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PubMed2003

Loneliness and pathways to disease.

Social isolation predicts morbidity and mortality from cancer, cardiovascular disease, and a host of other causes. The mechanisms by which the social world impacts on health are poorly understood, in part because of lack of specificity in the conceptualization and operationalization of relevant aspects of social relationships and physiological processes. Perceived social isolation, commonly termed loneliness, may represent a link between the epidemiological and biological levels of analysis. Research is presented that investigates loneliness as a social factor of importance in three predisease pathways: health behaviors, excessive stress reactivity, and inadequate or inefficient physiological repair and maintenance processes. Empirical evidence of autonomic, endocrine, and immune functioning suggests that the physiological effects of loneliness unfold over a relatively long time period. For cancer patients, interventions should be aimed at providing instrumental support for the immediate demands of the disease.

Cardiovascular Diseases↗
PubMed2003

Cytokine-induced sickness behavior.

The behavioral repertoire of humans and animals changes dramatically following infection. Sick individuals have little motivation to eat, are listless, complain of fatigue and malaise, loose interest in social activities and have significant changes in sleep patterns. They display an inability to experience pleasure, have exaggerated responses to pain and fail to concentrate. Proinflammatory cytokines acting in the brain cause sickness behaviors. These nearly universal behavioral changes are a manifestation of a central motivational state that is designed to promote recovery. Exaggerated symptoms of sickness in cancer patients, such as cachexia, can be life-threatening. However, quality of life is often drastically impaired before the cancer becomes totally debilitating. Although basic studies in psychoneuroimmunology have defined proinflammatory cytokines as the central mediators of sickness behavior, a much better understanding of how cytokine and neurotransmitter receptors communicate with each other is needed. Advances that have been made during the past decade should now be extended to clinical studies in an attempt to alleviate sickness symptoms and improve quality of life for cancer patients.

Animals↗
PubMed2003

Cytokines and depression: the need for a new paradigm.

Considerable clinical and experimental data support the existence of a relationship between cytokines and depression. At the experimental level, proinflammatory cytokines have been found to induce alterations in brain function analogous to the behavioral and biological abnormalities occurring in depressed patients, including social withdrawal, cognitive impairment, anhedonia, increased activity of the hypothalamus-pituitary-adrenal axis, altered neurotransmission, and cross-sensitization with stressors. At the clinical level, the evidence in favor of innate immune system activation in depressed patients is still controversial, despite accumulating evidence for an increased risk of depressive disorders in patients receiving recombinant cytokines for the treatment of cancer and viral infection. This last issue has received significant attention recently, given that the administration of therapeutic cytokines provides a quasi-experimental model for studying the mechanisms which underlie the effects of cytokines on mood, cognition, and neurovegetative functions. Although the vulnerability factors that account for the risk of depression have yet to be identified, tryptophan depletion, likely related to the induction of indoleamine 2,3-dioxygenase enzyme, may represent an important mediator for the development of depressed mood in cytokine-treated patients. This paper discusses ways in which these emerging data may lead to advances in the recognition and management of non-specific neurobehavioral symptoms associated with the development and progression of cancer.

Cytokines↗
PubMed2003

Immune-to-central nervous system communication and its role in modulating pain and cognition: Implications for cancer and cancer treatment.

This paper reviews the nature of communication from the immune system to the brain and some implications of this communication for phenomena that are not ordinarily considered to be modulated by immune function. Pro-inflammatory cytokines released by activated immune cells signal the brain by both blood-borne and neural routes, leading to alterations in neural activity. The cascade of altered neural activity includes the induction of pro-inflammatory cytokines within the brain and spinal cord. The cytokines in the brain, specifically in the hippocampus, interfere with the consolidation of memory, while the cytokines within the spinal cord exaggerate pain. Activation of this immune-to-central nervous system pathway, with the consequent production of cytokines within the central nervous system, may be involved in the mediation of a number of phenomena that occur during cancer and cancer treatment.

