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Viral infections during pregnancy are associated with increased incidence of psychiatric disorders in offspring. The pathological outcomes of viral infection appear to be caused by the deleterious effects of innate immune response-associated factors on development of the fetus, which predispose the offspring to pathological conditions in adulthood. The negative impact of viral infections varies substantially between pregnancies. Here, we explored whether differential stress sensitivity underlies the high heterogeneity of immune reactivity and whether this may influence the pathological consequences of maternal immune activation. Using mouse models of social dominance (Dom) and submissiveness (Sub), which possess innate features of stress resilience and vulnerability, respectively, we identified differential immune reactivity to the synthetic analogue of viral double-stranded RNA, Poly(I:C), in Sub and Dom nulliparous and pregnant females. More specifically, we found that Sub females showed an exacerbated pro- and anti-inflammatory cytokine response to Poly(I:C) as compared with Dom females. Sub offspring born to Sub mothers (stress sensitive offspring) showed enhanced locomotory response to the non-competitive NMDA antagonist, MK-801, which was potentiated by prenatal Poly(I:C) exposure. Our findings suggest that inherited stress sensitivity may lead to functional changes in glutamatergic signaling, which in turn is further exacerbated by prenatal exposure to viral-like infection. The maternal immunome seems to play a crucial role in these observed phenomena.

Social interactions for many species of animals are critical for survival, wellbeing, and reproduction. Optimal navigation of a social system increases chances for survival and reproduction, therefore there is strong incentive to fit into social structures. Social animals rely heavily on dominant-submissive behaviors in establishment of stable social hierarchies. There is a link between extreme manifestation of dominance/submissiveness and behavioral deviations. To understand neural substrates affiliated with a specific hierarchical rank, there is a real need for reliable animal behavioral models. Different paradigms have been consolidated over time to study the neurobiology of social rank behavior in a standardized manner using rodent models to unravel the neural pathways and substrates involved in normal and abnormal intraspecific social interactions. This review summarizes and discusses the commonly used behavioral tests and new directions for the assessment of dominance in rodents. We discuss the hierarchy inheritable nature and other critical issues regarding hierarchical rank manifestation which may help in designing social-rank-related studies that serve as promising pre-clinical tools in behavioral psychiatry.

Background Dominant-submissive relationships depend upon functionality of the neural circuits involving monoaminergic neurotransmission. Behavioral profiles of selectively bred dominant (Dom) and submissive (Sub) mice have been proposed to mimic hyperthymic- or depressive-like temperaments observed in patients with affective disorders. These mice differentially respond to psychotropic agents and stressful stimuli, however, the mechanisms underlying these differences remain unclear. To address these mechanisms, we analyzed the brain monoamine content and responses to paroxetine (PXT) in Dom and Sub mice. Methods The behavioral effects of PXT (3 mg/kg, single injection) were assessed with the Elevated Plus Maze (EPM) and Forced Swim Test (FST). Monoamine tissue content was analyzed by HPLC-ECD. Results Compared to Dom, Sub mice had decreased levels of serotonin (5-HT) in the brainstem (BS), reduced levels of norepinephrine (NE) in the prefrontal cortex (PFC), hippocampus (HPC), and striatum (STR) and elevated levels of dopamine (DA) in PFC, HPC, STR and BS. In EPM, PXT administration increased locomotion and exploration in Dom mice, with no effect in Sub mice. In FST, PXT disrupted immobility in Dom mice only. The PXT-produced differences in regional monoamine content were strain-dependent and consistent with the behavioral alterations. Limitations Chronic PXT treatment, in vivo monoamine assays and sex-dependent analysis were out of the scope of this study and will be performed in the future in order to provide an in-depth evaluation of the neurochemical mechanisms underlying temperament-dependent responses to SSRIs. Conclusions Our findings suggest neurochemical mechanisms that underlie temperament-based response to antidepressant treatment.

It is known that stress alters homeostasis and may lead to accelerated aging. However, little is known about the contribution of innate susceptibility to stress to the deterioration of physiological functions, acceleration of aging and developing of age-related diseases. By using socially-submissive stress susceptible (Sub) and socially-dominant stress resilient (Dom) selectively bred mouse model we observed a marked reduction in the lifespan of both male and female Sub mice. We found that innate susceptibility to stress correlates with chronic inflammation, development of splenomegaly and a significant increase in the levels of circulating pro-inflammatory cytokines IL-1β and IL-6. Furthermore, Sub mice showed a marked hypoglycemia, reduction of insulin levels, increase in GSK3 activity and elevation of IGF-1 serum levels, as well as low skin surface temperature and body weight. Interestingly, lifelong exposure of Sub mice to chronic mild stress did not further reduce their lifespan, indicating a high level of intrinsic stress. Taken together, our data reveal that social submissiveness coupled with innate stress sensitivity coincides with inflammation, leading to the deterioration of physiological functions and early aging independent of whether an individual is exposed to stress or not.

