Maureen P. O'Grady

Neonatal cytomegalovirus exposure decreases prepulse inhibition in adult rats: implications for schizophrenia.

The goal of these studies was to determine whether neonatal viral exposure leads to a deficit in information processing in adulthood. To accomplish this, rats were infected neonatally with rat cytomegalovirus, and acoustic startle responses were measured when rats were 120 days old. Acoustic startle was elicited by using a 118‐decibel (dB) white noise alone or after a prepulse 10 dB above background (65 dB); responses were measured after an injection of saline or the dopamine agonist apomorphine. Response amplitudes after the pulse alone were not significantly altered by either viral exposure or apomorphine. Responses of animals exposed to the prepulse before the pulse were approximately 10% of that after the pulse alone and did not differ between control or virus‐exposed animals injected with saline. Animals injected with apomorphine exhibited a greater startle response than animals injected with saline, and control and virus‐exposed rats injected with apomorphine differed in the magnitude of their responses. Apomorphine attenuated responses after the prepulse, and virus‐exposed animals exhibited more than twice the attenuation than non–virus‐exposed animals. Analysis of prepulse inhibition, calculated from the acoustic startle data, indicated that although viral exposure alone did not significantly affect information processing, when virus‐injected rats were exposed to apomorphine, a significant 38% decrease in prepulse inhibition was apparent. Findings demonstrate that rats infected neonatally with rat cytomegalovirus exhibit a deficit in sensorimotor gating upon dopamine stimulation, supporting a possible link between viral infection and schizophrenia. J. Neurosci. Res. 57:429–434, 1999.

Human recombinant interferon alpha inhibits naloxone binding to rat brain membranes.

Regulation of certain central nervous system (CNS) functions by the immune system may involve interferons (IFNs) acting through opioid receptors. Human recombinant interferon alpha (hrIFN alpha), as well as natural IFN alpha, have been reported to modulate a variety of physiological CNS functions both in vivo and in vitro. If the mechanism is via opioid receptors then IFN alpha should inhibit the binding of certain opioid radioligands to brain membranes. This study reports the inhibitory effect of hrIFN alpha on the binding of 3H-naloxone to rat brain membranes in vitro. The inhibitory effect at 37 degrees C is hrIFN alpha concentration dependent over the range of 500 to 6000 antiviral units per ml (U/ml) with 500 micrograms of membrane protein. The presence of NaCl (100mM) increases specific binding of naloxone and attenuates the inhibitory effect of hrIFN alpha. The inhibitory effect of hrIFN alpha is sensitive to temperature with maximum inhibition observed at 37 degrees C, and less as incubation temperature is reduced. These data suggest that IFN alpha may modulate certain physiologic functions via opioid pathways in the brain.

Interleukin-1β stimulates adrenocorticotropin and corticosterone release in 10-day-old rat pups

Interleukin-1 (IL-1) is a cytokine secreted in response to immunological challenge which has effects in many physiological systems in adult models. Among the central nervous system effects of IL-1 are its ability to alter sleep patterns, body temperature, and certain neuroendocrine parameters including the release of ACTH and corticosterone (B) in vivo. This study investigated the ability of IL-1 to induce ACTH and B release in 10-day-old rats. This age was chosen due to a well documented phenomenon, the stress hyporesponsive period (SHRP), in which rodents display a blunted pituitary-adrenal response to stressors during the first 2 postnatal weeks (postnatal days 3-14). Administration of IL-1 to rat pups during the SHRP resulted in robust ACTH and B increases. Data are discussed in terms of the site of action and ontogeny of negative feedback mechanisms in the hypothalamic-pituitary-adrenal axis.

Stress and Immunity in Humans: Modifying Variables

Publisher Summary A large number of variables capable of modifying either the stress response and/or the immune system have been identified. They can be divided into several categories including psychological, environmental, and behavioral variables. Behavioral interventions have the potential to act on either physiological or mental processes. This chapter focuses on the variables that are capable of modulating the effects of stressors on the human immune system. The categories of variables are numerous and complex. They include (1) biological and pharmacological factors, (2) structural and energetic interventions, (3) ethnomedical practices, (4) mind-body control, which would include guided imagery and hypnotherapy, and (5) lifestyle factors. The extent to which behavioral interventions might have efficacy based on the inherent properties of the intervention is sometimes difficult to determine. They exert a beneficial influence through those processes activated by the placebo phenomenon. Mind-body variables are correlated with health outcome in a number of different contexts.

Effects of exercise on immune functions of undernourished mice

Regular moderate exercise may modulate the response to a stressor and thus improve immune functions in conditions commonly associated with immunodepression and elevated levels of stress hormones. For example, anorexia nervosa patients, many of whom engage in regular aerobic exercise, generally have normal immune function and viral disease resistance in spite of their severe undernutrition. To test the hypothesis that exercise can prevent undernutrition-induced immunodepression, mice were fed a nutritionally complete, semi-purified diet, either ad libitum or in restricted quantities to induce 25% loss of initial weight over 3 weeks. Half the animals from each dietary group were run on a treadmill for 30 min/day, 5 days/week. Exercise had no effect on several measures of nutritional status. Spleen weight and blastogenic response to lipopolysaccharide were significantly increased by exercise in undernourished mice. In vivo antibody response to sheep red blood cells, and in vitro splenic responses to concanavalin A and phytohemagglutin were not significantly affected by exercise. Serum corticosterone level was increased by food restriction and significantly decreased by exercise in the undernourished mice. Within a treatment group there were no significant correlations between serum corticosterone level and any immune system measure. Hypothalamic concentration of uric acid was increased in food restriction groups and concentration of norepinephrine was increased in exercise groups. The results suggest that regular exercise may help prevent undernutrition-induced immunodepression, possibly through modulation of the stress response.