Animals↗
PubMed2003

Sensitization associated with stressors and cytokine treatments.

Like stressors, interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) increase hypothalamic-pituitary-adrenal (HPA) activity and monoamine turnover at hypothalamic and extrahypothalamic sites. These effects can be re-elicited more readily upon reintroduction of these challenges (sensitization), depending on their time of re-exposure and the particular system being assessed. Following TNF-alpha administration, the co-expression of corticotropin releasing hormone (CRH) and arginine vasopressin increased within the median eminence, peaking 7-14 days after treatment, and was associated with an early corticosterone sensitization. However, the re-elicitation of sickness symptoms and corticosterone release was most pronounced at lengthy re-exposure intervals (28 days), possibly reflecting histamine release from mast cells. In addition, the cytokine engendered the sensitization of norepinephrine and serotonin utilization, and CRH immunoreactivity at mesocorticolimbic sites, but these effects were most prominent at brief re-exposure intervals (1-7 days). Cytokines may independently prime multiple regulatory systems, and by virtue of the neurochemical changes imparted, have both immediate and proactive influences on the evolution of psychopathology.

Animals↗
PubMed2003

Bi-directional immune-brain communication: Implications for understanding stress, pain, and cognition.

The immune system and the central nervous system form a bi-directional communication network. The critical roles of pro-inflammatory cytokines in both the periphery and the nervous system are discussed. In the periphery, these cytokines initiate the processes that signal the brain that immune activation has occurred, and communicate this information over both neural and blood-borne routes. The arrival of these signals in the central nervous system induces a neural cascade that includes the de novo induction of pro-inflammatory cytokines. The functions of these cytokines in the nervous system are discussed, and it is argued that they play a key role in regulating the neural control of immune processes in the periphery. In addition, it is argued that these cytokines play a variety of other roles, and some implications of the cytokine network for understanding stress, behavior, sensory processing, mood, and cognition are described. The overall argument is that because brain-mediated host defense involves behavioral, sensory, mood, and cognitive alterations, immune activation, and immune products such as the cytokines can have a pervasive effect on these functions. Finally, these phenomena are placed in an evolutionary perspective.

Brain↗
PubMed2003

The effects of behavior and environmental enrichment on disease resistance of turkeys.

Turkey poults were provided with environmental enrichment for the first 14 days after hatch. At 2 days of age each bird was tested for the speed in which it would cross a T-maze. At 5 weeks of age birds were treated with dexamethasone and challenged with Escherichia coli. Enriched birds had higher body weights and incidence of disease and mortality and lower numbers of leukocytes when challenged. Challenged and enriched birds that tested FAST had higher mortality and air sacculitis scores and lower body weights than SLOW birds. Non-enriched, SLOW birds were the only ones to respond to challenge with increases in leukocyte counts and heterophil/lymphocyte ratios. These data suggest that environmental enrichment during the first 2 weeks after hatch may be detrimental to those birds with a FAST T-maze response, and that poults with a FAST response in the T-maze may be more susceptible to experimental bacterial infection.

Analysis of Variance↗
PubMed2003

Neuropeptide specificity of prostaglandin E2-induced activation of splenic and renal sympathetic nerves in the rat.