Epigenetic changes are an important pathogenic mechanism in many diseases, including a variety of psychiatric disorders such as Autism Spectrum Disorder (ASD) and depression. Methyl donors such as S-Adenosyl-Methionine (SAMe) may cause epigenetic modifications, especially during embryonic development when the epigenetic memory is established. We treated pregnant submissive (Sub) mice exhibiting depressive-like phenotype with SAMe during days 12-14 of gestation aiming to alleviate the depressive - like symptoms in their offspring and normalize the expression in their prefrontal cortex of several genes possibly involved in depression. We also aimed to define possible gender differences of the effects of SAMe on the measured parameters. Treatment of the Dams with SAMe did not affect the early neurodevelopmental milestones in males or females. The results of the behavioral tests showed improvement in some behavioral parameters compared to saline treated Sub mice. Several of these improvements were gender related. Prenatal SAMe treatment mainly improved sociability, as observed in the three chambers social interaction test, in both genders. It also improved the increased locomotion (as observed by the open field test) in the female mice, but not in males. Prenatal SAMe increased the expression of Vegfa and Flt1 in males, but not in females. The expression of IgfII and SynIIb increased in males and decreased in females and the expression of serotonin receptor Htr2A did not change in both genders. In our mouse model of depression, prenatal treatment with SAMe significantly improved some parameters of depressive like behavior and normalized the expression of several genes related to depression. The gender differences observed in our studies may explain the sex related differences in the clinical presentation of depression and the different gender related response to treatment.

We examined the effects of ALOS4, a cyclic peptide discovered previously by phage library selection against integrin αvβ3, on a human melanoma (A375) xenograft model to determine its abilities as a potential anti-cancer agent. We found that ALOS4 promoted healthy weight gain in A375-engrafted nude mice and reduced melanoma tumor mass and volume. Despite these positive changes, examination of the tumor tissue did not indicate any significant effects on proliferation, mitotic index, tissue vascularization, or reduction of αSMA or Ki-67 tumor markers. Modulation in overall expression of critical downstream αvβ3 integrin factors, such as FAK and Src, as well as reductions in gene expression of c-Fos and c-Jun transcription factors, indirectly confirmed our suspicions that ALOS4 is likely acting through an integrin-mediated pathway. Further, we found no overt formulation issues with ALOS4 regarding interaction with standard inert laboratory materials (polypropylene, borosilicate glass) or with pH and temperature stability under prolonged storage. Collectively, ALOS4 appears to be safe, chemically stable, and produces anti-cancer effects in a human xenograft model of melanoma. We believe these results suggest a role for ALOS4 in an integrin-mediated pathway in exerting its anti-cancer effects possibly through immune response modulation.

Non-invasive biosensors for indirect evaluation of routinely-measured blood components by sweat analysis have broad potential clinical applications. This trial tested a wrist-borne non-invasive glucose monitor (NIGM) to measure blood glucose (BG) levels using photoplethysmographic (PPG) optical sensors. Our aim was to determine the accuracy of the device in comparison with a standard, invasive clinical method for blood glucose monitoring. Adult participants (n = 200) of both sexes from 18 to 75 were recruited for the study. Exclusion criteria: hemophilia and other serious coagulation disorders, impaired venous access, other serious medical conditions. A biosensor was placed on the right wrist of each participant for a non-invasive indirect BG measurement. In parallel, blood from the antecubital vein was collected and glucose levels were assessed with YSI 2300 Bioanalyzer. The measurements were performed twice: before and after food intake, with a 1-h interval between measurements. There were no limitations to food type and quantity. In both anteprandial (ρ = 0.8994, p < 0.0001) and postprandial (ρ =0.9382, p < 0.0001) glucose measurements, NIGM correlated with values obtained by the YSI 2300 reference device - there was no significant difference between the two methods. Plotted on a Parkes Error Grid for Type II diabetes, NIGM readings did not deviate from those of the YSI 2300 in any clinically-significant way, with the majority of correlated readings falling within Parkes zone A. Very few readings fell within Parkes zone B. In anteprandial measurements, the mean bias between methods for all patient volunteers was 3.705 ± 7.838. In postprandial measurements gave a mean bias of 1.362 ± 10.15 for all patient glucose data. The mean absolute relative difference of currently available glucometer models ranges from 5.6% to 20.8%. The NIGM falls in the lower end of this error range at 7.40-7.54%, indicating that PPG-chemochrome sensors are capable of producing results comparable with those of direct measure glucometers. Data presented here demonstrates the reliability and accuracy of the NIGM system as an adjunctive, and perhaps substitutive, non-invasive tool for blood glucose monitoring.

