Nola Shanks

Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination

BACKGROUND There are many reports of psychological morbidity in spousal carers of patients with dementia. The consequences of this increased stress on the immune system are unclear. We investigated whether antibody responses to influenza vaccination differed between carers and a control group, and the relation of the antibody response to the hypothalamic-pituitary-adrenal (HPA) axis. METHODS 50 spousal carers of dementia patients, median age 73 years (IQR 66-77), and 67 controls (68 years [66-71]) of similar socioeconomic status were enrolled. Anxiety and depression were measured by the Savage Aged Personality Screening Scale and stress by the Global Measure of Perceived Stress scale. Principal-component analysis was used to yield a summary score of emotional distress from these two scales. Salivary cortisol concentrations were measured over a single day at three times (0800-1000, 1100-1300, and 2000-2200). Participants received a trivalent influenza vaccine and IgG antibody titres to each strain were measured on days 0, 7, 14, and 28. FINDINGS Mean scores of emotional distress were significantly higher in carers at each time point than in controls (all p<0.0003). Mean (SD) salivary cortisol concentrations, calculated as area under the curve (AUC), were higher in carers than controls at all three assessments (6 months 16.0 [8.0] vs 11.2 [4.4], p=0.0001; respectively). Eight (16%) of 50 carers and 26 (39%) of 67 controls had a four-fold increase in at least one of the IgG titres (p=0.007). There was an inverse relation between AUC cortisol and IgG antibody titre to the Nanchang strain that was significant on day 14 (r=-0.216, p=0.039). INTERPRETATION Elderly carers of spouses with dementia have increased activation of the hypothalamic-pituitary-adrenal axis and a poor antibody response to influenza vaccine. Carers may be more vulnerable to infectious disease than the population of a similar age.

Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity.

We reported previously that the neuropeptide oxytocin attenuates stress-induced hypothalamo–pituitary–adrenal (HPA) activity and anxiety behavior. This study sought to identify forebrain target sites through which oxytocin may mediate its anti-stress effects. Ovariectomized, estradiol-treated rats received intracerebroventricular infusions of oxytocin (1 or 10 ng/hr) or vasopressin (10 ng/hr), and the patterns of neuronal activation after restraint stress were determined by semiquantitative mapping of c-fos mRNA expression. Oxytocin administration significantly attenuated the release of ACTH and corticosterone and the increase in corticotropin-releasing factor mRNA expression in the hypothalamic paraventricular nucleus (PVN) in response to 30 min restraint. Restraint also induced the expression of c-fos mRNA in selective regions of the forebrain, including the PVN, paraventricular thalamic nucleus, habenula, medial amygdala, ventrolateral septum (LSV), most subfields of the dorsal and ventral hippocampus, and piriform and endopiriform cortices. In most cases, this level of gene expression was unaffected by concomitant administration of oxytocin. However, in the PVN, LSV, and throughout all subfields of the dorsal hippocampus, restraint evoked no detectable increase in c-fos mRNA in animals treated with either dose of oxytocin. Vasopressin had no effects on either HPA axis responses or neuronal activation in response to restraint, indicating that the effects were highly peptide selective. These data show that central oxytocin attenuates both the stress-induced neuroendocrine and molecular responses of the HPA axis and that the dorsal hippocampus, LSV, and PVN constitute an oxytocin-sensitive forebrain stress circuit.

Chronic stress in caregivers of dementia patients is associated with reduced lymphocyte sensitivity to glucocorticoids.

Caring for the chronically ill is associated with chronic distress. In view of the adverse effects of distress on cellular immune function, such distress may have implications for health. Indeed, it has been proposed that the hypothalamic-pituitary-adrenal (HPA) axis is a potential psychobiological mediator of these effects. In this study, we observed that elderly caregivers experienced greater distress and increased salivary cortisol than non-caregivers. In addition, caregivers had blunted mitogen-induced lymphocyte proliferation, lower mitogen-induced IL-2 production, and reduced lymphocyte sensitivity to glucocorticoids. These results indicate that chronic distress is associated with impaired cell-mediated immunity which is, in turn, associated with elevated basal steroid levels and altered steroid immunoregulation at the level of the lymphocyte.

The effects of early postnatal stimulation on Morris water-maze acquisition in adult mice: genetic and maternal factors.

Abstract Following stressor exposure BALB/cByJ mice exhibit hypersecretion of corticosterone and marked brain catecholamine alterations. In addition, mice of this strain exhibit impairments of performance in a Morris water-maze, which may be exacerbated by footshock application. In the present investigation it was demonstrated that early-life handling of mouse pups (coupled with brief separation periods from the dam over the course of 21 days postpartum) reduced the learning impairments seen when mice were tested in the Morris water-maze at 120 days of age and also prevented stress-induced disturbances in this task. Likewise, cross-fostering BALB/cByJ mice with a C57BL/6ByJ dam prevented the performance deficits. In contrast, C57BL/6ByJ mice cross-fostered to a BALB/cByJ dam exhibited proficient performance. Thus, maternal factors may be important in determining the Morris water-maze disturbances, provided that this was applied on the BALB/cByJ genetic background. Stressor exposure exacerbated the performance disturbances in BALB/cByJ mice, while diazepam treatment disrupted Morris water-maze performance in both BALB/cByJ and C57BL/6ByJ mice. Paralleling the behavioral changes associated with handling, the stress-induced hypercorticosterone secretion characteristic of the BALB/cByJ mouse was attenuated by the early handling procedure. Stressor exposure also produced strain-dependent variations of NE and 5-HT, but these effects were not appreciably influenced by the handling procedure. These data are consistent with the proposition that performance disturbances of BALB/cByJ mice tested in the Morris water-maze task are associated with excessive hypothalamic-pituitary-adrenal reactivity. Moreover, it appears that the influence of early-life stimulation may interact with genetic factors in determining endocrine and behavioral stress responses.

