Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders.

Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects, notably on synaptic plasticity together with an increase in cognitive processes. In contrast, overly intense stress can have deleterious behavioral effects leading to several stress-related pathologies such as anxiety, depression, substance use, obsessive-compulsive and stressor- and trauma-related disorders (e.g., post-traumatic stress disorder or PTSD in the case of traumatic events). Over a number of years, we have demonstrated that in response to stress, glucocorticoid hormones (GCs) in the hippocampus mediate a molecular shift in the balance between the expression of the tissue plasminogen activator (tPA) and its own inhibitor plasminogen activator inhibitor-1 (PAI-1) proteins. Interestingly, a shift in favor of PAI-1 was responsible for PTSD-like memory induction. In this review, after describing the biological system involving GCs, we highlight the key role of tPA/PAI-1 imbalance observed in preclinical and clinical studies associated with the emergence of stress-related pathological conditions. Thus, tPA/PAI-1 protein levels could be predictive biomarkers of the subsequent onset of stress-related disorders, and pharmacological modulation of their activity could be a potential new therapeutic approach for these debilitating conditions.

Great tits differ in glucocorticoid plasticity in response to spring temperature.

Fluctuations in environmental temperature affect energy metabolism and stimulate the expression of reversible phenotypic plasticity in vertebrate behavioural and physiological traits. Changes in circulating concentrations of glucocorticoid hormones often underpin environmentally induced phenotypic plasticity. Ongoing climate change is predicted to increase fluctuations in environmental temperature globally, making it imperative to determine the standing phenotypic variation in glucocorticoid responses of free-living populations to evaluate their potential for coping via plastic or evolutionary changes. Using a reaction norm approach, we repeatedly sampled wild great tit (Parus major) individuals for circulating glucocorticoid concentrations during reproduction across five years to quantify individual variation in glucocorticoid plasticity along an environmental temperature gradient. As expected, baseline and stress-induced glucocorticoid concentrations increased with lower environmental temperatures at the population and within-individual level. Moreover, we provide unique evidence that individuals differ significantly in their plastic responses to the temperature gradient for both glucocorticoid traits, with some displaying greater plasticity than others. Average concentrations and degree of plasticity covaried for baseline glucocorticoids, indicating that these two reaction norm components are linked. Hence, individual variation in glucocorticoid plasticity in response to a key environmental factor exists in a wild vertebrate population, representing a crucial step to assess their potential to endure temperature fluctuations.

Association of Infradian Rhythms of Motor Activity, Concentration of Glucocorticoid Hormones, and One-Minute-Step Oscillations of Body Temperature with Intensity of Fluctuations of Secondary Cosmic Rays.

The study compared the daily mean intensity of one-minute-step fluctuations in intensity of the secondary cosmic rays reflected by neutron count rate and dynamics of body temperature, motor activity, as well as concentration of glucocorticoid hormones in birds and rodents. A positive correlation was established between body temperature oscillations and neutron count rate fluctuations. A similar correlation was observed between physical parameter (neutron count rate), on the one hand, and daily mean motor activity and concentration of glucocorticoid hormones in the animals. The periods and phases of these processes presented in synchronous time series coincided. The facts of simultaneous variations or disturbances of the periods in dynamics of biological and physical parameters attest to their relationships. The study concluded that the infradian rhythms with the periods of 3-5 days depend on some external environmental factor related to fluctuations in intensity of secondary cosmic rays.

Desperately seeking stress: A pilot study of cortisol in archaeological tooth structures.

