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Abstract Experiencing psychosocial adversities in early life such as maternal separation (MS) increases the risk of psychiatric disorders. Immune-inflammatory responses have imperative roles in the pathophysiology of psychiatric disorders. MS relatively changes the composition of intestinal microbiota leading to an overactivation of the hypothalamic–pituitary–adrenal (HPA) axis, and subsequently increases the corticosterone level. In this study, we aimed to evaluate the role of corticosterone in behavioral changes and microbiota modifications in a mouse model of MS afflicted neuroinflammatory response in the hippocampus. For this purpose, 180 min of MS stress was applied to mice at postnatal day (PND) 2–14 followed by behavioral tests including forced swimming test (FST), splash test, open field test (OFT) and elevated plus maze (EPM) at PND 50–52. For evaluating the role of corticosterone, mice were subjected to adrenalectomy. Using real-time RT-PCR, the expression of inflammatory genes was determined in the hippocampus and colon tissues. We found that MS provoked depressive- and anxiety-like behaviors in adult male mice. In addition, MS was able to active a neuroimmune response in the hippocampus, motivate inflammation and histopathologic changes in the colon tissue and modify the composition of gut microbiota as well. Interestingly, our findings showed that adrenalectomy (decline in the corticosterone level), could modulate the above-mentioned negative effects of MS. In conclusion, our results demonstrated that overactivation of HPA axis and the subsequent increased level of corticosterone could act, possibly, as the deleterious effects of MS on behavior, microbiota composition changes and activation of neuroimmune response. Highlights • MS provoked negative behaviors, inflammatory responses in the hippocampus and colon tissues of adult male mice • MS led to overactivation of the HPA axis and overproduction of the corticosterone • MS altered composition of the gut microbiota • Corticosterone, likely, mediated negative effects of MS on behavior and inflammatory responses • Adrenalectomy restored, in part, microbiota composition in the gut and mitigated negative effects of MS [ABSTRACT FROM AUTHOR]

Summary: Context: Corticosteroid‐binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of high‐affinity CBG (haCBG) by neutrophil elastase at inflammatory sites causes cortisol release into tissues, facilitating immunomodulatory effects. Objective: To determine whether depletion of haCBG is related to mortality in septic shock. Design: A single‐center prospective observational cohort study of patients recruited with critical illness or septic shock, using serum samples collected at 0, 8, 24, 48 and 72 hours. Serum total and haCBG, and total and free cortisol were assayed directly. Glucocorticoid treatment was an exclusion criterion. Mortality was assessed at 28 days from Intensive Care Unit admission. Results: Thirty septic shock (SS) and 42 nonseptic critical illness (CI) patients provided 195 serum samples. SS/CI patients had lower total CBG, haCBG and low‐affinity CBG (laCBG) than controls. Total CBG and haCBG were significantly lower in septic shock patients who died than in those that survived (P < 0.009, P = 0.021, respectively). Total and free cortisol were higher in septic than nonseptic individuals. Free/total cortisol fractions were higher in those with low haCBG as observed in septic shock. However, cortisol levels were not associated with mortality. Albumin levels fell in sepsis but were not related to mortality. Conclusions: Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock. [ABSTRACT FROM AUTHOR]

Abstract Transportation noise affects urbanized, rural, and otherwise unaltered habitats. Given expanding transportation networks, alterations in the acoustic landscapes experienced by animals are likely to be pervasive and persistent (i.e. chronic). It is important to understand if chronic noise exposure alters behavior and physiology in free-living animals, as it may result in long-lasting impacts, such as reduced reproductive success. Here, we experimentally tested the effects of chronic traffic noise on baseline and stress-induced corticosterone (the primary avian glucocorticoid), parental feeding behavior, and fitness proxies in breeding tree swallows (Tachycineta bicolor). Our results show that chronic traffic noise is related to altered corticosterone in both adult female and nestling tree swallows, suggesting that noise may be a stressor in both groups. In adult females, our results suggest that traffic noise is related to a limited ability to respond to subsequent acute stressors (i.e. reduced stress-induced corticosterone levels after handling). Further, our results show no evidence of habituation to noise during the breeding season, as the negative relationship between traffic noise and adult female stress-induced corticosterone became stronger over time. In nestlings, we found a positive relationship between traffic noise exposure and baseline corticosterone. Finally, we found a negative relationship between traffic noise and nestling body condition, despite no detectable effects of noise on nestling provisioning (e.g. parental feeding rate, or insect bolus size/composition). These results highlight the potential long-term consequences of chronic noise exposure, as increased baseline corticosterone and reduced nestling body condition in noise-exposed areas may have negative, population-level consequences. Highlights • Chronic traffic noise related to reduced stress response in adult tree swallows • Adults do not habituate to traffic noise during the breeding season. • Nestling baseline corticosterone is positively related to traffic noise exposure. • Nestling body condition is negatively related to traffic noise exposure. • Reduced nestling body condition is not due to altered parental provisioning. [ABSTRACT FROM AUTHOR]