Stress-induced disturbances in Morris water-maze performance : interstrain variability

Marked differences were observed across strains of mice (i.e., DBA/2J, C57BL/6J, BALB/cByJ and CD-1 mice) in acquisition, performance and reversal of a place learning response in a Morris water-maze. While DBA/2J, C57BL/6J and CD-1 mice typically learned the response readily, only 20% of BALB/cByJ mice acquired the response. Commensurate with the effects of hippocampal disturbances, the performance deficits in BALB/cByJ mice were not evident when the position of the platform in the water-maze was cued. Exposure to uncontrollable foot shock did not affect the acquisition or performance of this response in the former three strains, but provoked a modest disruption of reversal performance in DBA/2J mice and markedly impaired reversal performance in BALB/cByJ mice. It seemed, however, that the response strategies adopted in these strains could be distinguished from one another. In the reversal paradigm BALB/cByJ mice initially persisted in returning to the original training quadrant rather than to the new goal quadrant. Following 2 days of training the perseveration was no longer apparent and animals seemed to adopt a random search strategy. In contrast, DBA/2J mice, which exhibited a smaller stress-induced disturbance, did not display a perseverative response style. These data suggest that inescapable shock does not disturb response-outcome associations, but may result from the induction of a perseverative response style. However, it appears that the mechanisms responsible for an interference of performance may not be uniform across strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular basis for the development of individual differences in the hypothalamic-pituitary-adrenal stress response

Summary1.Several years ago, investigators described the effects of infantile handling on the development of hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Rat pups exposed to brief periods of innocuous handling early in life showed reduced HPA responses to a wide variety of stressors, and the effect persists throughout the life of the animal. These effects are robust and provide an excellent model for understanding how early environmental stimuli, which are external to the organism, alter neural differentiation and, thus, neuroendocrine responsivity to stress.2.This paper reviews the endocrine mechanisms affected by early handling and our current understanding of the neural transduction of environmental events and their effects at the level of the target neurons (in the hippocampus and frontal cortex).3.In brief, handling serves to increase glucocorticoid receptor gene transcription, increasing sensitivity to glucocorticoid negative feedback regulation and, thus, altering the activity within hypothalamic corticotropin-releasing factor/vasopressin neurons. Together these changes serve to determine neuroendocrine responsivity to stress.

Restraint stress is associated with changes in glucocorticoid immunoregulation

Psychological stress has been associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired cell-mediated immune (CMI) responses. There is also evidence suggesting that intermittent chronic stress differentially alters CMI across different immune compartments, but the mechanisms underlying this phenomenon have not been explored in detail. In the present study, we investigated (i) acute and chronic restraint stress effects in Sprague-Dawley rats on both peripheral blood lymphocyte (PBL) and splenocyte mitogen-induced proliferation and (ii) also determined whether differential stress effects within these immune compartments might reflect alterations in lymphocyte sensitivity to glucocorticoids. It was found that while acute stress exposure significantly raised plasma corticosterone levels (1048% vs. controls, P<.001), this response was attenuated in the animals previously exposed to chronic intermittent stress (-79.66% vs. acute; P<.001). Acute stress increased phytohemagglutinin (PHA)-induced lymphocyte proliferation in the spleen (69.04%, P=.01) and suppressed PBL proliferation (-45.52%, P<.001). Neither of these changes were observed following chronic stress. We also demonstrated that reexposure to the stressor rapidly increased splenocyte sensitivity to in vitro dexamethasone (P<.05) and corticosterone (P<.05) in chronically stressed rats. Our data (1) confirm that acute stress is associated with compartment-specific changes in CMI function, (2) indicate that chronic stress is associated with habituated endocrine and immune responses and (3) that stressor exposure rapidly alters splenocyte sensitivity to glucocorticoids and we suggest that the latter may contribute to differential stress effects across immune compartments.

The maternal-neonatal neuro-immune interface: Are there long-term implications for inflammatory or stress-related disease?