Social hierarchy is considered to impart an adaptive advantage to the species by reducing long-term conflict between conspecifics. While social stratification is frequently established via stress-inducing stimuli, the subsequent integration of individuals into the hierarchy may attenuate anxiety. Presently, we hypothesized that repeated reinforcement of murine social hierarchy in the dominant-submissive relationship (DSR) food-competition test would engender divergent neuroplastic changes mediating both social and anxiety-like behavior among selectively-bred Dominant (Dom) and Submissive (Sub) mice. Two weeks of repeated respective social victory or defeat reduced serum corticosterone levels of both Dom and Sub mice, whereas socially-defeated Sub mice demonstrated markedly greater exploration of the open arms of the elevated plus maze (EPM). At the same time, social victory led to markedly greater expression of the immediate-early genes (IEGs) c-Jun and EGR-1 in the lateral septal nucleus (LSN) among Dom mice, in contrast with defeated Sub counterparts which demonstrated four-fold greater IEG expression in the cingulate gyrus (Cg). These findings point towards involvement of the Cg in the anxiety-like effect among Sub mice after repeated social defeat, and suggest stabilization of the social hierarchy to attenuate the stress-inducing nature of social interaction, particularly for subordinates. Further study of the potentially anxiolytic-like effects of Cg activity should shed light upon the functional significance of the Cg in social interaction, social hierarchical sorting and anxiety.

Background/aim Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. Patients and methods We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. Results Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). Conclusion Our results help towards finding new treatable molecular targets for these types of medulloblastomas.

The link between the gut microbiota and social behavior has been demonstrated, however the translational impact of a certain microbiota composition on stable behavioral patterns is yet to be elucidated. Here we employed an established social behavior mouse model of dominance (Dom) or submissiveness (Sub). A comprehensive 16S rRNA gene sequence analysis of Dom and Sub mice revealed a significantly different gut microbiota composition that clearly distinguishes between the two behavioral modes. Sub mice gut microbiota is significantly less diverse than that of Dom mice, and their taxa composition uniquely comprised the genera Mycoplasma and Anaeroplasma of the Tenericutes phylum, in addition to the Rikenellaceae and Clostridiaceae families. Conversely, the gut microbiota of Dom mice includes the genus Prevotella of the Bacteriodetes phylum, significantly less abundant in Sub mice. In addition, Sub mice show lower body weight from the age of 2 weeks and throughout their life span, accompanied with lower epididymis white adipose tissue (eWAT) mass and smaller adipocytes together with substantially elevated expression of inflammation and metabolic-related eWAT adipokines. Finally, fecal microbiota transplantation into germ-free mice show that Sub-transplanted mice acquired Sub microbiota and adopted their behavioral and physiological features, including depressive-like and anti-social behaviors alongside reduced eWAT mass, smaller adipocytes, and a Sub-like eWAT adipokine profile. Our findings demonstrate the critical role of the gut microbiome in determining dominance vs. submissiveness and suggest an association between gut microbiota, the eWAT metabolic and inflammatory profile, and the social behavior mode.

The developing fetus is highly sensitive to prenatal stress, which may alter Hypothalamic-Pituitary-Adrenal (HPA) axis programming and increase the risk of behavioral disorders. There is high variability among the human population, wherein many offspring of stressed pregnancies display resilience to adversity, while the remainder displays vulnerability. In order to identify biological substrates mediating between resilience or vulnerability to prenatal adversity, we exposed stress-resistant Dominant (Dom) and stress-sensitive Submissive (Sub) mice to mild prenatal restraint stress (PRS, 45 min on gestational days (GD) 15, 16 and 17). We hypothesized that PRS would differentially alter prenatal programming of limbic regions regulating the HPA axis and affect among Dom and Sub offspring. Indeed, PRS increased Sub offspring’s serum corticosterone, and exaggerated their anxiety- and depressive-like behavior, while Dom offspring remained resilient to the hormonal and behavioral consequences of PRS. Moreover, PRS exposure markedly facilitated glucocorticoid receptor (GR) recruitment to the hippocampus among Dom mice in response to restraint stress, which may be responsible for their resilience to stressful challenge. These findings suggest proclivity to adaptive or maladaptive prenatal programming of hippocampal GR recruitment to be inheritable and predictable by social dominance or submissiveness.

