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We show that the sex of human experimenters affects mouse behaviors and responses following administration of the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. Mice showed aversion to the scent of male experimenters, preference for the scent of female experimenters and increased stress susceptibility when handled by male experimenters. This human-male-scent-induced aversion and stress susceptibility was mediated by the activation of corticotropin-releasing factor (CRF) neurons in the entorhinal cortex that project to hippocampal area CA1. Exposure to the scent of male experimenters before ketamine administration activated CA1-projecting entorhinal cortex CRF neurons, and activation of this CRF pathway modulated in vivo and in vitro antidepressant-like effects of ketamine. A better understanding of the specific and quantitative contributions of the sex of human experimenters to study outcomes in rodents may improve replicability between studies and, as we have shown, reveal biological and pharmacological mechanisms.

Differential rodent responses to the sex of human experimenters could have far reaching consequences in preclinical studies. Here, we show that the sex of human experimenters affects mouse behaviours and responses to the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. We found that mice manifest aversion to human male odours, preference to female odours, and increased susceptibility to stress when handled by male experimenters. This male induced aversion and stress susceptibility is mediated by the activation of brain corticotropin-releasing factor (CRF) neurons projecting from the entorhinal cortrex to hippocampal area CA1. We further establish that exposure to male scent prior to ketamine administration activates CRF neurons projecting from the entorhinal cortex to hippocampus, and that CRF is necessary and sufficient for ketamine’s in vivo and in vitro actions. Further understanding of the specific and quantitative contributions of the sex of human experimenters to different experimental outcomes in rodents may lead not only to reduced heterogeneity between studies, but also increased capability to uncover novel biological mechanisms.

An early inflammatory insult is the most recognized risk factor associated with neurodevelopmental psychiatric disorders, even more so than genetic variants. Notably, complement component 4 (C4), a molecule involved in inflammatory responses, has been strongly associated with schizophrenia (SZ) and its role in other neurodevelopmental disorders, such as autism (ASD), is an area of active investigation. However, while C4 in SZ has been implicated in the context of synaptic pruning, little is known about its neuroinflammatory role. The subventricular zone (SVZ) is a region heavily involved in neurodevelopment and neuroimmune interactions through the lifespan; thus, it is a region wherein C4 may play a vital role in disease pathology. Using in situ hybridization with radioactive riboprobes and RNAscope, we identified robust astrocytic expression of C4 in the SVZ and in the septum pellucidum. C4 was also expressed in ependyma, neurons, and Ki67

Maternal immune activation (MIA) with the viral mimic poly I:C provides an established rodent model for studying schizophrenia (SZ) and other human neurodevelopmental disorders. Postnatal infections are additional risk factors in SZ and may cumulatively contribute to the emergence of pathophysiology. Underlying mechanisms may involve metabolites of the kynurenine pathway (KP) of tryptophan degradation, which is readily induced by inflammatory stimuli. Here we compared the expression of selected cytokines and KP enzymes, and the levels of selected KP metabolites, in the brain of MIA offspring following a second, acute immune challenge with lipopolysaccharides (LPS) on postnatal day (PND) 35 (adolescence) or PND 60 (early adulthood). Assessed in adolescence, MIA did not alter the expression of pro-inflammatory cytokines (except TNF-α) or KP metabolite levels compared to controls, but substantially reduced the expression of the anti-inflammatory cytokines IL-4 and IL-10 and influenced the expression of two of the four KP enzymes examined (IDO1 and TDO2). LPS treatment caused distinct changes in the expression of pro- and anti-inflammatory cytokines, as well as KP enzymes in MIA offspring, but had no effect on KP metabolites compared to control rats. Several of these effects were blunted in MIA offspring receiving LPS on PND 60. Notably, LPS caused a significant reduction in brain kynurenine levels in these animals. Of relevance for SZ-related hypotheses, these results indicate that MIA leads to an increasingly defective, rather than an overactive, immune regulation of cerebral KP metabolism during the postnatal period.

Psychological stress is known to have profound effects on immune function and to promote inflammatory conditions. Elevated circulating levels of cytokines associated with stress are known to increase the risk to several diseases, but little is known about this mechanism. This study assessed the role of T cells on cytokine levels after exposure to stress in the learned helplessness paradigm. Adoptive transfer of CD4+ T cells into Rag2-/- mice did not change cytokine levels to stress while CD8+ T cells resulted in an increase in TNF-α, IL-6 and IFN-γ in stressed Rag2-/- mice. Moreover, depletion of CD8+ T cells in WT mice abolished these cytokine responses to stress. Corticosterone and behavioral stress responsiveness was impaired in Rag2-/- mice reconstituted with CD8+ T cells. Notably, depletion of these cells in WT mice had no effect on behavior or corticosterone levels. Exposure to stress did not change the expression of canonical markers of T cell activation including CD62L and CD44 or modified intracellular cytokine content, suggesting that they are not the main producers of circulating cytokines in response to stress. These results show that CD8+ T cells promote TNF-α, IL-6 and IFN-γ responses to stress, possibly by stimulating non-lymphoid cells.

