Tamo Nakamura

Epidural Auditory Event-Related Potentials in the Rat to Frequency and duration Deviants: Evidence of Mismatch Negativity?

The capacity of the human brain to detect deviance in the acoustic environment pre-attentively is reflected in a brain event-related potential (ERP), mismatch negativity (MMN). MMN is observed in response to the presentation of rare oddball sounds that deviate from an otherwise regular pattern of frequent background standard sounds. While the primate and cat auditory cortex (AC) exhibit MMN-like activity, it is unclear whether the rodent AC produces a deviant response that reflects deviance detection in a background of regularities evident in recent auditory stimulus history or differential adaptation of neuronal responses due to rarity of the deviant sound. We examined whether MMN-like activity occurs in epidural AC potentials in awake and anesthetized rats to high and low frequency and long and short duration deviant sounds. ERPs to deviants were compared with ERPs to common standards and also with ERPs to deviants when interspersed with many different standards to control for background regularity effects. High frequency (HF) and long duration deviant ERPs in the awake rat showed evidence of deviance detection, consisting of negative displacements of the deviant ERP relative to ERPs to both common standards and deviants with many standards. The HF deviant MMN-like response was also sensitive to the extent of regularity in recent acoustic stimulation. Anesthesia in contrast resulted in positive displacements of deviant ERPs. Our results suggest that epidural MMN-like potentials to HF sounds in awake rats encode deviance in an analogous manner to the human MMN, laying the foundation for animal models of disorders characterized by disrupted MMN generation, such as schizophrenia.

Neonatal lipopolysaccharide exposure alters central cytokine responses to stress in adulthood in Wistar rats

“Perinatal programming” is a phenomenon describing how early life environmental conditions can produce long-term physiological alterations that either enhance or inhibit adaptive functioning. Previously, we have demonstrated that neonatal exposure to lipopolysaccharide (LPS) predisposes to anxiety-like behaviour in later life, which was associated with changes to the neuroendocrine response to stress. Given the known interactions between the neuroendocrine and neuroimmune systems, here we investigated whether neonatal exposure to a bacterial mimetic alters neuroimmune responses to acute stress in adulthood. Male and female Wistar rats were administered LPS (0.05 mg/kg, i.p.), or saline vehicle (equivolume) on days 3 and 5 post-partum. One group of rats was euthanised following early life treatment to assess immediate hypothalamic–pituitary–adrenal axis and central cytokine responses to treatment. A second group was assessed in adulthood (85 days) following exposure to either a “stress” (30-min restraint) or “no stress” condition. Blood was collected from all rats at baseline, 30, 60 and 90 min after “stress”, “no stress” treatment to assess peripheral corticosterone responses, and brains were collected 180 min following baseline to assess hippocampal content of interleukin-1β (IL-1β), tumour necrosis factor-α (TNFα) and IL-6 protein. Radioimmunoassay revealed that neonatal LPS treatment resulted in a prolonged corticosterone response to stress in adulthood compared to controls (p < 0.05). Enzyme-linked-immunosorbent assays revealed no group differences in hippocampal IL-6 content. However, brain IL-1β and TNFα protein concentrations were significantly greater in rats neonatally exposed to LPS and then exposed to stress in adulthood when compared to all other groups (p < 0.05). These findings suggest that early life bacterial toxin exposure results in a prolonged neuroendocrine response to acute stress in adulthood, which may be a consequence of increased release of IL-1β and TNFα in the brain.

Disclosing hepatitis C infection within everyday contexts: implications for accessing support and healthcare.

In this paper the authors quantify hepatitis C disclosure outcomes across social contexts and identify the factors associated with widespread disclosure of infection. In a cross-sectional survey of people with hepatitis C (N = 504) more than half reported receiving a bad reaction from someone following disclosure. Unauthorized disclosure occurred, and many participants had been pressured into disclosing their infection. The factors associated with widespread disclosure were: education level; knowing other people with hepatitis C; feeling fatigued; receiving disclosure advice; and experiencing unauthorized disclosure. Bad reactions following disclosure are common and may impede health-seeking behaviour including uptake of hepatitis C treatment.