Sivan Gershanov,1 Helen Toledano,2,3 Shalom Michowiz,3,4 Orit Barinfeld,3,5 Albert Pinhasov,1 Nitza Goldenberg-Cohen,5–7 Mali Salmon-Divon1 1Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel, Israel; 2Department of Pediatric Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Department of Pediatric Neurosurgery, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; 5The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Beilinson Hospital, Petah Tikva, Tel Aviv, Israel; 6Department of Ophthalmology, Bnai Zion Medical Center, Haifa, Israel; 7The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa,Israel Purpose: Medulloblastoma (MB), the most common malignant brain tumor in children, is divided into four tumor subgroups: wingless-type (WNT), sonic hedgehog (SHH), Group 3, and Group 4. ­Ideally, clinical practice and treatment design should be subgroup specific. While WNT and SHH subgroups have well-defined biomarkers, distinguishing Group 3 from Group 4 is not straightforward. MicroRNAs (miRNAs), which regulate posttranscriptional gene expression, are involved in MB tumorigenesis. However, the miRNA–messenger RNA (mRNA) regulatory network in MB is far from being fully understood. Our aims were to investigate miRNA expression regulation in MB subgroups, to assess miRNA target relationships, and to identify miRNAs that can distinguish Group 3 from Group 4. Patients and methods: With these aims, integrated transcriptome mRNA and miRNA expression analysis was performed on primary tumor samples collected from 18 children with MB, using miRNA sequencing (miRNA-seq), RNA sequencing (RNA-seq), and quantitative PCR. Results: Of all the expressed miRNAs, 19 appeared to be significantly differentially expressed (DE) between Group 4 and non-Group 4 subgroups (false discovery rate [FDR]

Ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a synthetic organotellurium compound with potent immunomodulatory and neuroprotective properties shown to inhibit the function of integrin αvβ3, a presynaptic cell-surface-adhesion receptor. As partial deletion of αvβ3 downregulated reuptake of serotonin by the serotonin transporter, we hypothesized that AS101 may influence pathways regulating anxiety. AS101 was tested in the modulation of anxiety-like behavior using the selectively bred Submissive (Sub) mouse strain that develop anxiety-like behavior in response to an i.p. injection. Mice were treated daily with AS101 (i.p., 125 or 200 μg/kg) or vehicle for 3 weeks, after which their anxiety-like behavior was measured in the elevated plus maze. Animals were then culled for the measurement of serum corticosterone levels by ELISA and hippocampal expression of brain-derived neurotrophic factor (BDNF) by RT-PCR. Chronic administration of AS101 significantly reduced anxiety-like behavior of Sub mice in the elevated plus maze, according to both time spent and entries to open arms, relative to vehicle-treated controls. AS101 also markedly reduced serum corticosterone levels of the treated mice and increased their hippocampal BDNF expression. Anxiolytic-like effects of AS101 may be attributed to the modulation of the regulatory influence integrin of αvβ3 upon the serotonin transporter, suggesting a multifaceted mechanism by which AS101 buffers the hypothalamic-pituitary-adrenal axis response to injection stress, enabling recovery of hippocampal BDNF expression and anxiety-like behavior in Sub mice. Further studies should advance the potential of AS101 in the context of anxiety-related disorders.

Background: Depression is a common comorbid condition with atopic dermatitis (AD), particularly during the active disease cycle. Controversial results regarding the contribution of biological sex, immunoglobulin E (IgE) sensitization, and cortisol on AD severity and comorbid depression justify further investigation. Objective and Methods: To explore the influence of sex and IgE sensitization on biochemical and psychological parameters, and severity of AD, a case-control study of 105 volunteers (56 AD, 49 healthy controls (HC); 50 males, 55 females) was conducted over 10 weeks, starting at dermatological symptom onset. Disease severity, serum IgE, cortisol and testosterone levels, and depression scores were assessed at study baseline and after 10 weeks of conventional treatment. Results: Dermatological severity differed among AD males by IgE sensitization and was elevated in males with extrinsic atopic dermatitis (EAD). Hamilton Depression Rating Scale (HAMD) scores were elevated in all patients at study baseline and improved with symptom reduction to HC levels, except female EAD. Severity of depression and dermatitis were correlated in EAD males at baseline and at week 10. Serum cortisol was elevated in male EAD at baseline, in contrast to males with intrinsic atopic dermatitis (IAD) at week 10. In addition, cortisol levels were found negatively correlated with SCORAD and HAMD scores in EAD males at week 10. Conclusion: Pathophysiological features of AD and depression are likely related to different inflammation-based effects and appear to be biological sex-dependent. Cortisol levels depend on biological sex and IgE sensitization in AD and increase in males with EAD at exacerbation and IAD males at resolution. Biological sex-related disease triggers, IgE sensitization, and cortisol levels are important for the understanding of the mechanisms underlying AD and comorbid depression.