Immunological abnormalities are increasingly reported in people with schizophrenia, but no clear functional biomarkers associated with genetic correlates of the disease have been found. Regulatory T cells (Tregs) are key immunoregulatory cells involved in the control of inflammatory processes and their functions are directly related to the human leucocyte antigen (HLA) gene, which has been implicated in schizophrenia genetic studies. However, there is a lack of studies reporting Treg status in people with schizophrenia. In the current study, the proportion of circulating Tregs was examined using flow cytometry in 26 medicated participants with schizophrenia and 17 healthy controls. Psychiatric symptoms and cognitive function were evaluated using the Scale for the Assessment of Negative Symptoms, the Brief Psychiatric Rating Scale, and the MATRICS Consensus Cognitive Battery. The proportion of Tregs was found to be significantly greater in the schizophrenia group compared to healthy controls. No differences were observed in total lymphocyte counts or CD3(+) and CD4 (+) T cells, confirming a specific effect for Tregs. Elevated Tregs in schizophrenia correlated with fewer negative symptoms, a core domain of the illness. These results suggest that Tregs may contribute to improved negative symptoms in schizophrenia, possibly by counteracting on-going inflammatory processes.

The concept of the brain as an immune privileged organ is rapidly evolving in light of new findings outlining the sophisticated relationship between the central nervous and the immune systems. The role of T cells in brain development and function, as well as modulation of behavior has been demonstrated by an increasing number of studies. Moreover, recent studies have redefined the existence of a brain lymphatic system and the presence of T cells in specific brain structures, such as the meninges and choroid plexus. Nevertheless, much information is needed to further the understanding of brain T cells and their relationship with the central nervous system under non-inflammatory conditions. In the present study we employed the Rag2(-/-) mouse model of lymphocyte deficiency and reconstitution by adoptive transfer to study the temporal and anatomical expansion of T cells in the brain under homeostatic conditions. Lymphopenic Rag2(-/-) mice were reconstituted with 10 million lymphoid cells and studied at one, two and four weeks after transfer. Moreover, lymphoid cells and purified CD4(+) and CD8(+) T cells from transgenic GFP expressing mice were used to define the neuroanatomical localization of transferred cells. T cell numbers were very low in the brain of reconstituted mice up to one week after transfer and significantly increased by 2weeks, reaching wild type values at 4weeks after transfer. CD4(+) T cells were the most abundant lymphocyte subtype found in the brain followed by CD8(+) T cells and lastly B cells. Furthermore, proliferation studies showed that CD4(+) T cells expand more rapidly than CD8(+) T cells. Lymphoid cells localize abundantly in meningeal structures, choroid plexus, and circumventricular organs. Lymphocytes were also found in vascular and perivascular spaces and in the brain parenchyma across several regions of the brain, in particular in structures rich in white matter content. These results provide proof of concept that the brain meningeal system, as well as vascular and perivascular spaces, are homing sites of lymphocytes and suggest the possibility of a brain specific T cell subtype.

Accumulating evidence supports a role of T cells in behavioral stress responsiveness. Our laboratory previously reported that lymphocyte deficient Rag2(-/-) mice on a BALB/c background display resilience to maladaptive stress responses when compared with immune competent mice in the predator odor exposure (POE) paradigm, while exhibiting similar behavior in a cued fear-conditioning (FC) paradigm. In the present study, Rag2(-/-) mice on a C57BL/6 background were assessed in the same behavioral paradigms, as well as additional tests of anxiety and depressive-like behavior. Furthermore, the effects of naïve CD4(+ ) T cells were evaluated by adoptive transfer of functional cells from nonstressed, wild-type donors to Rag2(-/-) mice. Consistent with our prior results, Rag2(-/-) mice displayed an attenuated startle response after POE. Nevertheless, reconstitution of Rag2(-/-) mice with CD4(+ ) T cells did not modify startle reactivity. Additionally, in contrast with our previous findings, Rag2(-/-) mice showed attenuated fear responses in the FC paradigm compared to wild-type mice and reconstitution with CD4(+ ) T cells promoted fear learning and memory. Notably, reconstitution with CD4(+ ) T cells had anxiolytic and antidepressant-like effects in Rag2(-/-) mice that had not been previously stressed, but had no effect after POE. Taken together, our results support a role of CD4(+ ) T cells in emotionality, but also indicate that they may promote fear responses by enhancing learning and memory processes.

The neurodevelopmental defects associated with ZIKV infections early in pregnancy are well documented, however the potential defects and long-term consequences associated with milder infections in late pregnancy and perinatal period are less well understood. To model these, we challenged 1 day old (P1) immunocompetent C57BL/6 mice with ZIKV. The animals developed a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10–15 days post-infection (dpi) but symptoms subsided after a week, and most animals survived. Despite apparent recovery, MRI of convalescent mice show reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80, Il-1α, and Ifn-γ together with Cd3, Cd8 and perforin (PrfA), suggested persistence of low-grade inflammation. Surprisingly, the brain parenchyma of convalescent mice harbor multiple small discrete foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and isolation of infectious virus derived from these convalescent mice by blinded passage in Vero cells confirmed long-term persistence of replicating ZIKV in CNS of convalescent mice. Although the infection appears to persist in defined reservoirs within CNS, the resulting inflammation could increase the risk of neurodegenerative disorders. This raises concern regarding possible long-term effects in asymptomatic children exposed to the virus and suggests that long-term neurological and behavioral monitoring as well as anti-viral treatment to clear virus from the CNS may be useful in patients exposed to ZIKV at an early age., Author summary Infections in the perinatal period are associated with lasting cognitive impairment and increased risk for affective disorders. The congenital brain malformations associated with ZIKV infections early in pregnancy are well documented, however whether perinatal exposure could lead to long term sequelae is not fully understood. Using a non-lethal neonatal mouse model of ZIKV, we examine host-pathogen interactions, anatomical changes and behavioral patterns by following survivors of the acute infection for over 1 year. We discover that ZIKV has the potential to remain in the CNS for extended periods, lodged within small foci surrounded by gliosis and infiltrating immune cells that may act to limit the viral spread, but also interfere with healing and contribute to ongoing neuropathic and behavioral sequelae. This suggests anti-viral treatment and long-term neurological and behavioral monitoring may be indicated for patients exposed to ZIKV early in life.