Abstract Examining the effects of acute stress across multiple modalities (behavioral, physiological, and endocrinological) can increase our understanding of the interplay among stress systems, and may improve the efficacy of stress detection. A multimodal approach also allows for verification of the biological stress response, which can vary between individuals due to myriad internal and external factors, thus allowing for reliable interpretation of behavioral markers of stress. Here, controlling for variables known to affect the magnitude of the stress response, we utilized the Trier Social Stress Test (TSST) to elicit an acute stress response in 80 healthy adult men and women. The TSST involves an interview-style oral presentation and critical social evaluation, and is highly effective in inducing psychosocial stress. Participants completed the study in individual 2 h sessions, during which we collected voice, polygraph and salivary hormone measures in baseline, stress, and relaxation phases. Our results show sizeable systematic increases in voice pitch (mean, minimum and variation in fundamental frequency, F 0), hormone levels (cortisol) and decreases in skin temperature and hand movement during psychosocial stress, with striking similarities between men and women. However, cortisol and skin temperature only weakly predicted changes in voice pitch during stress, in either women or men, respectively. Thus, while our results provide compelling evidence that psychosocial stress manifests itself behaviorally by increasing voice pitch and its variability alongside simultaneous activation of physiological and endocrinological stress systems, our results also highlight a relatively weak degree of intra-individual 'response coherence' across these stress systems, with dissociations among different stress measures related most strongly to sex. Highlights • Multimodal measurement of acute stress may improve stress detection. • Voice, hormone and polygraph measures were collected before, during, and after stress. • Psychosocial stress affected voice pitch, cortisol, skin temp and hand movement. • Cortisol and skin temp predicted changes in women's and men's voice pitch, respectively. • Behavioral, physiological and endocrine measures showed weak 'response coherence'. [ABSTRACT FROM AUTHOR]

Rationale: Initial drug abstinence (modeled here as Extinction Day 1, ED1) is a critical time point in the progression of addiction that is strongly influenced by stress and sex. ED1 induces corticosterone release in both sexes, and cocaine-seeking during ED1 can be mitigated by corticotrophin-releasing factor (CRF) antagonists more effectively in female rats. Oxytocin (OXT) is a neuropeptide that has several biological functions, including regulation of stress pathways.Methods: To investigate a relationship between OXT, sex, and cocaine-seeking, we examined Fos on ED1 in OXT neurons of paraventricular (PVN) and supraoptic nuclei (SON) compared to homecage (cocaine experienced) or naïve male and female rats. We also administered OXT 30 min prior to ED1 testing or cued reinstatement testing.Results: OXT neurons had decreased activity (as reflected by Fos protein) in PVN and SON on withdrawal day 1 (homecage) compared to naïve rats. Fos in OXT neurons was further decreased on ED1, compared to homecage controls, in both males and females even though in SON, cocaine exposure increased the number of OXT-expressing neurons. In addition, systemically administered OXT reduced cocaine-seeking during ED1 and cue-induced reinstatement of cocaine-seeking but delayed extinction, similarly among male and female rats.Conclusions: These data indicate that OXT neurons in PVN and SON may be involved in cocaine-seeking during ED1 and support OXT as a possible therapeutic to decrease cocaine-seeking during initial abstinence and in response to cocaine-associated cues. [ABSTRACT FROM AUTHOR]