OBJECTIVES: Cortisol is a glucocorticoid hormone produced through activation of the hypothalamic pituitary adrenal axis. It is known as the "stress hormone" for its primary role in the body's stress response and has been the focus of much modern clinical research. Within archaeology, only a few studies have analyzed cortisol in human remains and these have been restricted to hair (Webb et al., 2010; Webb, White, van Uum, & Longstaffe, 2015a; Webb, White, van Uum, & Longstaffe, 2015b). This study examines the utility of dentine and enamel, which survive well archaeologically, as possible reservoirs for detectable levels of cortisol. MATERIALS AND METHODS: Then, 69 teeth from 65 individuals from five Roman and Post-Roman sites in France were tested via competitive enzyme-linked immunosorbent assay (ELISA) to assess and quantify the cortisol concentrations present within tooth dentine and enamel. RESULTS: In both tooth dentine and enamel, detectable concentrations of cortisol were identified in multiple teeth. However, concentrations were low and not all teeth yielded results that were measurable through cortisol ELISA. Differences in cortisol values between dentine and enamel could suggest different uptake mechanisms or timing. DISCUSSION: These results suggest that cortisol is incorporated within tooth structures and merits further investigation in both modern and archaeological contexts. Analysis of the results through liquid chromatographic-mass spectrometry would verify current results and might yield values that could be better integrated with published cortisol studies. Future studies of cortisol in tooth structures would greatly expand the research potential of cortisol in the past and could have implications for studies of human stress across deep time.

Comparative Analysis of Pathobiochemical Changes in Major Depression and Post-Traumatic Stress Disorder.

Comparative analysis of available literature data on the pathogenetic neuroendocrine mechanisms of depression and post-traumatic stress disorder (PTSD) is provided in this review to identify their common features and differences. We discuss the multidirectional modifications of the activity of cortical and subcortical structures of the brain, levels of neurotransmitters and their receptors, and functions of the hypothalamic-pituitary-adrenocortical axis in depression and PTSD. The analysis shows that these disorders are examples of opposite failures in the system of adaptive stress response of the body to stressful psychotraumatic events. On this basis, it is concluded that the currently widespread use of similar approaches to treat these disorders is not justified, despite the significant similarity of their anxiety-depressive symptoms; development of differential therapeutic strategies is required.

Correlates of maternal glucocorticoid levels in a socially flexible rodent.

While it is generally accepted that social isolation has detrimental effects on social species, little is known about the importance of social interactions in less social species-particularly for wild reproductive females. We studied socially-flexible yellow-bellied marmots (Marmota flaviventer) and asked whether features of the social environment are associated with maternal fecal glucocorticoid metabolite (FGM) concentrations. Since changes in maternal baseline glucocorticoids may have positive or negative consequences for offspring fitness, we were also interested in estimating their relationship with measures of reproductive success. We fitted generalized linear mixed effects models to a dataset including maternal FGM measurements, social network metrics, maternal/alloparental care, and pup FGM and survival. Agonistic interactions were positively associated with maternal FGM levels, while mothers that engaged in relatively more affiliative interactions had reduced FGM levels when living in environments with low predator pressure. Pups associated with mothers exhibiting high FGM levels had low annual survival rates, received less maternal/alloparental care and had higher FGM levels. Interestingly, offspring from mothers with high FGM levels were more likely to survive the summer when born in small litters. In sum, social interactions likely influence and are influenced by glucocorticoid levels of facultatively social females. Potential benefits of social bonds may be context-specific, and agonistic interactions may be tightly correlated with fitness. Female marmots exhibiting high FGM levels had overall low reproductive success, which is predicted by the cort-fitness hypothesis. However, under adverse conditions, offspring summer survival can be maximized if pups are born in small litters.

Costs and drivers of helminth parasite infection in wild female baboons.

Helminth parasites can have wide-ranging, detrimental effects on host reproduction and survival. These effects are best documented in humans and domestic animals, while only a few studies in wild mammals have identified both the forces that drive helminth infection risk and their costs to individual fitness. Working in a well-studied population of wild baboons (Papio cynocephalus) in the Amboseli ecosystem in Kenya, we pursued two goals, to (a) examine the costs of helminth infections in terms of female fertility and glucocorticoid hormone levels and (b) test how processes operating at multiple scales-from individual hosts to social groups and the population at large-work together to predict variation in female infection risk. To accomplish these goals, we measured helminth parasite burdens in 745 faecal samples collected over 5 years from 122 female baboons. We combine these data with detailed observations of host environments, social behaviours, hormone levels and interbirth intervals (IBIs). We found that helminths are costly to female fertility: females infected with more diverse parasite communities (i.e., higher parasite richness) exhibited longer IBIs than females infected by fewer parasite taxa. We also found that females exhibiting high Trichuris trichiura egg counts also had high glucocorticoid levels. Female infection risk was best predicted by factors at the host, social group and population level: females facing the highest risk were old, socially isolated, living in dry conditions and infected with other helminths. Our results provide an unusually holistic understanding of the factors that contribute to inter-individual differences in parasite infection, and they contribute to just a handful of studies linking helminths to host fitness in wild mammals.