Psychological stress is known to have profound effects on immune function and to promote inflammatory conditions. Elevated circulating levels of cytokines associated with stress are known to increase the risk to several diseases, but little is known about this mechanism. This study assessed the role of T cells on cytokine levels after exposure to stress in the learned helplessness paradigm. Adoptive transfer of CD4(+) T cells into Rag2(−/−) mice did not change cytokine levels to stress while CD8(+) T cells resulted in an increase in TNF-α, IL-6 and IFN-γ in stressed Rag2(−/−) mice. Moreover, depletion of CD8(+) T cells in WT mice abolished these cytokine responses to stress. Corticosterone and behavioral stress responsiveness was impaired in Rag2(−/−) mice reconstituted with CD8(+) T cells. Notably, depletion of these cells in WT mice had no effect on behavior or corticosterone levels. Exposure to stress did not change the expression of canonical markers of T cell activation including CD62L and CD44 or modified intracellular cytokine content, suggesting that they are not the main producers of circulating cytokines in response to stress. These results show that CD8(+) T cells promote TNF-α, IL-6 and IFN-γ responses to stress, possibly by stimulating non-lymphoid cells.

Inflammatory diseases are highly associated with affective disorders including depression and anxiety. While the role of the innate immune system on emotionality has been extensively studied, the role of adaptive immunity is less understood. Considering that chronic inflammatory conditions are mediated largely by maladaptive lymphocyte function, the role of these cells on brain function and behavior during inflammation warrants investigation. In the present study we employed mice deficient in lymphocyte function and studied behavioral and inflammatory responses during challenge with bacterial lipopolysaccharides (LPS). Rag2−/− mice lacking mature lymphocytes were susceptible to death under sub-septic (5 mg/kg) doses of LPS and survived only to moderate (1 mg/kg) doses of LPS. Under these conditions, they displayed attenuated TNF-alpha responses and behavioral symptoms of sickness when compared with immunocompetent mice. Nevertheless, Rag2−/− mice had protracted motivational impairments after recovery from sickness suggesting a specific function for lymphocytes on the re-establishment of motivational states after activation of the innate immune system. The behavioral impairments in Rag2−/− mice were paralleled by an elevation in plasma corticosterone after behavioral tests. These results provide evidence that the absence of adaptive immunity may be associated with emotional deficits during inflammation and suggest that depressive states associated with medical illness may be mediated in part by impaired lymphocyte responses.

Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, acts as an endogenous antagonist of alpha7 nicotinic and NMDA receptors and is implicated in a number of neurophysiological and neuropathological processes including cognition and neurodegenerative events. Therefore, kynurenine aminotransferase II (KAT II/AADAT), the enzyme responsible for the formation of the majority of neuroactive kynurenic acid in the brain, has prompted significant interest. Using immunohistochemistry, this enzyme was localized primarily in astrocytes throughout the adult rat brain, but detailed neuroanatomical studies are lacking. Here, we employed quantitative in situ hybridization to analyze the relative expression of KAT II mRNA in the brain of rats under normal conditions and 6 h after the administration of lipopolysaccharides (LPSs). Specific hybridization signals for KAT II were detected, with the highest expression in the subventricular zone (SVZ), the rostral migratory stream and the floor of the third ventricle followed by the corpus callosum and the hippocampus. This pattern of mRNA expression was paralleled by differential protein expression, determined by serial dilutions of antibodies (up to 1:1 million), and was confirmed to be primarily astrocytic in nature. The mRNA signal in the SVZ and the hippocampus was substantially increased by the LPS treatment without detectable changes elsewhere. These results demonstrate that KAT II is expressed in the rat brain in a region-specific manner and that gene expression is sensitive to inflammatory processes. This suggests an unrecognized role for kynurenic acid in the brain’s germinal zones.

Background: Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology. Methods: We used postmortem brain tissue from the ventrolateral prefrontal cortex (VLPFC) to assess tissue levels of tryptophan and KP metabolites, the expression of several KP enzymes and a series of cytokines as well as tissue pathology, including microglial activation. Tissue samples came from nonpsychiatric controls (n = 36) and individuals with depressive disorder not otherwise specified (DD-NOS, n = 45) who died of natural causes, homicide, accident, or suicide. Results: We found a reduction in the enzymatic conversion of tryptophan to kynurenine, determined using the kynurenine:tryptophan ratio, and reduced messenger RNA expression of the enzymes indoleamine-2,3-dioxygenase 1 and 2 and tryptophan-2,3-dioxygenase in depressed individuals irrespective of the cause of death. These findings correlated with reductions in the expression of several cytokines, including interferon-γ and tumour necrosis factor-α. Notably, quinolinic acid levels were also lower in depressed individuals than controls. Limitations: Information on the use of antidepressants and other psychotropic medications was insufficient for statistical comparisons. Conclusion: Contrary to expectations, the present results indicate that depression, in the absence of medical illness or an overt inflammatory process, is associated with compromised, rather than increased, KP metabolism in the VLPFC.

Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1β and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.

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.

Objective An association between allergic disease and depression has been consistently reported, but whether the key mediating ingredients are predominantly biological, psychological, or mere artifacts remains unknown. In the current study, we examine the hypothesized relationship between allergen-specific immunoglobulin E (IgE) status and changes in allergy symptoms with worsening in depression scores in depressed sensitized individuals.