Maternal separation in early life impairs tumor immunity in adulthood in the F344 rat

Neonatal stress alters the hypothalamic–pituitary–adrenal (HPA) axis in rodents, such that, when these animals are exposed to stress as adults they hypersecrete corticosterone. Given that glucocorticoids are immunosuppressive, we examined the impact of maternal separation on HPA axis reactivity, natural killer (NK) cytotoxicity, and tumor growth in Fischer 344 rats following chronic restraint stress in adulthood. Pups underwent a chronic stress protocol whereby they were separated from their dams for 3 h on postnatal days 1–21. In adulthood, corticosterone responses were assessed following exposure to chronic (6 days for 10 h) restraint stress. Rats allocated to the chronic stress condition were inoculated with MADB106 tumor cells on day 4 of the restraint protocol. Blood was assessed for NK cytotoxicity on the final day of the chronic restraint protocol, and tumor colonization was assessed 3 weeks thereafter. Maternal separation impaired developmental weight gain (P < 0.05), depressed NK cytotoxicity (P < 0.05), and increased tumor colonization in the presence of chronic restraint stress in adulthood (P < 0.00 l). These findings occurred independently of circulating plasma corticosterone as only adult stress exposure potentiated corticosterone responses (P < 0.05). Our findings indicate that maternal separation and chronic stress can impair NK cytotoxicity and hence tumor immunity, but these effects are not directly mediated by perturbations in HPA axis function.

Prophylactic Role for Complementary and Alternative Medicine in Perinatal Programming of Adult Health

The health status of an individual in adulthood is proposed to be determined by events occurring in the prenatal and early postnatal period. A common early life event proven to have long lasting effects on the developing fetus is stress, including pain. Exposure of fetal and neonatal infants to repetitive psychological (e.g., maternal stress) or physiological (e.g., pain, infection, and noise) stress during this period is proposed to alter mechanisms involved in the regulation of stress, immunological maturation, pain perception, and cognition. Such changes, which persist into adulthood, may occur via alterations in the development of the hypothalamic-pituitary-adrenal (HPA) axis. This process is typically referred to as ‘perinatal programming’. Ontogenic alterations in the development of the HPA-axis have been related to a number of adult pathologies such as cardiovascular disease, type 2 diabetes, asthma, as well as psychopathologies such as anxiety and depression. Objective: In this review, the effectiveness of complementary and alternative medicine (CAM), such as music, dietary supplements, massage and aromatherapy, in reducing perinatal stress in mothers and infants is examined. An emphasis is placed on these therapies as preventative measures which may be of value to individuals at risk of developing disease profiles associated with the consequences of adverse perinatal programming. The widening interest in perinatal programming and CAM suggests the potential for CAM to become a valuable tool in offsetting negative adult health outcomes resulting from perinatal programming associated with adverse gestational early life environments.

Repetition suppression of the rat auditory evoked potential at brief stimulus intervals

An important prerequisite for the development of animal models of human auditory evoked potentials (AEP) is the accurate identification of homology. Prior research has revealed some remarkably similar response properties between rat and human AEPs, although there remains little consensus regarding the nature or validity of this correspondence. In the present study we seek to extend this research by examining the response properties of rat AEP as a function of stimulus repetition and interval. The aim being to determine whether rat AEP components show the same paradoxical reversal of repetition suppression observed for the human N100 AEP component at brief stimulus intervals. To achieve this, AEPs were recorded epidurally at the vertex in the freely moving rat in response to acoustic stimuli presented at random stimulus intervals between 50 and 5,000 ms. Using stimulation and analysis techniques to remove AEP waveform distortion due to overlapping AEP responses, the present results show that rat AEP components can be successfully resolved at intervals as brief as 50 ms. The results also demonstrate several fundamental types of correspondence between human and rat AEP components in terms of the sensitivity to stimulus interval and acoustic stimulus type. However the results found no evidence that rat AEP components show the reversal of repetition suppression at brief, relative to long, stimulus intervals as demonstrated for the N100 component in humans. The results are discussed in terms of EEG recording and AEP analysis procedures that provide promising avenues for future research.

Hippocampal IL-1β but not TNF-α or IL-6 is upregulated following neonatal LPS and adult stress exposure

420 Behavioural disturbances observed in experimental colitis are associated with activation of the kynurenine pathway and expression of hepatic tryptophan 2,3-dioxygenase A. Abautret-Daly , C. Medina , T.J. Connor , A. Harkin a,b a Trinity College Institute of Neuroscience, Lloyd Institute, Trinity College Dublin, Dublin, Co Dublin, Ireland b School of Pharmacy and Pharmaceutical Sciences, Ireland c School of Medicine, Trinity College Dublin, Ireland Inflammatory bowel diseases (IBD) are characterised by uncontrolled intestinal inflammation. In addition to physical symptoms, patients with IBD are at increased risk of depression and anxiety. Whether these psychological disturbances occur due to stress associated with symptoms of IBD, or as a result of biological mediators of inflammation is unknown. We examined the ability of trinitrobenzenesulphonic acid (TNBS)-induced colitis in rats to induce symptoms of anxiety and depression, and to activate the kynurenine pathway (KP). TNBS-induced colitis lead to weight loss, diarrhoea, macroscopic ulceration of the colon, and increased expression of inflammatory cytokines IL-1beta, IL-6, TNFalpha, and IFNgamma. When tested in the open field rats displayed increased thigmotaxis and spent significantly less time in the centre of the open field 3 and 8 days following TNBS treatment. Similarly, at day 3 and 8 post-TNBS, rats had decreased preference for a 0.01% saccharin solution suggestive of an anhedonic response. These behavioural changes were accompanied by decreased serum tryptophan and increased serum kynurenine/tryptophan 3 days post-TNBS, which is indicative of KP activation. KP activation was associated with increased TDO expression in the liver, whereas IDO expression was not altered in liver, spleen or colon. In summary, TNBS-induced colitis results in behavioural changes, coupled with KP activation. KP activation most likely occurs secondary to a stress-induced induction of TDO, as opposed to induction of IDO by inflammatory mediators. doi:10.1016/j.bbi.2010.07.165

