immunized with ovalbumin. After immunization, blood samples were taken, and analyzed by ELISA. The results showed that IC lesions disrupted the acquisition and evocation of CTA and CIS. Conversely, AM lesions disrupted only the acquisition of CIS. These data suggest that the IC is involved in the neural mechanisms underlying the acquisition and evocation of conditioned immunosuppression, and the amygdala could be important in mediating the input of the immune information necessary for the acquisition of conditioned immunosuppression.
TL;DR: It is concluded that plasma cortisol alone has no significant effect on natural killer (NK) cell activity in vivo.
Abstract: The aim of this study was to examine the effects of increasing and decreasing endogenous cortisol levels on natural killer (NK) cell activity in vivo. Normal healthy volunteers participated in the following studies: baseline (n = 27), metyrapone challenge test (n = 10), dexamethasone suppression test (n = 10), and adrenocorticotropic hormone (ACTH) stimulation test (n = 8). Each subject served as his own control for each study. Each subject was tested for NK activity and plasma cortisol levels at 9 a.m., just before the challenge drug administration, and at 10 a.m., except for the dexamethasone study, in which only the 9 a.m. blood was drawn, 10 h after the dexamethasone administration. On the baseline study day, a significant decrease in plasma cortisol levels was found from 9 to 10 a.m. (p <.02) along with a significant increase in NK activity (p <.001). On the metyrapone test day, plasma cortisol levels at 10 a.m. were significantly reduced (p <.005) as expected, while NK activity at the same time point was not affected and was increased to an extent equivalent to the baseline study day. On the dexamethasone test day, plasma cortisol concentrations were significantly decreased (p <.0001) as compared to the same time point on the baseline day, without any significant change in the NK activity. On the ACTH test day, plasma cortisol rose significantly at 10 a.m. (p <.02), with no change in NK activity. We conclude that plasma cortisol alone has no significant effect on NK activity in vivo.
TL;DR: It is shown that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma, and the FSL rat may be a useful model for studies of airway hyperresponsiveness.
Abstract: The excitatory innervation of the airway smooth muscle is primarily cholinergic in nature. However, the potential neural mechanism(s) underlying airway hyperresponsiveness, one of the hallmarks of asthma, is not fully understood. In this study, cholinergic hyperresponsive Flinders sensitive line (FSL) rats and their control counterparts, Flinders resistant line (FRL) rats, were repeatedly challenged with different doses of nebulized methacholine (0, 4, 16, 64, and 256 mg/ml) for 5 min. Airway responsiveness was assessed in spontaneously breathing, unrestrained animals by means of whole body plethysmography. Increased airway responsiveness of FSL rats was evidenced as a more pronounced increase in Penh value (enhanced pause, an index of bronchoconstriction) across different concentrations of methacholine. In subsequent experiments, FSL and FRL rats were sensitized to ovalbumin and challenged with nebulized antigen. Our results indicate that the genetically transmitted cholinergic hyperresponsiveness of the FSL rat is paralleled by an increased susceptibility to allergen-induced bronchoconstriction and inflammation of the airways. This study provides further evidence that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma. In addition, the FSL rat may be a useful model for studies of airway hyperresponsiveness.
TL;DR: The results obtained using this animal model indicate that experimental stress reduces the therapeutic efficacy of a cytotoxic antitumor drug; experimental and clinical implications are discussed.
Abstract: Treatment with the cytotoxic antitumor drug cyclophosphamide is highly effective in mice bearing Lewis lung carcinoma, causing the absence of macroscopically detectable tumors at necroscopy after sacrifice. When the effects of the treatment on survival are determined, a significant increase in survival time and in the proportion of long-term survivors is observed. When restraint stress is further applied, tumors develop in all of the mice treated with cyclophosphamide, and survival time and the fraction of long-term survivors are significantly reduced. Flow cytometry of splenic T-lymphocyte subsets in normal mice indicates a significant decrease in the number of CD3+, CD4+, and CD8+ subsets after treatment with cyclophosphamide and after application of restraint stress; the interaction of the two treatments is significant for CD3+ and marginally significant for CD4+ subsets. The attenuation by restraint stress which was observed for the effects of cyclophosphamide on the presence of tumors at necroscopy and for the survival of the treated mice might thus be interpreted as follows: restraint stress attenuates the immune functions of the host directed toward the weakly immunogenic tumor, an effect which, in the absence of restraint stress, interacts effectively with the cytotoxic action of cyclophosphamide toward tumor cells. The results obtained using this animal model thus indicate that experimental stress reduces the therapeutic efficacy of a cytotoxic antitumor drug; experimental and clinical implications are discussed.