Sympathetic activation occurs rapidly following intracerebroventricular (icv) injection of prostaglandin E2(PGE2). This study examined whether neuropeptides mediate PGE2-induced sympathetic nerve activation in urethane/chloralose-anesthetized Sprague-Dawley rats. Animals were pretreated (20.0 microg, icv) with the following receptor antagonists; CRF ([D-Phe12,Nle21,38,Calpha-MeLeu37]CRF12-41), AVP-V1 (Des-Gly-[Phaa1, D-Tyr(Et)2,Lys6,Arg8]-vasopressin), or OT (OT+V1, [d(CH2)5,Tyr(Me)2,Orn8]-vasotocin) followed 20 min later by PGE2 (2.0 microg, icv). Pretreatment with the CRF antagonist attenuated the increase in renal nerve activity induced by PGE2 when measured 10 and 30 min post-injection. PGE2-induced renal nerve activity was also inhibited at both time points by the AVP antagonist and, to a similar extent, the OT antagonist. The AVP antagonist did not effect splenic nerve responses to PGE2 whereas the CRF antagonist produced an incomplete and transient reduction in PGE2-induced activation of the splenic nerve. However, the OT antagonist completely blocked the activation of the splenic nerve after central injection of PGE2. ICV injections of AVP and OT produced immediate changes in splenic and renal nerve activity whereas CRF failed to alter the activity of either nerve in anesthetized or conscious animals. Thus, PGE2 acts through neuropeptide-specific pathways to initiate sympathetic outflow and OT is a specific component of the sympathetic pathway innervating the spleen.

Animals↗
PubMed2003

Asymmetrical modulation of interleukin-10 release in patients with intracerebral hemorrhage.

The brain modulates the immune system in an asymmetrical way. Intracerebral hemorrhage triggers IL-6 and IL-10 release into blood. We measured (using ELISA method) serum IL-6 and IL-10 in acute phase of intracerebral hemorrhage in 11 patients with right hemisphere's hematoma and 15 patients with left hemisphere's hematoma. These patients did not differ significantly with respect to their age, size, and location of hematoma. IL-6 level was comparable in patients with left hematoma and patients with right hematoma, but patients with left hematoma had significantly higher level of IL-10 than patients with right hematoma. These results suggest that left and right hemisphere could modulate IL-10 release in different way.

Aged↗
PubMed2003

The effects of lateral hypothalamic lesions on peripheral blood natural killer cell cytotoxicity in rats hyper- and hyporesponsive to novelty.

Individual variability in the central control of the cellular immune responses is the main subject of the study. Previously, it was found that destruction of the lateral hypothalamus (LH) produced long-term depression of the cytotoxicity of NK cells (NKCC) and their number (LGL). In the present experiment we compared changes in the peripheral blood NKCC, LGL number, as well as leukocyte and lymphocyte number, their mitogenic activity and plasma corticosterone level evoked by electrolytic LH lesions in rats which were categorized as either high (HR) and low (LR) responders according to their locomotor response to a new environment. It was found that: (1) before the lesion NKCC (measured by 51Cr release assay) was higher in the HRs than in LRs; (2) LH damage caused a drop in NKCC and LGL number (21st postlesion day) preceded by a transient enhancement (5th postlesion day) significant for HRs only. As a result of a greater decrease in the HRs than LRs the baseline differences between groups disappeared by 21st postlesion day; (3) NKCC and LGL depression was not accompanied by changes in lytic activity of a single NK cell (agarose assay) which indicates that NKCC decrease concerned the population level and was dependent on LGL redistribution and/or recycling rate; (4) on the 21st postlesion day there was a significant leuko- and lymphopenia in the lesioned groups both HRs and LRs; (5) proliferative lymphocyte response to PWM (colorimetric assay) and plasma corticosterone level were not affected either by the motility level or by the lesion. The results emphasize the importance of individual differences in behavioral reactivity for NKCC regulation and a possible involvement of LH in the mechanism which connects high locomotor activity with stimulation of NKCC.

Animals↗
PubMed2003

Circadian disruption in cancer: a neuroendocrine-immune pathway from stress to disease?