The OR37 subsystem is characterized by a variety of unique features. The odorant receptors (ORs) of this subfamily are selectively tuned to specific ligands which are supposed to play a role in social communication. OR37 expressing sensory neurons project their axons to a single receptor specific glomerulus per bulb which have been shown to be unusually stable in size and to possess a distinct repertoire of periglomerular cells. Since the neuronal network surrounding glomeruli is typically modified by the integration of adult born neurons, in this study it was investigated whether the number of adult born cells might be different for OR37 glomeruli compared to other OR-specific glomeruli. Towards this goal, 23 days after BrdU injection, BrdU labeled cells in the proximity of OR37A glomeruli as well as around OR18-2 and OR256-17 glomeruli were determined. It was found that the number of BrdU labeled cells in the periglomerular region of OR37A glomeruli was significantly lower compared to glomeruli of the other OR types. This finding was in line with a lower number of neuroblasts visualized by the marker protein doublecortin. Double labeling experiments for BrdU and marker proteins revealed that despite a relatively high number of calretinin expressing cells at the OR37A glomeruli, the number of cells co-stained with BrdU was quite low compared to other glomeruli, which may point to an individual turnover rate of this cell type for different glomeruli. Together, the results of the present study support the notion that the neuronal network at the OR37 glomeruli is less dynamic than that of other glomerulus types. This indicates a specific processing of social information in OR37 glomerular networks. [ABSTRACT FROM AUTHOR]

This study investigated the pattern of adult neurogenesis throughout the brains of three prosimian primate species using immunohistochemical techniques for endogenous markers of this neural process. Two species, Galago demidoff and Perodicticus potto, were obtained from wild populations in the primary rainforest of central Africa, while one species, Lemur catta , was captive-bred. Two brains from each species, perfusion-fixed with 4% paraformaldehyde, were sectioned (50 µm section thickness) in sagittal and coronal planes. Using Ki-67 and doublecortin (DCX) antibodies, proliferating cells and immature neurons were identified in the two canonical neurogenic sites of mammals, the subventricular zone of the lateral ventricle (SVZ) giving rise to the rostral migratory stream (RMS), and the subgranular zone of the dentate gyrus of the hippocampus. In addition a temporal migratory stream (TMS), emerging from the temporal horn of the lateral ventricle to supply the piriform cortex and adjacent brain regions with new neurons, was also evident in the three prosimian species. While no Ki-67-immunoreactive cells were observed in the cerebellum, DCX-immunopositive cells were observed in the cerebellar cortex of all three species. These findings are discussed in a phylogenetic context. [ABSTRACT FROM AUTHOR]

The potentially severe side effects of systemic corticosteroids and immunosuppressants used in Pemphigus vulgaris ( PV) call for novel therapeutic approaches. In this context, pharmacological inhibition of major pathogenic signalling effectors represents a promising alternative. However, we have also shown that overinhibition of effectors required for epidermal homeostasis can exacerbate PV pathophysiology implicating transepidermal keratinocyte fragility. A feedforward target validation therefore preferentially includes studies on knockout mouse models. We previously reported on successful amelioration of PV blisters following inhibition of non-apoptotic, low-level caspase-3. Here, we use conditional, keratinocyte-specific caspase-3-deficient mice (casp3 EKO) to demonstrate (i) absence of keratinocyte fragility upon injection of the potent Dsg3-specific antibody AK23 and (ii) amelioration of blistering on the background of known signalling effectors. Our results provide the experimental proof of concept justifying translation of the caspase-3 inhibitor approach into PV clinical trials. [ABSTRACT FROM AUTHOR]