The chemokine CCL27 has chemoattractant properties for memory T cells and has been implicated in skin allergic reactions. The present study reports the expression in the brain of two CCL27 splice variants localized in the cerebral cortex and limbic regions. CCL27-like immunoreactivity was identified mainly in neurons. Variant 1 was found elevated in the olfactory bulbs during allergic inflammation induced by intranasal challenge with allergen. This was accompanied by the presence of T cells in the olfactory bulbs. Intranasal administration of neutralizing antibodies against CCL27 reduced the presence of T cells in the olfactory bulbs suggesting a function in T cell activity in the brain.

Udgivelsesdato: 2009-Jun-15 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.

The intranasal pathway is a direct route of communication between the environment and the brain. This pathway is currently used for the delivery of several experimental therapeutic peptides and vaccines because it bypasses the blood brain barrier. It is also a route of entrance to the brain for several viruses and toxic substances. Airborne infectious, allergic and pollution agents are among the most common inflammatory factors which may affect brain function via the brain-nose interface. The inflammatory processes triggered in the upper respiratory tract by these agents are positioned to influence the immune response of the brain and therefore, influence its function and alter behavior. Several clinical and epidemiological studies find an association between inflammatory factors affecting the intranasal pathway and neurological disorders such as multiple sclerosis, Alzheimer and Parkinson diseases as well as mental disorders including anxiety and mood disorders. However the mechanisms of interaction between the immune response in the nasal epithelium and the brain are poorly understood. This article discusses current evidence about these mechanisms and associations with neurological and mental diseases.

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.

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-1beta, tumor necrosis factor-alpha, and interleukin-6 in several brain regions. Increased tumor necrosis factor-alpha 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.

Postpartum mood disorders can negatively affect women, their offspring, and their families when left untreated. The identification and treatment of postpartum depression remains problematic since health care providers may often not differentiate postpartum blues from depression onset. Recent studies found potentially new risk factors, etiologies, and treatments; thus, possibly improving the untreated postpartum depression rates. This integrated review examined several postpartum psychiatric disorders, postpartum blues, generalized anxiety, obsessive compulsive disorder, post-traumatic stress disorder, and postpartum psychosis for current findings on prevalence, etiologies, risk factors, and postpartum depression treatments.

Although growing evidence supports an association between allergy, allergens and depression, it remains unknown if this relationship is between “states” (possible triggers) or “traits” (possible vulnerabilities). We hypothesized that patients with recurrent mood disorders who are sensitized to tree pollen (as determined by allergen specific IgE antibodies), in comparison to those who are not sensitized, would report larger negative changes in mood during exposure to tree pollen in spring. We also hypothesized that differences between high and low tree pollen periods in self reported allergy symptoms would correlate positively with differences in self reported depression scores. We present 1-year preliminary data on the first 51 patients with unipolar or bipolar disorder (age: 19-63 years, 65% female, twelve patients were tree-pollen IgE positive). Ratings of mood and allergic disease status were performed once during the peak airborne pollen counts and once during the period of low airborne pollen counts, as reported by two local pollen counting stations. Linear regression models were developed to examine associations of changes in depression scores (dependent variable) with tree pollen sensitization, changes in the allergy symptom severity score, adjusted for gender and order of testing. We did not confirm the hypothesized relationship between a specific tree pollen sensitization and changes in mood during tree pollen exposure. We did confirm the hypothesized positive relationship between the changes in allergy symptoms and changes in subjects' depression scores (adjusted pchangesin allergy symptom scores andchangesin depression scores supports a state-level rather than only trait-level relationship, and thus lends optimism to future causality-testing interventional studies, which might then lead to novel preventative environmental interventions in mood disorders.

Suicide is a leading cause of mortality among adolescents. There is a pressing public health need to investigate triggers and novel vulnerabilities for suicide in order to improve risk assessment and develop innovative prevention strategies. Alcohol is a well established risk factor for adolescent suicide. In this paper, we outline a novel mechanism linking allergy, alcohol, and suicide, reviewing (a) the association between allergic inflammation, depression, and suicide; and (b) the role of alcohol in inducing phosphorylation and rearrangement of tight junction proteins of the blood-brain barrier (BBB) resulting in increased "leakiness", i.e. passage of cells and molecules. Seasonal peaks of suicide in spring have been consistently reported, but their causality is poorly understood. A preliminary epidemiologic study found increased nonviolent suicide rates in females in spring during intervals of high tree pollen, in comparison to similar intervals of low tree pollen. This initial report added to the emerging literature proposing a relationship between allergy and depression, and is being further pursued at clinical, epidemiological, animal and postmortem tissue levels. We propose that allergic inflammation influences depression-related brain function via molecular and cellular mediators, but those mediators have a very limited access to the brain when the BBB is intact. Alcohol intake disrupts BBB, allowing increased brain exposure to cellular mediators of allergy. Considering the greater prevalence of allergy in adolescence when alcohol use starts, studies investigating the connection between allergy, alcohol, and suicide should be expanded to also include a focus on youth.