Inflammatory stimuli reliably elicit hypothalamic-pituitary-adrenal (HPA) activation, and it is now established that the immune and HPA systems are mutually regulatory and that their interactions partly determine stress effects on immune function. What has not been extensively investigated, however, is the interactive nature of the development of the endocrine and immune systems and whether this might alter predisposition to inflammatory disease or stress-related pathologies. Increasing attention is now being focused on the role of early life environments determining long-term predisposition to disease, and a role for the HPA axis in disease predisposition is emerging. Stress generally refers to the condition where coping with actual or perceived stimuli alters the homeostatic state of the organism. The classic stress response involves the activation of central and peripheral catecholamine systems and HPA responses. Increased glucocorticoid levels are thought to protect the organism, both by providing energy substrates to deal with immediate environmental demands and by blocking potentially harmful overreaction by the immune system and other stress-reactive systems (1). However, to avoid immunosuppression and degenerative pathologies associated with increased glucocorticoid levels, the HPA stress response must terminate efficiently once the environmental demands are removed (2). Consequently, disturbances in endocrine-immune interactions upset the normal regulatory homeostatic balance and alter susceptibility to a variety of disease states associated with immune dysregulation (3). The physiological impact of stress is variable across individuals, and susceptibility to stress apparently depends on attributes of the organism, such as genetic endowment and age, and experiential factors, such as previous stress experiences, and early life events (4, 5). Indeed, the endocrine and immune systems and the CNS all respond to environmental pressures during development, and the interactive nature of these systems suggests that alterations in one system could have developmental consequences for the others and potential long-term implications for disease vulnerability. Plasticity in most developing physiological systems is thought to be of adaptive importance, enabling an organism to better meet the demands of the environment in which it matures and will most likely reside. However, the short-term reorganization or re-setting of regulatory systems to deal with immediate demands may also have long-term consequences for normal physiological function, thereby predisposing an organism to pathology. This may particularly be the case when the environmental pressures differ between development and adulthood. A number of epidemiological studies have indicated that nutritional factors early in life have long-term implications for cardiovascular and metabolic disease in adulthood. Most data suggest that maternal nutrition and limited intrauterine growth are responsible for reorganizing metabolic regulation and results in metabolic and cardiovascular pathologies in adult life (6). The concept of “perinatal programming” is not new and has long been investigated in neuroendocrine development of both the adrenal and the gonadal axes (see review, ref. 7). Immune responses, too, are influenced by early life experiences, and it has been suggested that pathogen exposure during development is important for the developing immune repertoire and that too little activation may be associated with the development of allergy (8). Available data also indicate that there are long-term consequences following endocrine-immune interactions during the first week of life. Thus, the administration of steroids during antigen exposure alters the development of immune tolerance (9), and immune challenge during the first week of life is associated with altered endocrine development (10, 11). These data demonstrate the interactive nature of both the immune and the neuroendocrine systems during development and show that these interactions can alter both immune and endocrine function in the long term. Maternal factors represent some of the most salient environmental influences altering endocrine development (12–14). Indeed, there is an extensive literature detailing both prenatal and postnatal influences on the development of the HPA axis. It is also well established that immune factors passed in utero and also to the neonate via milk have a direct impact on the its immunocompetence (15, 16). However, evidence examining the neuro-immune interface and maternal factors is limited.

The role of stressors and psychosocial variables in the stress process: a study of chronic caregiver stress.

Objective An investigation was conducted 1) to examine the relative importance of stressor types (ie, daily hassles, caregiving-specific stressors, and life events) on the stress response, 2) to assess the stability of relationships between psychosocial variables and stress over a 6-month period, and 3) to explore how the nature and magnitude of the contributions made by stressors and psychosocial factors to the stress process varied according to the qualitative characteristics of the stress response (ie, anxiety, depression, and stress). Methods Fifty spousal caregivers of patients with dementia were recruited and asked to participate in a detailed psychosocial evaluation at 3-month intervals; the evaluation involved measurement of stressor frequency, psychosocial variables, and indices of the stress response (ie, anxiety, depression, and stress). Results The data revealed that the effects of stressors and psychosocial factors on the stress response were considerable (accounting for 49–63% of the variance in stress response measures). Furthermore, there was some evidence of stability in the effects of the stressor and mediator variables on the stress response. Specifically, the contributions of life events and caregiver difficulties were largely consistent at both 3 and 6 months, and the psychosocial factor of “reactive coping and self-appraisal” influenced all three stress response indices at both 3 and 6 months. Conclusions There is some evidence of stability in the effects of stressors and psychosocial variables on the stress process over a 6-month period. However, it would also seem that the nature of the stress process differs according to the qualitative characteristics of the stress response.

Hypothalamic-Pituitary-Adrenal Function

Basal hypothalamic-pituitary-adrenal (HPA) function is characterised by pulses of corticosterone secretion followed by a transient refractory period when the axis appears to be inhibited. In females pulses of corticosterone secretion occur approximately once per hour with variation in pulse amplitude underlying a diurnal rhythm. Males show smaller pulses of secretion which become widely spaced during the early light phase nadir. Pulsatility is altered by genetic programming, early life experiences and reproductive status. Activation of the HPA axis during adjuvant induced arthritis results in an increase in the pulse frequency. This is associated with a marked change in hypothalamic gene expression with a diminution of CRH mRNA and a marked increase of AVP mRNA which becomes the predominant HPA secretagogue.