Leonardo H. Tonelli

Tumor necrosis factor alpha, interleukin-1 beta, interleukin-6 and major histocompatibility complex molecules in the normal brain and after peripheral immune challenge

Abstract The capacity of the brain to activate an inflammatory reaction involving the production of cytokines in response to an immune challenge in the periphery has been well established. Interleukin-1 beta is a cytokine that responds with the most widespread pattern of expression followed by tumor necrosis factor alpha and interleukin-6. In addition, our laboratory has shown that class I major histocompatibility complex molecules are upregulated in the brain in response to peripheral administration of bacterial products. Remarkably, during recent years, all these immune genes have been shown to participate in activity-dependent structural synaptic changes in specific neurochemical circuitries in the normal brain. These processes range from the refinement of synaptic connections in sensory systems to learning and memory storage functions of the hippocampus. Therefore, the mechanisms of defense against pathogens can dramatically affect brain structure and function-inducing changes in cognition, mood and behavior. The immune reactions initiated by viruses, bacteria and parasites may result in latent vulnerabilities which could become manifest with future stressors or challenges. Other inflammatory challenges may function as triggers for uncovering pre-existing vulnerabilities or exacerbation of previous functional deficits, or clinical symptoms of neurological or psychiatric conditions. This review will discuss the importance of infections on basic neuronal processes owing to the alteration in the brain of the balance of cytokines involved in higher brain functions.

The outdoor air pollution and brain health workshop

Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide.

Objective:  Based on the reported association between cytokines with depression and suicide, and evidence of increased markers of inflammation in the brain of suicide victims, the present study examined the expression of cytokines in the orbitofrontal cortex of suicide victims.

Toxoplasma gondii Antibody Titers and History of Suicide Attempts in Patients With Recurrent Mood Disorders

Toxoplasma gondii (T.gondii) is an obligate intracellular protozoan parasite infecting one-third of the world population, residing relatively silently in the brain of the immunocompetent host. We hypothesized that T.gondii seropositivity and serointensity are associated with having a history of attempting suicide and, in those attempting suicide, a greater number of attempts. T.gondii seropositivity and antibody titers were compared between (a) patients with recurrent mood disorders with history of suicide attempt (99 individuals) versus (b) patients with recurrent mood disorders without history of suicide attempt (119 individuals), and (c) healthy controls (39 individuals). Diagnosis was made using the Structured Clinical Interview for DSM-IV. Statistical methods included chi square, analysis of variance, and linear and logistic regression analyses. Suicide attempters had higher T.gondii antibody titers than nonsuicide attempters (p = 0.004). The logistic regression analysis revealed a predictive association between titers of anti- T.gondii antibodies and history of suicide attempt with OR = 1.55 (1.14–2.12), p = 0.006. No significant relationship was found between T.gondii seropositivity and suicide attempt status, number of prior suicide attempts, and recurrent mood disorder diagnosis. Although preliminary and bearing replication, this is the first report, to our knowledge, of an association between attempting suicide and T. gondii.

Intranasal Immune Challenge Induces Sex-Dependent Depressive-Like Behavior and Cytokine Expression in the Brain

The association between activation of the immune system and mood disorders has been reported by several studies. However, the mechanisms by which the immune system affects mood are only partially understood. In the present study, we detected depressive-like behavior in a rat animal model which involves the induction of inflammation in the nasal cavities by intranasal (i.n.) instillation of bacterial lipopolysaccharides (LPS). Female rats showed depressive-like behavior as evidenced by the forced swim test after repeated i.n. administration of LPS. These responses were not paralleled by alterations in motor activity as measured by the open field test. In the same animals, corticosterone responses after the swimming sessions were the highest of all the groups evaluated. Real-time RT PCR was used to analyze the transcriptional regulation of the cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6 in several brain regions. Increased tumor necrosis factor-α was detected in the hippocampus and brainstem of female rats challenged with i.n. LPS. These results suggest that peripheral inflammation in the upper respiratory tract is an immune challenge capable of inducing depressive-like behavior, promoting exaggerated glucocorticoid responses to stress, and increasing cytokine transcription in the brain. These results further our understanding of the role that the immune system may play in the pathophysiology of depression.