Study Question: What are the mechanisms by which corticotrophin-releasing hormone (CRH) and corticosterone impair the development of preimplantation embryos in the oviduct.Summary Answer: CRH and corticosterone do not affect preimplantation embryos directly, but impair their development indirectly by triggering apoptosis of oviductal epithelial cells (OECs) through activation of the Fas system.What Is Known Already: Studies report that stress impairs embryo development with facilitated secretion of CRH and glucocorticoids. Although an in vivo study demonstrated that preimplantation stress impaired embryo development in conjunction with oviductal apoptosis and activation of the Fas system, whether CRH or glucocorticoids damage embryos directly or indirectly by way of oviductal cells remains to be clarified.Study Design, Size, Duration: Mice of Kunming strain, the generalized lymphoproliferative disorder (gld) mice with a germline mutation F273L in Fas ligand in a C57BL/6J genomic background and the wild-type C57BL/6J mice were used. Female mice were used 8-10 weeks after birth.Participants/materials, Setting, Methods: While some female mice were killed 48 h after being injected with equine CG to collect oviducts and prepare OECs, others were killed to recover zygotes after mating with males following superovulation with eCG and hCG. The zygotes obtained were cultured with or without CRH or corticosterone (CRH/Cort) either in Chatot-Ziomek-Bavister (CZB) medium with or without OECs or in conditioned medium (CM) conditioned with OECs pretreated or not with CRH/Cort. Preimplantation development, levels of redox potential and apoptosis, and expression of CRH receptor 1 (CRHR1), glucocorticoid receptor (GR), Fas and 11β-hydroxysteroid dehydrogenase (HSD) were observed in embryos recovered at different times of in vitro culture. After culture of OECs with or without CRH/Cort, levels of redox potential and apoptosis, mRNA and protein expression of growth factors, and protein expression of CRHR1, GR and Fas were examined in OECs and the level of FasL was measured in CM. The gld mice were used to confirm a role for the Fas system in triggering apoptosis of embryos and oviducts.Main Results and the Role Of Chance: This study showed that blastocyst development was unaffected when mouse zygotes were cultured in CZB medium containing various concentrations of CRH/Cort but was impaired when embryos were cultured with CRH/Cort plus OECs or in CM conditioned with OECs pretreated with CRH/Cort (treatment CM). Culture in treatment-CM induced oxidative stress and apoptosis in embryos. Preimplantation embryos expressed GR and Fas at all stages and CRHR1 at the blastocyst stage only. Mouse 4-cell embryos and blastocysts expressed HSD2 but not HSD1. Culture of OECs with CRH/Cort increased their oxidative stress, apoptosis, CRHR1, Fas and FasL while decreasing their GR and growth factors. Blastocyst development in treatment-CM conditioned with OECs from gld mice harboring FasL mutations was superior to treatment-CM conditioned with wild-type mouse OECs. The results suggest that CRH/Cort impairs embryo development indirectly by inducing oviductal apoptosis via activating the Fas system. The insensitivity of preimplantation embryos to CRH and corticosterone is due to, respectively, a lack of CRHR and the exclusive expression of HSD2 that inactivate corticosterone.Large Scale Data: Not applicable.Limitations, Reasons For Caution: Although significant, the conclusions were drawn from limited results obtained using mice and thus they need further verification in other species. For example, bovine embryos express both HSD1 and HSD2 at all the preimplantation stages whereas mouse preimplantation embryos express HSD2 exclusively without HSD1.Wider Implications Of the Findings: The data are important for our understanding of the mechanisms by which stress affects female reproduction in both human and animals, as early stages of pregnancy are considered more vulnerable to stress than the late stages.Study Funding and Competing Interest(s): This study was supported by grants from the National Basic Research Program of China (Nos. 2014CB138503 and 2012CB944403), the China National Natural Science Foundation (Nos. 31272444 and 30972096) and the Animal breeding improvement program of Shandong Province. All authors declare that their participation in the study did not involve factual or potential conflicts of interests. [ABSTRACT FROM AUTHOR]