Optimal group size in a highly social mammal.

Group size is an important trait of social animals, affecting how individuals allocate time and use space, and influencing both an individual's fitness and the collective, cooperative behaviors of the group as a whole. Here we tested predictions motivated by the ecological constraints model of group size, examining the effects of group size on ranging patterns and adult female glucocorticoid (stress hormone) concentrations in five social groups of wild baboons (Papio cynocephalus) over an 11-y period. Strikingly, we found evidence that intermediate-sized groups have energetically optimal space-use strategies; both large and small groups experience ranging disadvantages, in contrast to the commonly reported positive linear relationship between group size and home range area and daily travel distance, which depict a disadvantage only in large groups. Specifically, we observed a U-shaped relationship between group size and home range area, average daily distance traveled, evenness of space use within the home range, and glucocorticoid concentrations. We propose that a likely explanation for these U-shaped patterns is that large, socially dominant groups are constrained by within-group competition, whereas small, socially subordinate groups are constrained by between-group competition and predation pressures. Overall, our results provide testable hypotheses for evaluating group-size constraints in other group-living species, in which the costs of intra- and intergroup competition vary as a function of group size.

Time-dependent association of glucocorticoids with adverse outcome in community-acquired pneumonia: a 6-year prospective cohort study.

BACKGROUND: The hypothalamic-pituitary-adrenal stress axis plays a crucial role in community-acquired pneumonia (CAP), with high cortisol being associated with disease severity and corticosteroid treatment resulting in earlier time to recovery. Our aim in the present study was to compare different glucocorticoid hormones, including cortisol, 11-deoxycortisol, cortisone, and corticosterone, regarding their association with short- and long-term adverse outcomes in a well-defined CAP cohort. METHODS: We prospectively followed 285 patients with CAP from a previous Swiss multicenter trial for a median of 6.1 years and measured different admission glucocorticoid serum levels by liquid chromatography coupled with tandem mass spectrometry. We used adjusted Cox regression models to investigate associations between admission hormone levels and all-cause mortality at different time points. RESULTS: Mortality was 5.3% after 30 days and increased to 47.3% after 6 years. High admission cortisol was associated with adverse outcome after 30 days (adjusted OR 3.85, 95% CI 1.10-13.49, p = 0.035). In the long term (i.e.,), however, high admission cortisol was associated with better survival (adjusted HR after 3 years 0.53, 95% CI 0.32-0.89, p = 0.017; adjusted HR after 6 years 0.57, 95% CI 0.36-0.90, p = 0.015). Compared with 11-deoxycortisol, cortisone, and corticosterone, cortisol showed the highest association with mortality. CONCLUSIONS: Among different glucocorticoid hormones, cortisol showed the highest association with mortality in CAP. Whereas a more pronounced glucocorticoid stress response on hospital admission was associated with higher short-term adverse outcome, long-term outcome was favorable in these patients. These data should support the correct interpretation of glucocorticoid blood data.

Untangling the complex relationship between dietary acid load and glucocorticoid metabolism.

The kidney's maintenance of the metabolic component of acid-base homeostasis is critical for normal health. The study by Esche and colleagues in this issue of Kidney International shows that normal children with higher levels of renal net acid excretion and of dietary acid loads have stimulation of glucocorticoid hormone metabolism. Thus, normal variations in dietary acid intake and renal net acid excretion have important biological correlates.

Glucocorticoids and Metabolic Control.

In response to stress, the central nervous system initiates a signaling cascade, which leads to the production of glucocorticoids (GCs). GCs act through the glucocorticoid receptor (GR) to coordinate the appropriate cellular response with the primary goal of mobilizing the storage forms of carbon precursors to generate a continuous glucose supply for the brain. Although GCs are critical for maintaining energy homeostasis, excessive GC stimulation leads to a number of undesirable side effects, including hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting leading to severe metabolic dysfunction. Summarized below are the diverse metabolic roles of glucocorticoids in energy homeostasis and dysregulation, focusing specifically on glucose, lipid, and protein metabolism.