Increased calcium influx through L-type voltage-gated calcium channels (L-VGCC) has been implicated in the neuronal dysfunction underlying age-related memory declines. In the present study we sought to test the specific role of Cacna1c (which encodes Cav1.2) in modulating age-related memory dysfunction. Short-term, spatial, and contextual/emotional memory was evaluated in young and aged, wild-type as well as mice with one functional copy of Cacna1c (haploinsufficient), using the novel object recognition, Y-maze, and passive avoidance tasks respectively. Hippocampal expression of Cacna1c mRNA was measured by quantitative polymerase chain reaction (qPCR). Aging was associated with object recognition and contextual/emotional memory deficits and a significant increase in hippocampal Cacna1c mRNA expression. Cacna1c haploinsufficiency was associated with decreased Cacna1c mRNA expression in both young and old animals. However, haploinsufficient mice did not manifest an age-related increase in expression of this gene. Behaviorally, Cacna1c haploinsufficiency prevented object recognition deficits during aging in both male and female mice. A significant correlation between higher Cacna1c levels and decreased object recognition performance was observed in both sexes. We have also observed a sex-dependent protective role of decreased Cacna1c levels in contextual/emotional memory loss, specifically in male mice. These data provide evidence for an association between increased hippocampal Cacna1c expression and age-related cognitive decline. Additionally, they indicate an interaction between the Cacna1c gene and sex in the modulation of age-related contextual memory declines.

The expression of pro-thyrotropin-releasing hormone (pro-TRH) mRNA was analyzed in the hypothalamus of inflammatory susceptible LEW/N and resistant F344/N rats at baseline and in adrenalectomized and lipopolysaccharide-treated animals. In saline-treated control animals, increased pro-TRH transcription was detected in LEW/N with respect to F344/N rats. This increased LEW/N pro-TRH expression was stable regardless of condition in contrast to F344/N increased pro-TRH transcription post-adrenalectomy and decreased pro-TRH after lipopolysaccharide administration. The LEW/N increase in pro-TRH mRNA was independent of changes in hormonal status suggesting alteration of the thyroid axis at the central level in this strain.

The expression of interleukin-1 beta (IL-1beta) mRNA was compared in the brain of inflammatory susceptible LEW/N and resistant F344/N rats at 3, 6, and 12 h after peripheral administration of lipopolysaccharide (LPS) or saline. No differences between strains were observed in the circumventricular organs (CVOs) and choroid plexus. At 12 h after LPS administration, increased IL-1beta mRNA expression was detected in the hypothalamus of LEW/N rats. In contrast, increased IL-1beta mRNA expression was detected in the cerebral cortex of F344/N rats. These data show region-specific differences of IL-1beta mRNA expression in the brain of these rat strains that differ in their susceptibility to inflammation.

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.

The expression of class I major histocompatibility complex (MHC) mRNA was compared in the brains of inflammatory susceptible, hypothalamic-pituitary-adrenal (HPA)-axis blunted Lewis rats and inflammatory resistant, HPA-axis hyperresponsive Fischer rats by quantitative in situ hybridization following lipopolysaccharide (LPS) or vehicle administration. Lewis rats showed lower levels of class I MHC in the hypothalamic paraventricular nucleus (PVN) and retrochiasmatic area (RCA) compared to Fischer rats under both vehicle and LPS conditions. No differences were detected in other brain structures. Differential class I MHC expression in Lewis rats suggests an alteration in mechanisms related to cellular activity of neuroendocrine cells rather than alterations specific to neuroendocrine molecules.

Accumulating evidence has shown that adaptive immune cells are capable of modulating behavior and cognition via interactions with the brain and central nervous system elements. Nevertheless, since a vast majority of these studies were conducted in adult, constitutive knockout models of immune deficiency, it raises the question of whether compensatory mechanisms associated with development in a lymphopenic environment may explain some of the behavioral observations. To address this, neonate Rag2-/- (P2) mice were reconstituted with whole lymphocytes (ReconWL) derived from GFP+ wild type donors. Starting at 5 weeks of age (mid-adolescence) ReconWL, saline injected Rag2-/- and C57BL/6 J control mice underwent a series of behavioral tests including the open field, social interaction and sucrose preference tests. Then at 12 weeks (young adult) they were evaluated in the Morris Water Maze. Remarkably, reconstituted mice showed changes in almost all aspects that were assessed. Perhaps most notable however, was the complete rescue of impaired social behavior displayed by non-reconstituted Rag2-/- mice. While Rag2-/- mice preferred a non-social area and spent significantly less time with a conspecific mouse, ReconWL mice were comparable to wild type mice. Additionally, consistent with previous reports, Rag2-/- mice had deficits in reversal learning in the MWM that were rescued by reconstitution. These findings support a role for lymphocytes in modulating a spectrum of behavioral and cognitive processes across the lifespan.

The enzyme kynurenine-3-monooxygenase (KMO) converts kynurenine into 3-hydroxy-kynurenine (3-HK) along the kynurenine pathway (KP) of tryptophan metabolism. Increased or decreased function of this enzyme has been implicated in a number of neuropathological states. Deletion of this gene in mice has been shown to result in a number of neurobehavioral alterations suggesting a role in the brain. However, studies detailing neuroanatomical descriptions of KMO expression in the brain are lacking. In the present study, high sensitive radioactive in situ hybridization along with conventional RT-PCR and real time RT- PCR were employed to quantify in the rat brain and peripheral organs the expression of KMO in normal conditions and after peripheral administration of LPS. KMO mRNA expression was detected in the brain by real-time RT-PCR in normal conditions with the highest expression in the hippocampus. This signal was increased 2-fold after LPS administration. However, full length mRNA for KMO was not detected in any brain region under any condition. In situ hybridization using full length probes detected robust signals in the liver, kidney and spleen. Nevertheless, these probes failed to detect specific signals in the brain under any condition. This data shows that while mRNA for KMO can be detected by real-time RT-PCR, full length mRNA for KMO in the rat brain is below detection levels of conventional expression methods, both under normal and inflammatory conditions.