Seasonal spring peaks of suicide in victims with and without prior history of hospitalization for mood disorders

BACKGROUND Seasonal spring peaks of suicide are highly replicated, but their origin is poorly understood. As the peak of suicide in spring could be a consequence of decompensation of mood disorders in spring, we hypothesized that prior history of mood disorders is predictively associated with suicide in spring. METHODS We analyzed the monthly rates of suicide based upon all 37,987 suicide cases in the Danish Cause of Death Registry from 1970 to 2001. History of mood disorder was obtained from the Danish Psychiatric Central Register and socioeconomical data from the Integrated Database for Labour Market Research. The monthly rate ratio of suicide relative to December was estimated using a Poisson regression. Seasonality of suicide between individuals with versus without hospitalization for mood disorders was compared using conditional logistic regression analyses with adjustment for income, marital status, place of residence, and method of suicide. RESULTS A statistically significant spring peak in suicide was observed in both groups. A history of mood disorders was associated with an increased risk of suicide in spring (for males: RR=1.18, 95% CI 1.07-1.31; for females: RR=1.20, 95% CI 1.10-1.32). LIMITATIONS History of axis II disorders was not analyzed. Danish socioeconomical realities have only limited generalizability. CONCLUSIONS The results support the need to further investigate if exacerbation of mood disorders in spring triggers seasonal peaks of suicide. Identifying triggers for seasonal spring peaks in suicide may lead to uncovering novel risk factors and therapeutic targets for suicide prevention.

Tree pollen peaks are associated with increased nonviolent suicide in women

SIR—Research on seasonality of suicide has identified a highly replicated and robust peak in late spring and a somewhat less consistent peak in late summer and early fall. While a number of psychosocial and environmental factors, such as increased exposure to light in the spring, have been suggested to be associated with the spring peak, none satisfactorily explains the temporal association of the peak in suicide with the proposed environmental trigger. Based on the influence of cytokines on mood, cognition, and behavior in healthy individuals and patients with medical and psychiatric conditions, the reciprocal immune–brain interactions, and the cytokine expression during allergic reactions, we hypothesized that tree pollen (which peaks in spring) and ragweed pollen (which peaks in late summer/ early fall) may act as environmental triggers for suicide in vulnerable individuals. We explored this hypothesis by comparing the suicide rates before, during and after periods of peak atmospheric pollen. Tree and ragweed pollen data were obtained from the American Academy of Allergy, Asthma, & Immunology for the years 1995–1998 for the continental US and Canada. Periods of allergen exposure were derived from histograms expressing pollen counts as particles per cubic meter (p/m) on a log scale from 0 to 1000 (y-axis) by months (x-axis) within each year. Raters identified three periods for each allergen in time units of quartermonths at each location for up to 4 years divided as follows: a prepollen period (pollen countso10p/m3 for trees and omid-way on the log scale between 1 and 10p/m for ragweed), a peak-pollen period (4100p/m for trees and4mid-way on the log scale between 10 and 100p/m for ragweed), and a postpollen period when concentrations returned to the prepollen levels. Intervals with intermediate pollen counts were discarded. Suicide data were obtained from the General Mortality Database compiled by the National Center for Health Statistics. Each suicide was classified by county and state of occurrence, date, sex, age, and type (violent, nonviolent, other, or unknown) based on the ICD-9 codes. Suicides by other or unknown means accounted for 6% of the total. For annual rates, person-years were estimated by summing each county’s population from the 2000 Census across the years of observation by sex and age categories. For the analysis of rates and relative rates (RRs) by allergen season and pollen-level period, person-years were estimated by multiplying the population for each age and sex category in each county by the total number of days in each pollen-level period (1⁄4number of quarter months days per quarter month (1⁄47.6 days)) summed across years of observation and divided by 365.25 days per year. Annual and seasonal suicide rates, RRs, and their standard errors were estimated in Poisson’s regression models. RRs for each allergen season and suicide type were estimated setting the prepollen period as the referent and peak and postpollen periods as indicator variables. Since interaction by sex and age was found to be significant, rates and RRs for the effect of allergen exposure were calculated separately by the four age by sex strata. A post hoc analysis of a possible confounding effect of light (using a proxy measure, ‘sunshine’) was performed for the specific pollen periods that showed significant differences in suicide rates using mixed effects repeated measures ANOVAwith pollenperiod and year as within-location effects. The total population of these counties in 2000 was 37 824174 (Table 1). The total number of quarter months of peak-pollen was 670 in the tree season (mean1⁄414.3) and 476 in the ragweed season (mean1⁄49.5). In 92705 505 person-years, 9528 suicides were recorded (rate1⁄410.3/100 000 personyears, 95% confidence interval (CI)1⁄410.1, 10.5) (Table 2). As in other population-based samples of completed suicide, the rate in males was greater than in females (RR1⁄4 4.1, 95% CI1⁄43.9, 4.3), and greater in older people compared with younger (RR1⁄41.4, 95% CI1⁄41.3, 1.5). The rate in older males was greater than in younger males (RR1⁄41.8, 95% CI1⁄4 1.7, 1.9). No difference by age was seen in females. A total of 2417 suicides were recorded in the tree season and 1811 in the ragweed season (Table 3). During the tree allergy season, there was a two-fold increase in the rate of nonviolent suicides among younger females in the peak-pollen period compared with the prepollen period (95% CI1⁄4 1.3, 3.0) (Table 3). There was no difference between the postpollen period and the prepollen period. In older females, the rate of nonviolent suicide in the postpollen period was 4.6 times that of the prepollen period (95% CI1⁄41.2, 17.8), with no increase in the peak-pollen period relative to the prepollen period (Table 3). It is unlikely that a greater exposure to natural light during the peak-pollen season would have spuriously increased suicide rates in younger women, because a greater suicide rate was found in the peak-pollen period, while a greater ‘sunshine’ was found in the postpollen period. However, in older women, it is possible that a greater light exposure during the postpollen period could have spuriously inflated the rate of suicide during that period. The differences in the tree pollen period effect between younger and older women may also represent a consequence of Molecular Psychiatry (2005) 10, 232–238 & 2005 Nature Publishing Group All rights reserved 1359-4184/05