The systemic control of circadian gene expression.

The mammalian circadian timing system consists of a central pacemaker in the brain's suprachiasmatic nucleus (SCN) and subsidiary oscillators in nearly all body cells. The SCN clock, which is adjusted to geophysical time by the photoperiod, synchronizes peripheral clocks through a wide variety of systemic cues. The latter include signals depending on feeding cycles, glucocorticoid hormones, rhythmic blood-borne signals eliciting daily changes in actin dynamics and serum response factor (SRF) activity, and sensors of body temperature rhythms, such as heat shock transcription factors and the cold-inducible RNA-binding protein CIRP. To study these systemic signalling pathways, we designed and engineered a novel, highly photosensitive apparatus, dubbed RT-Biolumicorder. This device enables us to record circadian luciferase reporter gene expression in the liver and other organs of freely moving mice over months in real time. Owing to the multitude of systemic signalling pathway involved in the phase resetting of peripheral clocks the disruption of any particular one has only minor effects on the steady state phase of circadian gene expression in organs such as the liver. Nonetheless, the implication of specific pathways in the synchronization of clock gene expression can readily be assessed by monitoring the phase-shifting kinetics using the RT-Biolumicorder.

Adrenocortical stress responses influence an invasive vertebrate's fitness in an extreme environment.

Continued range expansion into physiologically challenging environments requires invasive species to maintain adaptive phenotypic performance. The adrenocortical stress response, governed in part by glucocorticoid hormones, influences physiological and behavioural responses of vertebrates to environmental stressors. However, any adaptive role of this response in invasive populations that are expanding into extreme environments is currently unclear. We experimentally manipulated the adrenocortical stress response of invasive cane toads (Rhinella marina) to investigate its effect on phenotypic performance and fitness at the species' range front in the Tanami Desert, Australia. Here, toads are vulnerable to overheating and dehydration during the annual hot-dry season and display elevated plasma corticosterone levels indicative of severe environmental stress. By comparing unmanipulated control toads with toads whose adrenocortical stress response was manipulated to increase acute physiological stress responsiveness, we found that control toads had significantly reduced daily evaporative water loss and higher survival relative to the experimental animals. The adrenocortical stress response hence appears essential in facilitating complex phenotypic performance and setting fitness trajectories of individuals from invasive species during range expansion.

Morphogenic Effect of Exogenous Glucocorticoid Hormones in the Girardia tigrina Planarian (Turbellaria, Tricladida).

We have studied the effect of two glucocorticoid hormones: hydrocortisone and its synthetic analogue methylprednisolone on the regeneration activity of head and tail blastema of the Girardia tigrina planarian. The regeneration activity was studied in head and tail blastema formed after resection by means of lifetime computer morphometry and immunohistochemical labeling of neoblasts. The search for orthologous proteins-glucocorticoid receptors (hydrocortisone) was performed using the SmedGD database of the Schmidtea mediterranea planarian. The results indicate that both hormones influence the recovery rate of the regenerating head and tail blastema. The worms with regenerating tail blastema have less sensitivity to the hormones' treatment compared to the ones with regenerating head blastema. Hydrocortisone at a high concentration (10-3 M) suppressed the regeneration rate, while stimulating it at lower concentrations (10-4-10-6 M). The same concentrations of methylprednisolone inhibited the regeneration of head blastema, but did not affect the tail blastema regeneration. The two hormones acted differently: while hydrocortisone stimulated the proliferation of neoblasts in the periwound region, methylprednisolone reduced the mitotic activity, mainly on the tail zone furthest from the wound surface. We suggest that exogenous glucocorticoids can influence endogenous mechanisms of hormone-dependent regeneration.

Cortisol in deciduous tooth tissues: A potential metric for assessing stress exposure in archaeological and living populations.