Angiotensin II (Ang II) AT1 receptors are involved in the regulation of the stress response. In adult male rats, acute restraint increased AT1A mRNA in paraventricular nucleus. Repeated restraint increased AT1A mRNA and AT1 binding in paraventricular nucleus and AT1 binding in subfornical organ and median eminence. AT1B and AT2 receptors were not expressed in brain areas involved in the stress response. Acute restraint increased anterior pituitary AT1A mRNA and AT1 binding and decreased AT1B mRNA. During repeated restraint, the increase in AT1A mRNA in the anterior pituitary was maintained, but AT1B mRNA and AT1 binding returned to normal levels. In adrenal zona glomerulosa, AT1B mRNA, AT1 binding, AT2 mRNA and AT2 binding decreased during acute restraint. Receptor mRNA and binding returned to normal after repeated stress, with the exception of rebound increase in adrenal zona glomerulosa AT2 mRNA. In adrenal medulla, AT1A mRNA increased and AT2 mRNA decreased during acute restraint. AT1A mRNA remained increased during repeated restraint, while alterations in AT2 mRNA were no longer present. Expression of AT1A, AT1B and AT2 receptors in the hypothalamic-pituitary-adrenal axis is tissue specific and is different in acute and repeated stress. Increased brain, pituitary and adrenomedullary AT1A receptor expression correlates with hypothalamic-pituitary-adrenal axis stimulation, supporting the hypothesis of Ang II, through selective AT1A receptor stimulation, as an important determinant of the acute and repeated stress response. Decreased adrenal zona glomerulosa and anterior pituitary AT1B receptors during acute stress can be interpreted as compensatory to increased stimulation by Ang II. There may be additional roles for adrenal AT2 receptors during acute stress, possibly related to interaction or cross-talk with AT1 receptors.

Rodent animal models of inflammatory and autoimmune disease have been important tools in the study of the interaction between neuroendocrine physiology and the immune responses. The rat has been particularly useful in part because, in contrast to other species, most rat models of autoimmune/inflammatory disease are induced rather than spontaneous. This allows for systematic and controlled manipulations of the neuroendocrine system in relation to exposure to the antigen or proinflammatory trigger. The most frequently used immune challenges include lipopolysaccharide-induced septic shock, carrageenan-induced local inflammation and adjuvant or bacterial cell wall-induced arthritis. By analyzing the responses to these challenges in different strains of rats and mice it has been possible to define the relationships between the neuroendocrine and immune systems and to identify some mechanisms through which these connections confer susceptibility and resistance to autoimmune and inflammatory diseases. The present review will discuss data obtained from rodent physiology, indicating that an important component in the susceptibility or resistance to development of these diseases is due to dysfunctional regulation of the immune response by the neuroendocrine hypothalamic-pituitary-adrenal axis. In particular, the importance of neurons of the paraventricular hypothalamic nucleus in determining susceptibility or resistance to autoimmune and inflammatory disease will be discussed.

Lewis (LEW/N) and Fischer (F344/N) rats differ on a myriad of behavioral and physiological endpoints, some of which have been reported to be affected by maternal experience in outbred rats and other strains. To assess whether epigenetic factors contribute to the differential behavioral responses to stress and pro-inflammatory challenges in these strains, the effects of cross fostering on open-field, acoustic startle, and glucocorticoid reactivity to lipopolysaccharide (LPS) were examined in the present experiment. In the open-field test, although in-fostered female LEW/N and F344/N strains did not differ, female LEW/N rats displayed significantly greater activity than female F344/N rats in the cross-fostered condition. Differences between males of the two strains were increased by cross fostering, with the LEW/N strain displaying greater total activity. In acoustic startle, there was little strain difference between in-fostered or cross-fostered female rats. On the other hand, in-fostered male LEW/N rats had a significantly greater startle response than in-fostered male F344/N rats, an effect that was dramatically reduced by cross fostering. In-fostered female LEW/N rats displayed a blunted corticosterone response relative to in-fostered female F344/N rats, an effect that was reduced by cross fostering. Conversely, although there was no strain difference between male in-fostered rats, cross-fostered male F344/N rats displayed a significantly greater corticosterone response to LPS than cross-fostered male LEW/N rats. Finally, body weight differences between in-fostered LEW/N and F344/N rats were reduced by cross fostering. Together, these data illustrate that maternal factors play a role in the behavioral and physiological responses to stress between the two strains.

Significant evidence suggests that exposure to traumatic and/or acute stress in both mice and humans results in compromised immune function that in turn may affect associated brain processes. Additionally, recent studies in mouse models of immune deficiency have suggested that adaptive immunity may play a role during traumatic stress exposure and that impairments in lymphocyte function may contribute to increased susceptibility to various psychogenic stressors. However, rodent studies on the relationship between maladaptive stress responses and lymphocyte deficiency have been complicated by the fact that genetic manipulations in these models may also result in changes in CNS function due to the expression of targeted genes in tissues other than lymphocytes, including the brain. To address these issues we utilized mice with a deletion of recombination-activating gene 2 (Rag2), which has no confirmed expression in the CNS; thus, its loss should result in the absence of mature lymphocytes without altering CNS function directly. Stress responsiveness of immune deficient Rag2(-/-) mice on a BALB/c background was evaluated in three different paradigms: predator odor exposure (POE), fear conditioning (FC) and learned helplessness (LH). These models are often used to study different aspects of stress responsiveness after the exposure to an acute stressor. In addition, immunoblot analysis was used to assess hippocampal BDNF expression under both stressed and non-stressed conditions. Subsequent to POE, Rag2(-/-) mice exhibited a reduced acoustic startle response compared to BALB/c mice; no significant differences in behavior were observed in either FC or LH. Furthermore, analysis of hippocampal BDNF indicated that Rag2(-/-) mice have elevated levels of the mature form of BDNF compared to BALB/c mice. Results from our studies suggest that the absence of mature lymphocytes is associated with increased resilience to stress exposure in the POE and does not affect behavioral responses in the FC and LH paradigms. These findings indicate that lymphocytes play a specific role in stress responsiveness dependent upon the type, nature and intensity of the stressor.