The effects of cannabis reported by users range from experiences of euphoria and anxiolytic effects to paranoia, anxiety, and increased risk of depression. Attempts to reconcile the apparent contradictions in user response have not been conclusive. Here, we utilized selectively-bred stress-resilient socially dominant (Dom) and stress-sensitive socially submissive (Sub) mice to elucidate this contradiction. Following short-term, repeated treatment with delta-9-tetrahydrocannabinol (THC) at two different doses (1.5 mg/kg and 15 mg/kg), Sub mice presented significant place-aversion in a Conditioned Place Preference paradigm at a high dose, whereas Dom mice displayed no place preference or aversion. Forced Swim test conducted after 6-week of washout period, revealed differential impact of the two THC doses depending upon behavioral pattern. Specifically, the low dose alleviated depressive-like behavior in Sub mice, while the high dose produced the opposite effect in Dom mice. Interestingly, corticosterone concentration in serum was elevated at the high dose regardless of the mice-population tested. We conclude here that differences in dominance behavior and stress vulnerability are involved in the regulation of cannabis response among users and should be considered when prescribing THC-containing medications to patients.

Depression is apparently the most common psychiatric disease among the mood disorders affecting about 10% of the adult population. The etiology and pathogenesis of depression are still poorly understood. Hence, as for most human diseases, animal models can help us understand the pathogenesis of depression and, more importantly, may facilitate the search for therapy. In this review we first describe the more common tests used for the evaluation of depressive-like symptoms in rodents. Then we describe different models of depression and discuss their strengths and weaknesses. These models can be divided into several categories: genetic models, models induced by mental acute and chronic stressful situations caused by environmental manipulations (i.e., learned helplessness in rats/mice), models induced by changes in brain neuro-transmitters or by specific brain injuries and models induced by pharmacological tools. In spite of the fact that none of the models completely resembles human depression, most animal models are relevant since they mimic many of the features observed in the human situation and may serve as a powerful tool for the study of the etiology, pathogenesis and treatment of depression, especially since only few patients respond to acute treatment. Relevance increases by the fact that human depression also has different facets and many possible etiologies and therapies.

// Shiri Yacobovich 1 , Lena Tuchinsky 1 , Michael Kirby 1 , Tetiana Kardash 1 , Oryan Agranyoni 1 , Elimelech Nesher 1, 2 , Boris Redko 3 , Gary Gellerman 3 , Dror Tobi 1 , Katerina Gurova 2 , Igor Koman 1 , Osnat Ashur Fabian 4 , Albert Pinhasov 1 1 Department of Molecular Biology, Ariel University, Ariel, Israel 2 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA 3 Department of Chemical Sciences, Ariel University, Ariel, Israel 4 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to: Albert Pinhasov, email: albertpi@ariel.ac.il Keywords: cancer, cyclic peptide, integrin, ALOS4, melanoma Received: March 13, 2016 Accepted: July 27, 2016 Published: August 18, 2016 ABSTRACT ALOS4, a unique synthetic cyclic peptide without resemblance to known integrin ligand sequences, was discovered through repeated biopanning with pIII phage expressing a disulfide-constrained nonapeptide library. Binding assays using a FITC-labeled analogue demonstrated selective binding to immobilized αvβ3 and a lack of significant binding to other common proteins, such as bovine serum albumin and collagen. In B16F10 cell cultures, ALOS4 treatment at 72 h inhibited cell migration (30%) and adhesion (up to 67%). Immunofluorescent imaging an ALOS4-FITC analogue with B16F10 cells demonstrated rapid cell surface binding, and uptake and localization in the cytoplasm. Daily injections of ALOS4 (0.1, 0.3 or 0.5 mg/kg i.p.) to mice inoculated with B16F10 mouse melanoma cells in two different cancer models, metastatic and subcutaneous tumor, resulted in reduction of lung tumor count (metastatic) and tumor mass (subcutaneous) and increased survival of animals monitored to 45 and 60 days, respectively. Examination of cellular activity indicated that ALOS4 produces inhibition of cell migration and adhesion in a concentration-dependent manner. Collectively, these results suggest that ALOS4 is a structurally-unique selective αvβ3 integrin ligand with potential anti-metastatic activity.