TL;DR: It is reported here that, in basal conditions, mutant mice are characterized by altered immune functions and it is indicated that interleukin-6 is not a key factor in the immunosuppression observed after restraint stress.
Abstract: To better determine the role of interleukin-6 in the mechanisms that regulate stress-induced immunosuppression, we used in this study an interleukin-6-deficient mice model recently generated by gene targeting. We report here that, in basal conditions, mutant mice are characterized by altered immune functions. Natural killer activity and interleukin-2 production are lower in splenocytes of interleukin-6 deficient mice compared to those of controls, whereas Concanavalin A-induced splenocyte proliferation is comparable with that observed in wild-type mice. Moreover, splenocyte concentrations of the immunosuppressive opioid peptide beta-endorphin are higher in interleukin-6 deficient mice while serum corticosterone concentrations are unchanged. After exposure to 16 h of restraint stress, a significant suppression of the immune parameters is exhibited and a significant increase of splenocyte beta-endorphin concentrations are present in knock-out and normal animals. Finally, corticosterone is normally induced in stressed interleukin-6-deficient mice, thus demonstrating that interleukin-6 is not crucial for the activation of the hypothalamic-pituitary-adrenal axis. In conclusion, our results indicate that interleukin-6 is not a key factor in the immunosuppression observed after restraint stress.
TL;DR: Results add to the growing evidence that lupus-associated behavioral abnormalities are a direct effect of the autoimmune disease.
Abstract: NZB × NZW F1 hybrid (B/W) mice develop altered behavior in the elevated plus maze and novel object tasks between 6 and 12 weeks of age in parallel with lupus-like autoimmune disease. To confirm the relationship between disease progression and development of behavioral abnormalities, B/W and nonautoimmune NZW mice received chronic treatment with a soluble IFNγ receptor (sIFNγR), a treatment known to retard autoimmune disease progression, or vehicle, beginning at 6 weeks of age. After 6 weeks of treatment, elevated plus maze and novel object testing revealed that although sIFNγR treated B/W mice still differed from NZW mice, chronic sIFNγR treatment significantly retarded the development of behavioral abnormalities in the B/W mice, while the NZW mice were not affected by this treatment. sIFNγR treated B/W mice were more active in both the plus maze and novel object tasks, and displayed less plus maze anxiety behavior and more exploratory activity in the novel object task compared to vehicle treated B/W mice. To clarify the role of acute action of the sIFNγR on the elevated IFNγ levels of B/W mice, a second experiment examined the effects of a single injection of sIFNγR on B/W and NZW mice. Unlike chronic treatment, acute treatment with the same dose of sIFNγR did not affect plus maze or novel object behavior in 12-week-old mice. These results add to the growing evidence that lupus-associated behavioral abnormalities are a direct effect of the autoimmune disease.
TL;DR: Results indicate that L1+ cells were most numerous before nerves appeared and reduced in number and extent as the thymus differentiated, and may always contain a reservoir of cells potentially capable of producing neuropeptides and transmitter factors required for thymic growth and regeneration.