Psychosocial Interventions and Immune Function

This chapter discusses psychosocial interventions and immunity. The therapeutic effects of psychosocial intervention are dependent on a strong belief on the part of the subject that the intervention is going to have a beneficial outcome. The strength of ones belief in the efficacy of a protocol is not the only important ingredient in psychosocial interventions. Consequently, those interventions that involve relaxation, which would include guided imagery, prayer, and biofeedback, may work through an independent mechanism that serves to downregulate the anxiety-and stress-induced production of immunoregulatory hormones and signals from the sympathetic branch of the autonomic nervous system. Overstimulation of the sympathetic branch of the autonomic nervous system has been implicated in sudden cardiac death, which can be brought on by psychosocial stress. When attempting to understand the mechanism via which psychosocial interventions might modulate immunity, one must realize that the intervention strategy and how it is carried out and perceived by the individual may in turn be a partial reflection of the immunologic status of the individual. Just as there are bidirectional chemical pathways that link the brain with the immune system, there may well be bidirectional links between behavior and the immune system such that each can influence the other.

The effects of interleukin-1 receptor antagonist protein (IRAP) infusion following spinal cord transection in rats

A laminectomy was performed at the T5-T6 vertebral level in adult, male, Sprague-Dawley rats and the spinal cord transected with a scalpel. A group of sham animals was subjected to the same surgery without the transection step. A group of unhandled control rats was also included. A subgroup of transected animals received a subcutaneous osmotic minipump that dispensed IL-1 receptor antagonist protein (IRAP) at the transection site for 7 consecutive days. Another transected subgroup received a minipump that infused the vehicle only. IRAP-treated rats displayed a significant reduction in body temperature (p < 0.05) compared with vehicle-treated rats. The IRAP-treated rats were also less active when assessed for locomotor behavior using an HVS computerized tracking system (p < 0.01). IRAP treatment had no effect on serum corticosterone, beta-endorphin levels, Con A, PHA, or LPS-induced splenocyte mitogenesis when compared with vehicle-treated animals. However, half of the IRAP-treated animals exhibited a substantive reduction in the number of reactive astrocytes near the transection site, suggesting a possible effect of IRAP on astrocyte activation.

Thymic regulation of the hypothalamic-pituitary-gonadal axis.

The thymus gland and the cells that it regulates produce a number of soluble factors that are capable of indirectly modulating the immune system via reproductive neuroendocrine circuits. Studies dating to the turn of the century were designed to evaluate the effects of partially purified thymic extracts in treating various reproductive disorders as well as changes in gonadal tissue weights. More recent studies have focused on the chemical nature of the factors responsible for regulating reproductive function. A number of factors have been described. These include thymosin beta 4 which has been found to stimulate the release of luteinizing hormone releasing hormone and luteinizing hormone (LH). Other factors such as interleukin-1 (IL-1) have been found to inhibit the release of these two peptides. IL-1 has also been found to alter the expression of LH receptors in rat granulosa cells. Certain interferons have been found capable of suppressing estrogen and progesterone release. While many of the studies have been carried out using adult animal models, there is increasing evidence that exposure to cytokines during early development can have long lasting if not permanent effects upon the reproductive axis. These and related topics are the subject of this review.

Long-Term Effects of Neuroendocrine–Immune Interactions during Early Development

This chapter discusses long-term effects of neuroendocrine–immune interactions during early development. The immune system is modulated by the central nervous system (CNS). The chapter presents a study that demonstrated a structural link between the nervous system and the immune system by observing the innervation of lymphoid tissue by noradrenergic and peptidergic fibers. In addition to altering immune responsiveness through autonomic nervous system projections, the CNS modulates bodily defenses through neuroendocrine activity. Many hormones that are under the control of the brain are capable of potentiating or diminishing certain measures of immune performance. These measures range from alterations in tumor rejection in vivo to changes in cell-mediated or humoral immunity in vitro . In addition to its immunoregulatory, antiviral, and antiproliferative effects, interferon is capable of modulating the neuroendocrine activity. Interferon used in treating certain hormone-dependent cancers based on evidence that estradiol, progesterone, and thyroxine are suppressed in normal women after interferon administration and that the secretion of testosterone is diminished in Leydig cells in vitro after incubation with interferon.

Thymic Hormones and Immune Function: Mediation via Neuroendocrine Circuits

This chapter discusses the role of thymic hormones and immune function. The thymus is a glandular structure derived from the third and fourth pharyngeal pouches, which is located beneath the sternum immediately adjacent to the heart. Insufficient data are available to draw any conclusions regarding the physiological significance of the ability of the immune system to activate classic neuroendocrine pathways. However, the fact that such pathways linking the immune system with neuroendocrine circuits do exist warrants further investigation as to what their physiological and potential clinical role is. Any model that is proposed should take into account the dynamic nature of the immune system and the potential interactive effects when multiple hormones are simultaneously released. Thus, a hypothesis predicated on the potential inhibitory effects on the immune system arising from the release of glucocorticoids would have to account for the simultaneous release of β-endorphin, which in some assay systems has been found to increase certain measures of immunity.