To examine the effect of seasonality and rs6265 genotype on depression outcome and brain-derived neurotrophic factor (BDNF) level with dermatitis patients from onset through remission.Atopic dermatitis (AD, 56) and psoriasis (PS, 33) patients and healthy controls (HC, 49) were recruited over the 2014 calendar year. Patients were subdivided by immunoglobulin E (IgE) sensitivity (AD only), season and rs6265 genotype. Assessments were performed at onset and week 10 (Hamilton Depression Rating Scale [HAM-D], SCORAD/PASI, IgE, BDNF). Patients received standard corticosteroid and antihistamine interventions.All patients responded to corticosteroid treatment. Seasonally differential outcomes were observed in all groups. HAM-D was elevated at onset and improved over 10 weeks: AD cohort 1 (autumn/winter, AD-1) patients improved and AD cohort 2 (spring/summer, AD-2) patients remained elevated. BDNF levels were elevated in AD and seasonal differential: AD-2 declined at 10 weeks, whereas AD-1 remained high (intrinsic AD) or elevated further (extrinsic AD). PS cohort 2 declined to below control at 10 weeks. AD Val/Val had persistently elevated HAM-D and AD Val/Met were either normal (AD-1) or persistently elevated (AD-2).Findings presented here suggest a strong influence of seasonality on depression outcome and BDNF expression in AD and PS and likely reflect separate patient populations which differentially respond to environment-based stressors.

Spatial memory depends on the hippocampus, which is particularly vulnerable to aging. This vulnerability has implications for the impairment of navigation capacities in older people, who may show a marked drop in performance of spatial tasks with advancing age. Contemporary understanding of long-term memory formation relies on molecular mechanisms underlying long-term synaptic plasticity. With memory acquisition, activity-dependent changes occurring in synapses initiate multiple signal transduction pathways enhancing protein turnover. This enhancement facilitates de novo synthesis of plasticity related proteins, crucial factors for establishing persistent long-term synaptic plasticity and forming memory engrams. Extensive studies have been performed to elucidate molecular mechanisms of memory traces formation; however, the identity of plasticity related proteins is still evasive. In this study, we investigated protein turnover in mouse hippocampus during long-term spatial memory formation using the reference memory version of radial arm maze (RAM) paradigm. We identified 1592 proteins, which exhibited a complex picture of expression changes during spatial memory formation. Variable linear decomposition reduced significantly data dimensionality and enriched three principal factors responsible for variance of memory-related protein levels at (1) the initial phase of memory acquisition (165 proteins), (2) during the steep learning improvement (148 proteins), and (3) the final phase of the learning curve (123 proteins). Gene ontology and signaling pathways analysis revealed a clear correlation between memory improvement and learning phase-curbed expression profiles of proteins belonging to specific functional categories. We found differential enrichment of (1) neurotrophic factors signaling pathways, proteins regulating synaptic transmission, and actin microfilament during the first day of the learning curve; (2) transcription and translation machinery, protein trafficking, enhancement of metabolic activity, and Wnt signaling pathway during the steep phase of memory formation; and (3) cytoskeleton organization proteins. Taken together, this study clearly demonstrates dynamic assembly and disassembly of protein-protein interaction networks depending on the stage of memory formation engrams.

Penetration of the blood brain barrier (BBB) by appropriate fluorescent probes remains a challenge in optical imaging and diagnostics. We designed, synthesized and observed the in vivo BBB penetration of a LASER syn-bimane probe. Results demonstrate that the Aib transporter unit in our probe may lead a fluorescent bimanyl moiety across the BBB.

Psoriasis is a chronic inflammatory disease characterized by skin lesions. Psoriasis development has been associated both with genetic and environmental factors. Though skin and gut microbiota has been implicated in number of pathologies including atopic dermatitis, inflammatory bowel disease, Crohn’s disease, allergy, obesity, its role has been poorly studied in psoriatic disease, which incorporates both psoriasis and psoriatic arthritis. This literature review summarizes the most recent and major findings on microbiota features in psoriatic disease as well as gives immune system role in the given condition. Despite conflicting findings, psoriasis patients were frequently found to have distinct microbial composition in both skin and guts especially in the major bacterial phyla, Firmicutes, Bacteroidetes, and Akkermansia. Furthermore, bacterial DNA has been found in psoriatic patients both locally and systemically, and altogether suggesting role of bacteria in the chronic disease and future studies in this field.

Studies of personality have suggested that dissimilarities in ability to cope with stressful situations results in differing tendency to develop addictive behaviors. The present study used selectively bred stress-resilient, socially-dominant (Dom) and stress-vulnerable, socially-submissive (Sub) mice to investigate the interaction between environmental stress and inbred predisposition to develop addictive behavior to cocaine. In a Conditioned Place Preference (CPP) paradigm using cocaine, Sub mice displayed an aversion to drug, whereas Dom mice displayed drug attraction. Following a 4-week regimen of Chronic Mild Stress (CMS), Sub mice in CPP displayed a marked increase (>400%) in cocaine attraction, whereas Dom mice did not differ in attraction from their non-stressed state. Examination of hippocampal gene expression revealed in Sub mice, exposure to external stimuli, stress or cocaine, increased CRH expression (>100%), which was evoked in Dom mice only by cocaine exposure. Further, stress-induced decreases in DRD1 (>60%) and DRD2 (>50%) expression in Sub mice differed markedly from a complete lack of change in Dom mice. From our findings, we propose that social stratification dictates vulnerability to stress-induced attraction that may lead to addiction via differential regulation of hippocampal response to dopaminergic input, which in turn may influence differing tendency to develop addictive behaviors.