Neurite growth is an important process for the adult hippocampal neurogenesis which is regulated by a specific range of the intracellular free Ca2+ concentration ([Ca2+]i). Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable channel and activation of it causes an increase in [Ca2+]i. We recently reported that TRPV4 activation promotes the proliferation of stem cells in the adult hippocampal dentate gyrus (DG). The present study aimed to examine the effect of TRPV4 activation on the dendrite morphology of newborn neurons in the adult hippocampal DG. Here, we report that intracerebroventricular injection of the TRPV4 agonist GSK1016790A for 5 days (GSK1016790A-injected mice) reduced the number of doublecortin immunopositive (DCX+) cells and DCX+ fibers in the hippocampal DG, showing the impaired dendritic arborization of newborn neurons. The phosphorylated AMP-activated protein kinase (p-AMPK) protein level increased from 30 min to 2 h, and then decreased from 1 to 5 days after GSK1016790A injection. The phosphorylated protein kinase B (p-Akt) protein level decreased from 30 min to 5 days after GSK1016790A injection; this decrease was markedly attenuated by the AMPK antagonist compound C (CC), but not by the AMPK agonist AICAR. Moreover, the phosphorylated mammalian target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6k) protein levels were decreased by GSK1016790A; these changes were sensitive to 740 Y-P and CC. The phosphorylation of glycogen synthase kinase 3b (GSK3β) at Y216 was increased by GSK1016790A, and this change was accompanied by increased phosphorylation of microtubule-associated protein 2 (MAP2) and collapsin response mediator protein-2 (CRMP-2). These changes were markedly blocked by 740 Y-P and CC. Finally, GSK1016790A-induced decrease of DCX+ cells and DCX+ fibers was markedly attenuated by 740 Y-P and CC, but was unaffected by AICAR. We conclude that TRPV4 activation impairs the dendritic arborization of newborn neurons through increasing AMPK and inhibiting Akt to inhibit the mTOR-p70S6k pathway, activate GSK3β and thereby result in the inhibition of MAP2 and CRMP-2 function. [ABSTRACT FROM AUTHOR]

Doublecortin like kinase 1 (DCLK1) was observed overexpressed in several types of human cancers, and played a functional role in tumorigenicity, but little is known about the biological function of DCLK1 in basal-like breast cancer. In our results, the expressions of DCLK1 mRNA and protein were elevated in basal-like breast cancer tissues and cell lines. DCLK1 high-expression associated with clinical stage, lymph node metastasis, distant metastasis and histological grade. DCLK1 high-expression was an independent unfavorable prognostic factor for basal-like breast cancer patients. The biological experiments suggested knockdown of DCLK1 induced inhibition of basal-like breast cancer cells proliferation, migration and invasion. In conclusion, DCLK1 serves as a prognostic biomarker for basal-like breast cancer and a potential therapeutic target for basal-like breast cancer. [ABSTRACT FROM AUTHOR]

Oligodendrocyte precursor cells (OPC) are glial cells that differentiate into myelinating oligodendrocytes during embryogenesis and early stages of post-natal life. OPCs continue to divide throughout adulthood and some eventually differentiate into oligodendrocytes in response to demyelinating lesions. There is growing evidence that OPCs are also involved in activity-driven de novo myelination of previously unmyelinated axons and myelin remodeling in adulthood. Considering these roles in the adult brain, OPCs are likely mobile cells that can migrate on some distances before they differentiate into myelinating oligodendrocytes. A number of studies have noted that OPCs express doublecortin (DCX), a microtubule-associated protein expressed in neural precursor cells and in migrating immature neurons. Here we describe the distribution of DCX in OPCs. We found that almost all OPCs express DCX, but the level of expression appears to be much lower than what is found in neural precursor. We found that DCX is downregulated when OPCs start expressing mature oligodendrocyte markers and is absent in myelinating oligodendrocytes. DCX does not appear to signal an immature neuronal phenotype in OPCs in the adult mouse brain. Rather, it could be involved either in cell migration, or as a marker of an immature oligodendroglial cell phenotype. [ABSTRACT FROM AUTHOR]

The porcine brain closely resembles the human brain in aspects such as development and morphology. Temporal miRNA profiling in the developing embryonic porcine cortex revealed a distinct set of miRNAs, including miR-34c and miR-204, which exhibited a highly specific expression profile across the time of cortical folding. These miRNAs were found to target Doublecortin (DCX), known to be involved in neuron migration during cortical folding of gyrencephalic brains. In vivo modulation of miRNA expression in mouse embryos confirmed that miR-34c and miR-204 can control neuronal migration and cortical morphogenesis, presumably by posttranscriptional regulation of DCX. [ABSTRACT FROM AUTHOR]