Psychosocial factors may modulate the course of cancer, but few data have been gathered on the biological mechanisms by which these effects may be mediated. We briefly review evidence of psychosocial effects on cancer progression and discuss one potential pathway that may underlie these effects: the disruption of neuroendocrine and immune circadian rhythms. Circadian system alterations occur in tumor tissue, tumor-bearing animals, and cancer patients with greater disruption seen in more advanced cases. Rhythm alterations include diminished amplitude, phase shifts, period changes, and erratic peaks and troughs in endocrine, metabolic, immunological, and rest- activity cycles. Psychosocial factors can engender dysregulation of circadian function. Cancer-related circadian dysregulation may also be driven by genetic factors, environmental and behavioral influences, and effects of the tumor on host clock regulation. There are several mechanisms by which circadian disruption might hasten tumor growth: via direct effects of altered hormone levels on tumor cells, effects on tumor versus host metabolism, neuroimmune effects resulting in cancer-relevant immunosuppression, or reduced efficacy and tolerability of cancer treatments for which the timing of administration is based upon the assumption of normal circadian rhythms. Emerging data in the human and animal literature suggest that circadian regulation may be an important prerequisite for the maintenance of host defenses against cancer. Thus, stress-related circadian disruption may have negative implications for cancer prognosis. Psychosocial effects on cancer progression may be measured, and possibly mediated, by disruption of circadian function.

Animals↗
PubMed2003

Contribution of the adrenal glands and splenic nerve to LPS-induced splenic cytokine production in the rat.

Both the hypothalamic pituitary adrenal axis (HPAA) and the sympathetic nervous system (SNS) can inhibit immune function and are regarded as the primary efferent pathways for neural-immune interactions. To determine if this relationship is maintained in vivo in response to an inflammatory stimulus, rats were injected intravenously (iv) with various doses of lipopolysaccharide (LPS) and splenic cytokine mRNA and protein levels were measured at several dose and time intervals post-injection. The spleen was chosen as the target organ because both the neural and hormonal inputs to the spleen can be selectively removed by splenic nerve cut (SNC) and adrenalectomy (ADX), respectively. Data from our dose response studies established that maximum levels of splenic cytokines were induced in response to relatively low doses of LPS. Minimal changes in LPS-induced splenic cytokine levels were observed in response to ADX, SNC, or a combination of the two procedures across several doses of LPS. These results suggest that there are aspects of immune regulation that are functionally removed from these central modulatory systems and that the counter-regulatory responses induced by LPS have minimal impact on the concurrent induction of cytokines by this inflammatory stimulus. The conceptual model of neural-immune regulation as an inhibitory feedback system, at least with regards to the early activational effects induced by an inflammatory stimulus, was not supported by these studies.

Adrenal Glands↗
PubMed2004

Consequences of repeated early isolation in domestic piglets (Sus scrofa) on their behavioural, neuroendocrine, and immunological responses.

Stress in the form of intermittent maternal deprivation and social isolation during early postnatal life in rats and monkeys produces persistent changes in physiology and behaviour. In farm animals physiological consequences of disrupting mother-infant interactions with respect to health and animal welfare are relatively unknown. Therefore, the aim of the present study was to investigate the behavioural, neuroendocrine and immunological consequences of a 2 h daily social isolation from day 3 to day 11 of age in domestic piglets as well as potential long-term effects on the brain-endocrine-immune regulation. Repeated social isolation resulted in significantly decreased open-field activity (locomotion, vocalization) during the isolation period, increased basal cortisol concentrations and decreased lymphocyte proliferation in response to concanavalin A and pokeweed mitogen one day after the isolation. There was also a significant increase of interleukin-1beta (IL-1beta) concentration in hippocampus in isolated piglets compared to controls at this time. Six weeks after isolation significant enhanced basal ACTH concentrations as well as higher IL-1beta content and glucocorticoid receptor (GR) binding in hippocampus were found. These endocrine and immune responses were associated with decreased CRH levels in the hypothalamus and increased CRH content in the amygdala. The present data indicate that early social isolation in pigs may cause changes in behavioural, neuroendocrine, and immune regulation and produce long-term effects not only on the activity of the hypothalamic-pituitary-adrenal (HPA) system, but also on the immune-brain circuitry with possible negative consequences in health and welfare of commercial pigs. Using the pig as a suitable animal model, the finding of this study may also have some implications for the etiology of anxiety and depression in humans.