Prenatal stress may increase concentrations of maternal glucocorticoids, which restrict fetal growth, with variable impact upon postnatal development. Among key regulators of stress hormone effects are the glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase-2 (11βHSD2), the enzyme that inactivates glucocorticoid. This study utilized mice selectively bred for social dominance (Dom) or submissiveness (Sub), respectively exhibiting resilience or sensitivity to stress, to test whether stress-induced alterations in placental GR and 11βHSD2 protein expression may mediate divergent effects of prenatal adversity upon postnatal development. Pregnant Dom and Sub dams underwent prenatal restraint stress (PRS) for 45 min on gestational days (GD) 15-17. PRS induced a similar spike in serum corticosterone concentrations of dams from each strain on GD15 (p < .001, n = 8), and impaired fetal growth (p < .01, n = 5 litters), although Dom placentae were larger than Sub placentae (p < .01). Among placentae from Dom dams, PRS elevated protein contents of both GR (p < .05, n = 5 litters) and 11βHSD2 (p < .01) on GD19. In contrast, GR contents were reduced among placentae from PRS-exposed Sub mice (p < .01), without changes in 11βHSD2 content. Correspondingly, Dom PRS pup growth recovered by PND14, yet Sub PRS pups remained underweight into adolescence (p < .0001, n = 40 pups). Thus, prenatal stress more strongly increased placental GR and 11βHSD2 levels among Dom mice than in Subs. Increased GR may improve placental function and up-regulate 11βHSD2 expression, protecting fetuses from effects of prenatal stress upon postnatal development. Placental recruitment of GR and 11βHSD2 are potential markers of stress-induced developmental disorders, in accordance with maternal resilience or sensitivity to stress.

Memory deficit is a common manifestation of age-related cognitive impairment, of which depression is a frequently occurring comorbidity. Previously, we developed a submissive (Sub) mouse line, validated as a model of depressive-like behavior. Using learning paradigms testing hippocampus-dependent spatial and nonspatial memory, we demonstrate here that Sub mice developed cognitive impairments at earlier age (3 months), compared with wild-type mice. Furthermore, acute hippocampal slices from Sub animals failed to display paired-pulse facilitation, whereas primed burst stimulation elicited significantly enhanced long-term potentiation in region CA1, relative to control mice. Changes in synaptic plasticity were accompanied by markedly reduced hippocampal messenger RNA expression of insulin-like growth factor and brain-derived neurotrophic factor. Finally, we identified markedly elevated protein levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the hippocampi of Sub mice, which was exacerbated with age. Taken together, the results point to a linkage between depressive-like behavior and the susceptibility to develop age-related cognitive impairment, potentially by hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated glutamatergic signaling.

Psychiatric conditions, in many cases, arise from social interactions necessary for optimal mental functioning. Dominance and submissiveness are two opposite poles of behavior, stemming from processes of social interactions between members inside one group or species. Extreme dominance and submissiveness expressions in humans is accompanied by mental impairments, including mania and depression. Here, taking advantage of animals bred selectively for traits of dominance and submissiveness, we assess protein expression profiles in dominant and submissive mice in the context of social interaction.Proteins extracted from hippocampi of naïve and social interaction subjected dominant, submissive and wild type mice (15 mice per each group) are quantified using label-free quantitative LC/MS/MS analysis. Complexity of social interaction-related protein expression is resolved by factor analysis and enriched with GO and protein-protein interaction functional network analyses.In total, 1146 proteins exhibiting expression changes in the wild type mice, as well as dominant and submissive mice are enriched in protein datasets responsible for: 1) socially triggered dominance (90 proteins), 2) inherent submissiveness (75 proteins), 3) socially triggered submissiveness (117 proteins), and 4) social interaction triggered protein expression changes, related to resilience/adaptation to stress (69 proteins). Among the most enriched categories, extensive changes are found in proteins related to presynaptic release, ion channel regulation, circadian rhythm, MAPK, ErbB and NF-kB pathways.Data extracted from this first extensive proteomic study of a social interaction paradigm may facilitate decoding of molecular mechanisms responsible for pathogenesis of psychiatric disorders.