93. Prenatal exposure to lipopolysaccharide alters febrile response to bacteria in adult wistar rats

As part of the inflammasome, capsase-1/ICE (interleukin-1b converting enzyme) is an intracellular protease that processes IL-1b and IL-18 to their active forms. In addition to its ability to bind TLR4, lipopolysaccharide (LPS) can activate the inflammasome and caspase-1. Mice that lack caspase-1 are resistant to the central LPSinduced reduction in food-motivated behavior, but the potential role of central caspase-1 on LPS-induced depressive-like behavior has not yet been studied. Caspase-1 knock out (KO) and wild-type (WT) mice were injected intracerebroventricularly (i.c.v.) with saline or LPS. Sickness (exploration of a novel juvenile at 4, 8, 12 and 24 h postLPS), depressive-like behavior (immobility during the forced swim test (FST) 25 h post-LPS) and feed disappearance were measured. Cumulative feed disappearance with LPS-treated WT mice was reduced at all time points, whereas this effect was observed only at 4 and 8 h with KO mice. LPS caused a reduction in social exploration by WT, but not KO, mice at 4 h (p < 0.02) compared to salinetreated controls. LPS increased duration of immobility in the FST. There was a trend for a strain by treatment interaction (p < 0.10), as LPS tended to increase immobility more in WT than KO mice. These encouraging data (with n = 5) implicate a critical role of brain caspase-1 in central LPS-induced sickness and depressive-like behavior. Supported by the NIH (KWK MH 51569, AG029573; RD MH079829, MH71349).

66. Long-term alterations in neuroimmune and neuroendocrine responses following neonatal exposure to lipopolysaccharide in Wistar rats

was mirrored by prominent c-Fos expression in arousal-supporting orexin and histamine neurons of saline-treated rats, whereas c-Fos expression in these populations was greatly diminished in the LPStreated rats. Arcuate neurons expressing cocaine-amphetaminereated transcript (CART) also expressed prominent c-Fos in salinetreated rats, probably related to ingestion of food. Paradoxally, LPS treatment completely suppressed activity of these CART neurons in the arcuate nucleus, which are implicated in satiety-induced suppression of feeding (serving an anorexigenic role). These findings support our notion that arousal-supporting systems, including the orexin and histaminergic components, which project to large parts of the brain, are functionally disengaged during sickness. This lack of functional activation, critical for goal-directed behavior, may underlie the characteristic lack of behavioral arousal during illness. This study was supported by NIH Grant MH068834.

37. Neonatal lipopolysaccharide exposure alters neonatal and adulthood neuroendocrine functioning, sexual maturation and blood composition in the rodent

Uncontrolled surgical stress may cause a weaker immune response that may lead to delayed wound healing. The phenomenon of unplanned perioperative hypothermia is known to expose patients to additional uncontrolled surgical stress. The aim of this experimental study was to evaluate the eect of a prewarming intervention using a forced-air warming (FAW) device versus routine care (RC) using warmed cotton blankets on the development of unplanned hypothermia, cytokine production, and endocrine responses. It was hypothesized that (1) FAW participants would experience less unplanned hypothermia than RC participants; (2) FAW participants would experience lower catecholamine and cortisol levels than RC participants; and (3) FAW participants would experience higher proinflammatory cytokine and CRP production intraand post-operatively than RC participants. Tympanic temperatures and blood samples were taken at four time intervals from each of the 28 (n = 14 each group) randomized participants that underwent routine general anesthesia surgery. Serum concentrations of CRP, cortisol and IL-1b, IL-6, TNF-a, and IFN-g, and plasma concentrations of epinephrine and norepinephrine were measured. To test the hypotheses, a repeated measures ANOVA design was used. Though FAW was not associated with a dierential endocrine or inflammatory response in this preliminary study, further study of forced air warming as a preoperative nursing intervention is warranted. The finding of higher than expected IL-6 levels in the preoperative period suggests a potential role for anxiety, an important factor in psychoneuroimmunological pathways, that could aect recovery and healing. The relationship between surgical stress, anxiety, and preoperative IL-6 deserves further study.