Adrenocorticotropic Hormone↗
PubMed2004

Effects of bacterial superantigens on behavior of mice in the elevated plus maze and light-dark box.

Bacterial superantigens, such as staphylococcal enteroxins A and B (SEA/SEB) stimulate T cells to produce high levels of cytokines in blood. Previously it had been shown that these toxins were capable of stimulating increased neuroendocrine activity and enhanced behavioral reactivity to novel gustatory and non-gustatory stimuli. Therefore, it was suggested that these superantigens may promote anxiety-like behavior. In the current set of experiments, BALB/cByJ and C57BL/6J male mice were challenged with either SEB (50 microg) or SEA (5 or 10 microg) and tested for behavior in the elevated plus maze (EPM). Results suggested an absence of increased anxiety-like behavior, with exploration of the open arms being enhanced by SEA or SEB treatment. In another test of anxiety, the light-dark box, SEB challenge of BALB/cByJ mice 90 min prior to testing, did not alter exit latency, activity nor time spent in the dark. However, in a second experiment, it was found that if animals were first tested for consumption, followed by testing in the light-dark box, SEB challenged animals displayed increased exit latency and reduced exploration. These studies suggest that in standard tests of rodent anxiety-like behavior, evidence for the induction of anxiety-like processes subsequent to challenge with SEA or SEB is not patently discernable. However, neurobiological events induced by immunological challenge might synergize with reactivity to psychogenic and/or gustatory stimuli, thereby resulting in increased anxiety-like behavior that could be unmasked by standard behavioral tests such as the light-dark box or EPM.

Analysis of Variance↗
PubMed2003

Natural killer cells do not mediate facial motoneuron survival after facial nerve transection.

The goal of the current study was to determine if natural killer (NK) cells mediate facial motoneuron (FMN) survival following injury. Wild-type (WT), perforin/recombinase activating gene-2 knockout (pfp/RAG-2 KO), and common gamma-chain (gammac)/RAG-2 KO mice received a right facial nerve axotomy. In WT mice, FMN survival was 86+/-1.0% relative to the contralateral control side. In contrast, pfp/RAG-2 and gammac/RAG-2 KO mice exhibited significant decreases in FMN survival ( approximately 20% and approximately 30%, respectively), relative to WT. Reconstitution of pfp/RAG-2 and gammac/RAG-2 KO mice with normal NK cells alone, failed to restore FMN survival levels to those of WT, but did restore functional lytic activity against YAC-1 cells. Reconstitution of pfp/RAG-2 and gammac/RAG-2 KO mice with splenocytes, and pfp/RAG-2 KO mice with CD4+ T-lymphocytes alone or in combination with NK cells, restored FMN survival levels to those of WT. Thus, NK cells appear to not be a component of immune cell-mediated rescue of motoneurons from axotomy induced cell death.

Animals↗
PubMed2004

The relationship between distress and the development of a primary immune response to a novel antigen.

Forty-five medical students were recruited to examine the effects of distress on the development of an immune response to the novel antigen, keyhole limpet hemocyanin (KLH). The subjects' level of distress was manipulated by immunizing them either at the time of an important viva voce examination (n=22) or during examination-free term time (n=23). This manipulation increased variance amongst the subjects, but the emphasis in this research was on individual distress as a predictor of immune function. In the group as a whole, the likelihood of developing DTH skin responses to KLH was reduced in the more distressed subjects (r=-.45; p=.002), independently of a number of behavioral (e.g., sleep disturbance) and demographic (e.g., sex) variables. Proliferation of T cells against KLH in vitro and the development of anti-KLH IgG antibodies were not related to levels of distress. Thus, cellular, rather than humoral, immune responses in vivo appear susceptible to the influence of distress. This immunization model provides the opportunity to further dissect the basis of these stress-immune pathways.

Adult↗