Abstract: In order to study the functional development of a thymus in an experimental model, small pieces of adult rat thymic tissue were cultured for 9 days and implanted under the kidney capsule of littermates The tissues were examined with a panel of antibodies raised against thymic and neural factors and neural crest cells at intervals from 5 to 13 days At 5 days post-implantation, there were groups of L1+ cells within the implants that reacted with antibodies raised against neural and neural crest cell markers L1+ cells were highly mitotic, rounded cells measuring 87 ± 06 μm in diameter Double immunostaining with different combinations of antibodies showed that 94% of the L1+ cells were also TH+, and many were HNK-1/NCAM+, PGP 95+, NGF+, chromogranin A+, VIP+, S100+, CGRP+, GAD+, and A2B5+ A few were also pan-cytokeratin+ These results indicate that these cells are derived from neural crest derived cells and belong to the neuroepithelial line of development The L1+ cells were most numerous before nerves appeared (about Day 9) and reduced in number and extent as the thymus differentiated The neural crest cells occasionally had long cytoplasmic extensions, but it was not possible to decide if they formed the nerves that appeared in the implants Adult thymuses also contained a population of L1+ and HNK-1/NCAM+ cells, mainly in the subcapsular cortex, the septa, and the medulla These cells could be a source of neural crest cells able to repopulate the implant The adult thymus may always contain a reservoir of cells potentially capable of producing neuropeptides and transmitter factors required for thymic growth and regeneration
TL;DR: Dual-antigen labeling demonstrates that corticotrophin releasing factor-containing neurons in the PVN are activated by chemical sympathectomy; however, neurons containing neurotransmitters which may modulate CRF neurons, such as vasopressin, tyrosine hydroxylase, and adrenocorticotropin, do not coexpress Fos.
Abstract: Many studies have demonstrated that ablation of the sympathetic nervous system (SNS) alters subsequent immune responses. Researchers have presumed that the altered immune responses are predominantly the result of the peripheral phenomenon of denervation. We, however, hypothesized that chemical sympathectomy will signal and activate the central nervous system (CNS). Activation of the CNS was determined by immunocytochemical visualization of Fos protein in brains from male C57BL/6 mice at 8, 24, and 48 h following denervation. A dramatic induction of Fos protein was found in the paraventricular nucleus (PVN) of the hypothalamus and other specific brain regions at 8 and 24 h compared to vehicle control mice. Dual-antigen labeling demonstrates that corticotrophin releasing factor (CRF)-containing neurons in the PVN are activated by chemical sympathectomy; however, neurons containing neurotransmitters which may modulate CRF neurons, such as vasopressin, tyrosine hydroxylase, and adrenocorticotropin, do not coexpress Fos. Our findings suggest an involvement of the CNS in sympathectomy-induced alterations of immunity.
TL;DR: Although representing preliminary data from a small number of subjects, these observations provide further support for the presence of interactions between the brain and the immune system.
Abstract: To study brain-immune relations, we correlated positron emission tomographic (PET) measures of regional cerebral blood flow (rCBF) with immune measures in 10 female volunteers. The natural killer (NK) activity correlated negatively with activity bilaterally in the secondary sensory cortex, whereas the Concanavalin A (Con A) response correlated positively with rCBF bilaterally in secondary visual, motor, and sensory cortices, the thalamus, the putamen, and the left hippocampus. Although representing preliminary data from a small number of subjects, these observations provide further support for the presence of interactions between the brain and the immune system.
TL;DR: The development of sophisticated genetic analytical methods and gene mapping techniques now provide the "tools" to determine the influence of genetics on behavior-neuroendocrine-immune interactions--an area of study that may represent the next frontier in psychoneuroimmunology.
Abstract: Psychoneuroimmunology is an exciting, complex field that elucidates interactions among the nervous, endocrine, and immune systems. The contribution of psychosocial factors and behavioral processes to these interactions has been the focus of numerous studies designed to investigate the intricate pathways that are involved in the “mind-body connection.” In addition, the effects of this connection on the development and progression of various disease conditions are of considerable interest. Although efforts have been made to identify the cellular and molecular mechanisms underlying these relationships, the impact of genetic makeup on the communication among these systems has yet to be fully realized. The development of sophisticated genetic analytical methods and gene mapping techniques now provide the “tools” to determine the influence of genetics on behavior–neuroendocrine–immune interactions—an area of study that may represent the next frontier in psychoneuroimmunology.