Recent studies indicate that an oil extract from Salvia sclarea may provide clinical benefits in various pathological conditions. In comparison to extracts from other Salvia species, S. sclarea oil contains twice as much omega-3 fatty acids, which are involved in eicosanoid synthesis pathways, and has been found to contain significant levels of the psychoactive monoterpane linalool. In the present study, we examined the mood stabilizing and anxiolytic-like effects of chronic food administration of S. sclarea oil extract on behavioral and physiological parameters of mice with prominent dominant and submissive features in behavioral assays used to test mood stabilizing and antidepressant drugs. Experimental animals received oil supplemented food from the age of 4 weeks or from conception via their pregnant dams. Each age group received either S. sclarea oil- or sunflower oil-enriched feed. Dominant animals, whose pregnant mothers received S. sclarea oil-enriched feed from the date of conception, showed a significant reduction of dominant and anxiety-like behavior, in comparison to their sunflower oil-treated counterparts. S. sclarea oil-treated submissive animals exhibited a similar tendency, and showed a significant reduction in blood corticosterone levels. These findings enforce the hypothesis that S. sclarea oil possesses anxiolytic properties.

Depression represents an important global public health concern. It is a complex phenomenon characterized by multifarious etiology and many clinical subtypes. Recent studies show that neuropeptides acting as neurotransmitters and neuromodulators may be involved in the etiology of depression. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide linked to a wide range of biological activities. PACAP regulates monoamine metabolism, modulates HPA axis activity, and plays a critical role in the regulation of distinct neurotransmission pathways, the deterioration of which may lead to behavioral abnormalities, including depression. This mini-review outlines the current state of knowledge regarding the involvement of the PACAP signaling system in depressive disorders.

The routine detection of large and medium copy number variants (CNVs) is well established. Hemizygotic deletions or duplications in the large Duchenne muscular dystrophy DMD gene responsible for Duchenne and Becker muscular dystrophies are routinely identified using multiple ligation probe amplification and array-based comparative genomic hybridization. These methods only map deleted or duplicated exons, without providing the exact location of breakpoints. Commonly used methods for the detection of CNV breakpoints include long-range PCR and primer walking, their success being limited by the deletion size, GC content and presence of DNA repeats. Here, we present a strategy for detecting the breakpoints of medium and large CNVs regardless of their size. The hemizygous deletion of exons 45-50 in the DMD gene and the large autosomal heterozygous PARK2 deletion were used to demonstrate the workflow that relies on real-time quantitative PCR to narrow down the deletion region and Sanger sequencing for breakpoint confirmation. The strategy is fast, reliable and cost-efficient, making it amenable to widespread use in genetic laboratories.

Incensole acetate (IA), a constituent of Boswellia resin (‘frankincense’), was previously demonstrated to exhibit an antidepressive-like effect in the Forced Swim Test (FST) in mice following single dose administration (50 mg/kg). Here, we show that acute administration of considerably lower dose (10 mg/kg) IA to selectively bred mice, showing prominent submissive behavior, exerted significant antidepressant-like effects in the FST. Furthermore, chronic administration of 1 or 5 mg/kg per day of IA for three consecutive weeks dose- and time-dependently reduced the submissiveness of the mice in the Dominant–Submissive Relationship test, developed to screen the chronic effect of antidepressants. This behavioral effect was concomitant to reduced serum corticosterone levels, dose-dependent down-regulation of corticotropin releasing factor and up-regulation of brain derived neurotrophic factor transcripts IV and VI expression in the hippocampus. These data suggest that IA modulates the hypothalamic–pituitary–adrenal (HPA) axis and influences hippocampal gene expression, leading to beneficial behavioral effects supporting its potential as a novel treatment of depressive-like disorders.

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) is a multi-functional neuropeptide that acts through activation of three common G-protein coupled receptors (VPAC1, VPAC2 and PAC1). In this study, we have investigated the gene expression profile of PAC1 isoforms (Hop1, Hip, Hip-Hop) and VPAC1, VPAC2 receptors in distinct brain regions during different stages of rat postnatal development. Using quantitative real time PCR approach we found that PAC1 isoforms were highly expressed in the cortex of newborns with marked decrease in expression during later stages of development. In contrast, mRNA levels of VPAC1, VPAC2 receptors were markedly lower in newborns in comparison to later developmental stages. Expression of PAC1 isoforms predominated in the hippocampus, while expression of VPAC1 was more prominent in the cortex and VPAC2 in the striatum and hippocampus. In addition we found that during early stages of postnatal development the expression of PAC1 receptor in the hippocampus was significantly higher in females than in males. No sex dependent differences in expression were observed for the VPAC1 and VPAC2 receptors. In summary, differential expression of PAC1, VPAC1 and VPAC2 receptors during postnatal development as well as gender dependent differences of PAC1 receptor expression in the hippocampus, will contribute to our understanding of the role of PACAP/VIP signaling system in normal brain development and function.