OBJECTIVE: Cortisol is a glucocorticoid hormone produced by the hypothalamic-pituitary-adrenal axis that is regularly assessed in modern human and non-human populations in saliva, blood, and hair as a measure of stress exposure and stress reactivity. While recent research has detected cortisol concentrations in modern and archaeological permanent dental tissues, the present study assessed human primary (deciduous) teeth for cortisol concentrations. MATERIALS AND METHODS: Fifty-one dentine and enamel samples from nine modern and 10 archaeological deciduous teeth were analyzed for cortisol concentrations via enzyme-linked immunosorbent assay (ELISA). RESULTS: Detectable concentrations of cortisol were identified in 15 (of 32) dentine and 8 (of 19) enamel samples coming from modern and archaeological deciduous teeth. CONCLUSIONS: This study is the first known analysis of cortisol from deciduous dental tissues, demonstrating the potential to identify measurable concentrations. SIGNIFICANCE: The ability to analyze deciduous teeth is integral to developing dental cortisol methods with multiple potential future applications, including research on the biological embedding of stress in the skeleton. This study marks a key step in a larger research program to study stress in primary dentition from living and archaeological populations. LIMITATIONS: Multiple samples generated cortisol values that were not detectable with ELISA. Minimum quantities of tissue may be required to generate detectable levels of cortisol. SUGGESTIONS FOR FURTHER RESEARCH: Future research should include larger sample sizes and consideration of intrinsic biological and extrinsic preservation factors on dental cortisol. Further method validation and alternative methods for assessing dental cortisol are needed.

The Need to Consider Context in the Evaluation of Anti-infectious and Immunomodulatory Effects of Vitamin A and its Derivatives.

Vitamin A and its derivatives (retinoids) act as potent regulators in many aspects of mammalian reproduction, development, repair, and maintenance of differentiated tissue functioning. Unlike other vitamins, Vitamin A and retinoids, which have hormonal actions, present significant toxicity, which plays roles in clinically relevant situations, such as hypervitaminosis A and retinoic acid ("differentiation") syndrome. Although clinical presentation is conspicuous in states of insufficient or excessive Vitamin A and retinoid concentration, equally relevant effects on host resistance to specific infectious agents, and in the general maintenance of immune homeostasis, may go unnoticed, because their expression requires either pathogen exposure or the presence of inflammatory co-morbidities. There is a vast literature on the roles played by retinoids in the maintenance of a tolerogenic, noninflammatory environment in the gut mucosa, which is considered by many investigators representative of a general role played by retinoids as anti-inflammatory hormones elsewhere. However, in the gut mucosa itself, as well as in the bone marrow and inflammatory sites, context determines whether one observes an anti-inflammatory or proinflammatory action of retinoids. Both interactions between specialized cell populations, and interactions between retinoids and other classes of mediators/regulators, such as cytokines and glucocorticoid hormones, must be considered as important factors contributing to this overall context. We review evidence from recent studies on mucosal immunity, granulocyte biology and respiratory allergy models, highlighting the relevance of these variables as well as their possible contributions to the observed outcomes.

Developmental plasticity of the stress response in female but not in male guppies.

To survive, animals must respond appropriately to stress. Stress responses are costly, so early-life experiences with potential stressors could adaptively tailor adult stress responses to local conditions. However, how multiple stressors influence the development of the stress response remains unclear, as is the role of sex. Trinidadian guppies (Poecilia reticulata) are small fish with extensive life-history differences between the sexes and population variation in predation pressure and social density. We investigated how sex and early-life experience influence hormonal stress responses by manipulating conspecific density and perceived predation risk during development. In adults, we sampled cortisol twice to measure initial release and change over time in response to a recurring stressor. The sexes differed considerably in their physiological stress response. Males released more cortisol for their body mass than females and did not reduce cortisol release over time. By contrast, all females, except those reared at high density together with predation cues, reduced cortisol release over time. Cortisol responses of males were thus less dynamic in response to current circumstances and early-life experiences than females, consistent with life-history differences between the sexes. Our study underscores the importance of early-life experiences, interacting ecological factors and sex differences in the organization of the stress response.

Testing for Short- and Long-Term Thermal Plasticity in Corticosterone Responses of an Ectothermic Vertebrate.