Rationale: Arginine methylation by protein N -arginine methyltransferases (PRMTs) is an important posttranslational modification in the regulation of protein signaling. PRMT2 contains a highly conserved catalytic Ado-Met binding domain, but the enzymatic function of PRMT2 with respect to methylation is unknown. The JAK-STAT pathway is proposed to be regulated through direct arginine methylation of STAT transcription factors, and STAT3 signaling is known to be required for leptin regulation of energy balance. Objective: To identify the potential role of STAT3 arginine methylation by PRMT2 in the regulation of leptin signaling and energy homeostasis. Methods and Results: We identified that PRMT2 −/− mice are hypophagic, lean, and have significantly reduced serum leptin levels. This lean phenotype is accompanied by resistance to food-dependent obesity and an increased sensitivity to exogenous leptin administration. PRMT2 colocalizes with STAT3 in hypothalamic nuclei, where it binds and methylates STAT3 through its Ado-Met binding domain. In vitro studies further clarified that the Ado-Met binding domain of PRMT2 induces STAT3 methylation at the Arg31 residue. Absence of PRMT2 results in decreased methylation and prolonged tyrosine phosphorylation of hypothalamic STAT3, which was associated with increased expression of hypothalamic proopiomelanocortin following leptin stimulation. Conclusions: These data elucidate a molecular pathway that directly links arginine methylation of STAT3 by PRMT2 to the regulation of leptin signaling, suggesting a potential role for PRMT2 antagonism in the treatment of obesity and obesity-related syndromes.

It has been reported that allergies are associated with depression and possibly suicide in women. Aggression is an important behavioral component that predisposes depressed individuals to suicidal acts. In the present study we examined the relationship between allergies and aggression to determine a potential contribution of allergies in factors of risk for suicidal behavior. Because stress plays a critical role in the manifestation of clinical symptoms of allergies and also in suicidal behavior, we also studied the role of acute stress. Female inbred Brown Norway rats known for their susceptibility to respiratory allergies were sensitized and challenged with a mixture of tree pollen and evaluated in the resident-intruder test for detection of aggressive behaviors. They were also subjected to acute stress by sessions of inescapable forced swimming and re-evaluated in the resident intruder test. Animals made allergic to tree pollen and subjected to acute stress displayed increased aggressive-like behavior as compared with control-saline treated animals or to their own aggressive scores previous to the stress session. These results suggest that allergies and stress increases aggressive-like behavior, indicating that these conditions may be important factors promoting altered emotional reactivity with the potential to influence suicidal behavior.

Allergic inflammation is associated with mood disorders, exacerbation of depression, and suicidal behavior. Mediators of inflammation modulate sleep , with Th1 cytokines promoting NREM sleep and increasing sleepiness and Th2 cytokines (produced during allergic inflammation) impairing sleep. As sleep impairment is a rapidly modifiable suicide risk factor strongly associated with mood disorders, we review the literature leading to the hypothesis that allergic rhinitis leads to mood and anxiety disorders and an increased risk of suicide via sleep impairment. Specifically, allergic rhinitis can impair sleep through mechanical (obstructive) and molecular (cytokine production) processes. The high prevalence of mood and anxiety disorders and allergy, the nonabating suicide incidence, the currently available treatment modalities to treat sleep impairment and the need for novel therapeutic targets for mood and anxiety disorders, justify multilevel efforts to explore disturbance of sleep as a pathophysiological link. Language: en

Considering clinical and animal evidence suggesting a relationship between allergy and anxiety, we hypothesized that, from low to high aeroallergen exposure, changes in anxiety symptom scores in patients with primary mood disorders will correlate with changes in allergy symptom scores. We also anticipated that sensitization to tree pollen, as determined by allergen specific IgE antibodies, will predict a greater worsening of anxiety during exposure to tree pollen. 51 patients with unipolar or bipolar disorder (age: 19-63 years, 65% female) were recruited. Tree- pollen IgE positive subjects (12) were included as the experimental group and patients negative to a multi-allergen serological test (39) were included in the control group. Self reports of anxiety and allergy symptoms were obtained once during the peak airborne pollen counts and once during the period of low airborne pollen counts, as reported by two local pollen counting stations. Using linear regression models, we confirmed a significant positive association between allergy scores and anxiety scores (p

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 corticostereone 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 (TH2) 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 one hour 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 TH2 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.