Anthrax lethal factor represses glucocorticoid and progesterone receptor activity

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Allergic rhinitis induces anxiety-like behavior and altered social interaction in rodents.

We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery. LeTx-nuclear receptor repression is selective, repressing GR, progesterone receptor B (PR-B), and estrogen receptor α (ERα), but not the mineralocorticoid receptor (MR) or ERβ. GR repression was also caused by selected p38 mitogen-activated protein (MAP) kinase inhibitors, suggesting that the LeTx action may result in part from its known inactivation of MAP kinases. Simultaneous loss of GR and other nuclear receptor activities could render an animal more susceptible to lethal or toxic effects of anthrax infection by removing the normally protective antiinflammatory effects of these hormones, similar to the increased mortality seen in animals exposed to both GR antagonists and infectious agents or bacterial products. These finding have implications for development of new treatments and prevention of the toxic effects of anthrax.

Inhibitory Effects of Progesterone Differ in Dendritic Cells from Female and Male Rodents

Epidemiological and clinical studies report higher incidences of anxiety and increased emotional reactivity in individuals suffering from respiratory allergies. To evaluate if respiratory allergies are capable of promoting anxiety-like behavior in rodents, we used models of allergic rhinitis and behavioral evaluations followed by assessment of mRNA for cytokines in relevant brain regions. Mice and rats were sensitized to ovoalbumin or pollen, respectively, following standard sensitization and challenge protocols. After challenge, the animals were evaluated in the open field, elevated plus-maze and resident-intruder tests. Cytokines and corticotropin-releasing factor expression were assessed in several brain regions by real-time RT-PCR and plasma corticosterone concentrations by radioimmunoassay. Mice and rats sensitized and exposed to allergen showed increased anxiety-like behavior and reduced social interaction without any overt behavioral signs of sickness. T-helper type 2 (T(H)2) cytokines were induced in both rats and mice in the olfactory bulbs and prefrontal cortex and remained unchanged in the temporal cortex and hypothalamus. The same results were found for CRF mRNA expression. No differences were observed in corticosterone concentrations 1h after the last behavioral test. These results show that sensitization and challenge with allergens induce anxiety across rodent species and that these effects were paralleled by an increased expression of T(H)2 cytokines and CRF in the prefrontal cortex. These studies provide experimental evidence that sensitized rodents experience neuroimmune-mediated anxiety and reduced social interaction associated with allergic rhinitis.