Phenotypic plasticity, broadly defined as the capacity of one genotype to produce more than one phenotype, is a key mechanism for how animals adapt to environmental (including thermal) variation. Vertebrate glucocorticoid hormones exert broad-scale regulation of physiological, behavioral, and morphological traits that influence fitness under many life-history or environmental contexts. Yet the capacity for vertebrates to demonstrate different types of thermal plasticity, including rapid compensation or longer acclimation in glucocorticoid hormone function, when subject to different environmental temperature regimes remains poorly addressed. Here, we explore whether patterns of urinary corticosterone metabolites respond (i.e., evidence of acclimation) to repeated short-term and sustained long-term temperature exposures in an amphibian, the cane toad (Rhinella marina). In response to three repeated short (30-min) high-temperature (37°C) exposures (at 10-d intervals), toads produced urinary corticosterone metabolite responses of sequentially greater magnitude, relative to controls. However, toads subjected to 4 wk of acclimation to either cool (18°C)- or warm (30°C)-temperature environments did not differ significantly in their urinary corticosterone metabolite responses during exposure to a thermal ramp (18°-36°C). Together, these results indicate that adult toads had different, including limited, capacities for their glucocorticoid responses to demonstrate plasticity to different regimes of environmental temperature variation. We advocate further research as necessary to identify plasticity, or lack thereof, in glucocorticoid physiology, to better understand how vertebrates can regulate organismal responses to environmental variation.

[The influence of methylprednisolone on the ability of CD4+CD95+HLA-DR+ T-cells to produce proinflammatory medators in cultures of TCR-activated CD3+CD45RO+ T-lymphocytes from patients with rheumatoid arthritis]. / Vliianie metilprednizolona na sposobnost' CD4+CD95+HLA-DR+ T-kletok v kul'turakh TCR-aktivirovannykh CD3+CD45RO+ T-limfotsitov bol'nykh revmatoidnym artritom produtsirovat' provospalitel'nye mediatory.

The effect of different concentrations of the glucocorticoid (GC) methylprednisolone (MP) on CD4+CD95+HLA-DR+ T-cells and their ability to produce proinflammatory mediators in cultures of TCR-stimulated CD3+CD45RO+ T-lymphocytes in the in vitro system was investigated. T cells were obtained from healthy donors and patients with rheumatoid arthritis (RA).Under conditions of TCR-activation, MP increased the number of CD4+HLA-DR+CD95+ cells in CD3+CD45RO+ cultures obtained from RA patients and did not change their content in the control group. In general, MP decreased production of proinflammatory factors (IFN-, IL-2, IL-17, IL-21 and TNF-) by TCR-activated CD3+CD45RO+ cells from healthy donors and RA, consistent with the overall immunosuppressive mechanism of GC action. The correlation between CD4+CD45RO+HLA-DR+CD95+ T-cell contents and parameters reflecting production of proinflammatory mediators (IL-17, IL-21 and TNF-) in RA patients indicates maintenance of the pro-inflammatory potential of this T-cell population exposed to GC action. We suggest that relative resistance of CD4+CD45RO+CD95+HLA-DR+ T-cells of RA patients to the suppressor effect of GC leads to maintenance and even enhancement in the functional capacities of autoreactive cells in the pathogenesis of RA.

BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity.

Reduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNFVal66Met (hBDNFVal66Met) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the long-term effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30ms and 100ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100ms ISI identified that, irrespective of CORT treatment, the hBDNFVal/Met genotype was associated with significantly reduced PPI. In contrast, PPI was not different between hBDNFMet/Met and hBDNFVal/Val genotype mice. At the 30ms ISI, CORT treatment selectively disrupted sensorimotor gating of hBDNFVal/Met heterozygote mice but not hBDNFVal/Val or hBDNFMet/Met mice. Analysis of startle reactivity revealed that chronic CORT reduced startle reactivity of hBDNFVal/Val male mice by 51%. However, this was independent of the effect of CORT on PPI. In summary, we provide evidence of a distinct BDNFVal66Met heterozygote-specific phenotype using the sensorimotor gating endophenotype of schizophrenia. These data have important implications for clinical studies where, if possible, the BDNFVal/Met heterozygote genotype should be distinguished from the BDNFMet/Met genotype.