Background: Steroid hormones, such as progesterone, are known to have immunomodulatory effects. Our research group previously reported direct effects of progesterone on dendritic cells (DCs) from female rodents. Primarily affecting mature DC function, progesterone effects included inhibition of proinflammatory cytokine secretion, downregulation of cell surface marker (major histocompatibility complex class II, CD80) expression, and decreased T-cell proliferative capacity, and were likely mediated through progesterone receptor (PR) because the PR antagonist RU486 reversed these effects. Objective: The goal of this study was to assess differences in response to progesterone by DCs from female and male rodents. Methods: Using real-time reverse-transcriptase polymerase chain reaction, transcriptional expression of steroid hormone receptors was measured in immature bone marrow-derived DCs (BMDCs) from male and female rats. Expression of steroid hormone receptor protein was also assessed in these cells using flow cytometry and fluorescence microscopy. To evaluate functional differences between BMDCs from female and male rats in response to the steroid hormone progesterone, levels of secreted cytokines were measured using enzyme-linked immunosorbent assay. Results: Higher numbers of immature BMDCs from males expressed glucocorticoid receptor (GR) and androgen receptor (AR) proteins compared with females (males vs females, mean [SD]: GR = 68.75 [7.27] vs 43.61 [13.97], P = NS; AR = 75.99 [15.38] vs 8.25 [1.88], P = 0.002), whereas higher numbers of immature BMDCs from females expressed PR protein compared with males (females vs males: PR = 74.19 [12.11] vs 14.14 [4.55], P = 0.043). These differences were not found at the level of transcription (females vs males: GR = 0.088 vs 0.073, P = NS; AR = 0.076 vs 0.069, P = NS; PR = 0.075 vs 0.065, P = NS). Compared with those from females, mature BMDCs from males produced higher quantities of cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-1β, IL-10) (females vs males: TNF-α = 920.0 [79.25] vs 1100.61 [107.97], P = NS; IL-1β = 146.60 [38.04] vs 191.10 [10.47], P = NS; IL-10 = 167.25 [4.50] vs 206.15 [23.48], P = NS). Conversely, BMDCs from females were more sensitive to progesterone, as indicated by a more dramatic reduction in proinflammatory cytokine secretion (females vs males, highest concentration of progesterone: TNF-α = 268.94 [28.59] vs 589.91 [100.98], P = 0.04; IL-1β = 119.50 [10.32] vs 154.35 [6.22], P = NS). Conclusions: These findings suggest that progesterone effects on DCs in rodents may be more pronounced in females than in males, and this is likely due to differences in PR protein expression. Our observations may help elucidate disparities in the incidence and severity of autoimmune disorders between females and males, and the role specific steroid hormones play in regulating immune responses.

Prepartum and postpartum depression have negative, and sometimes devastating, effects on women and their families. As inflammatory processes are related to depression in general, we hypothesized that inflammatory perturbations, prepartum and postpartum, contribute to triggering and worsening of symptoms of peripartum depression. We conducted a longitudinal preliminary study on 27 women at high risk for developing postpartum depression measuring SIGH-SAD scores at three time points: 35-38 weeks gestation, 1-5 days postpartum, and 5-6 weeks postpartum. Serum C-reactive protein and interleukin-6, both markers of inflammation, as well as tryptophan, kynurenine, and the kynurenine/tryptophan ratio, as consequences of inflammation and pathophysiological steps towards depression, were measured at each time point. C-reactive protein levels were found to be positively related to atypical and total depression scores in the prepartum period and with atypical depression scores in the early postpartum period. Tryptophan was found to be negatively associated with total depression scores in the prepartum, as well. These findings warrant further investigation that could lead to novel interventions to decrease poor outcomes from peripartum depression.

The rates of depression, anxiety, and sleep disturbance (suicide risk factors) are greater in patients with allergic rhinitis than in the general population. The rate of allergy is also greater in patients with depression. Preliminary data suggest that patients with a history of allergy may have an increased rate of suicide. Clinicians should actively inquire to diagnose allergy in patients with depression and depression in patients with allergy. Spring peaks of suicide are highly replicated, but their origin is poorly understood. Preliminary epidemiologic data suggest that seasonal spring peaks in aeroallergens are associated with seasonal spring peaks in suicide. Our research in Brown Norway rats demonstrates that sensitization and exposure to aeroallergens induces anxiety-like and aggressive behaviors as well as allergy-related helper T-cell type 2 (Th2) cytokine gene expression in the prefrontal cortex. Thus, it is possible that sensitization and exposure to aeroallergens, which peak in spring, may be conducive to seasonal exacerbation of suicide risk factors such as anxiety, depression, hostility/aggression, and sleep disturbance. Connecting allergy with suicide and suicide risk factors adds to previous neurologic literature connecting allergy with migraines and seizure disorders. Our recent report of Th2 (allergy-mediating) cytokine expression in the orbitofrontal cortex of suicide victims should lead to future studies to test the hypothesis that mediators of allergic inflammation in the nasal cavities may result in Th2 cytokine expression in the brain, influencing affect and behavioral modulation. Certain medications used to treat allergy can exacerbate suicide risk factors, potentially worsening suicide risk and even triggering suicide. Systemic (but not topical) corticosteroids have been associated with manic and depressive episodes and mixed mood states. Recently, the US Food and Drug Administration started investigating the possibility that montelukast may trigger suicide. Although this association requires further exploration and confirmation, clinicians should err on the side of caution, inquiring about past suicide attempts; hopelessness; reasons for living; and suicidal ideation, intent, or plan; and referring the patient to a mental health professional for evaluation if appropriate.

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. METHOD: In a postmortem sample obtained from the Brodman area 11 of suicides (n = 34) and controls (n = 17), real-time RT-PCR was used to compare the expression of mRNA species for tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, 4, 5, 6, and 13. RESULTS: Increased expression of IL-4 was found in women suicide victims and IL-13 in men suicide victims. Elevated but not significant cytokine expression was also observed for TNF-alpha in women suicide victims. CONCLUSION: To our knowledge, these results provide the first evidence of the presence of mRNA transcripts of type 2 T-helper cytokines in the human orbitofrontal cortex and their increased expression in the brain of suicides. Language: en