Doublecortin is a microtubule-associated protein produced during neurogenesis. The protein stabilizes microtubules and stimulates their polymerization, which allows migration of immature neurons to their designated location in the brain. Mutations in the gene that impair doublecortin function and cause severe brain formation disorders are located on a tandem repeat of two doublecortin domains. The molecular mechanism of action of doublecortin is only incompletely understood. Anti-doublecortin antibodies, such as the rabbit polyclonal Abcam 18732, are widely used as neurogenesis markers. Here, we report the generation and characterization of antibodies that bind to single doublecortin domains. The antibodies were used as tools to obtain structures of both domains. Four independent crystal structures of the N-terminal domain reveal several distinct open and closed conformations of the peptide linking N- and C-terminal domains, which can be related to doublecortin function. An NMR assignment and a crystal structure in complex with a camelid antibody fragment show that the doublecortin C-terminal domain adopts the same well defined ubiquitin-like fold as the N-terminal domain, despite its reported aggregation and molten globule-like properties. The antibodies' unique domain specificity also renders them ideal research tools to better understand the role of individual domains in doublecortin function. Asingle chain camelid antibody fragment specific for the C-terminal doublecortin domain affected microtubule binding, whereas a monoclonal mouse antibody specific for the N-terminal domain did not. Together with steric considerations, this suggests that the microtubule-interacting doublecortin domain observed in cryoelectron micrographs is the C-terminal domain rather than the N-terminal one. [ABSTRACT FROM AUTHOR]

Summary Many microtubule (MT) functions are mediated by a diverse class of proteins (+TIPs) at growing MT plus ends that control intracellular MT interactions and dynamics and depend on end-binding proteins (EBs) [ 1 ]. Cryoelectron microscopy has recently identified the EB binding site as the interface of four tubulin dimers that undergoes a conformational change in response to β-tubulin GTP hydrolysis [ 2, 3 ]. Doublecortin (DCX), a MT-associated protein (MAP) required for neuronal migration during cortical development [ 4, 5 ], binds to the same site as EBs [ 6 ], and recent in vitro studies proposed DCX localization to growing MT ends independent of EBs [ 7 ]. Because this conflicts with observations in neurons [ 8, 9 ] and the molecular function of DCX is not well understood, we revisited intracellular DCX dynamics at low expression levels. Here, we report that DCX is not a +TIP in cells but, on the contrary, is excluded from the EB1 domain. In addition, we find that DCX-MT interactions are highly sensitive to MT geometry. In cells, DCX binding was greatly reduced at MT segments with high local curvature. Remarkably, this geometry-dependent binding to MTs was completely reversed in the presence of taxanes, which reconciles incompatible observations in cells [ 9 ] and in vitro [ 10 ]. We propose a model explaining DCX specificity for different MT geometries based on structural changes induced by GTP hydrolysis that decreases the spacing between adjacent tubulin dimers [ 11 ]. Our data are consistent with a unique mode of MT interaction in which DCX specifically recognizes this compacted GDP-like MT lattice. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids are adrenal steroid hormones essential to homeostatic maintenance. Their daily variation at low concentrations regulates physiology and behavior to sustain proper immunological and metabolic function. Glucocorticoids rise well above these baseline levels during stress to elicit emergency-state responses that increase short-term survival. Despite this essence in managing life processes under both regular and adverse conditions, relationships of glucocorticoid release to environmental and intrinsic factors that vary at daily and seasonal scales are rarely studied in the wild. Methods: This study on 41 passerine species of the Ecuadorian Chocó applied a standardized capture-and-restraint protocol to examine diurnal variation in baseline and stress-related release of corticosterone, the primary avian glucocorticoid. Tests for relationships to relative body mass, hemoglobin concentration, molt status and date complemented this evaluation of the time of day effect on corticosterone secretion in free-living tropical rainforest birds. Analyses were also partitioned by sex as well as performed separately on two common species, the wedge-billed woodcreeper and olive-striped flycatcher. Results: Interspecific analyses indicated maximum baseline corticosterone levels at the onset of the active phase and reductions thereafter. Stress-related levels did not correspond to time of day but accompanied baseline reductions during molt and elevations in birds sampled later during the September - November study period. Baseline corticosterone related negatively to hemoglobin in the wedge-billed woodcreeper and stress-related levels increased with body mass in the olive-striped flycatcher. There were no substantial sex-related differences. Conclusions: The results of this study suggest a diurnal rhythmicity in baseline corticosterone release so robust as to emerge in pooled analyses across a highly variable dataset. While this detection in nature is singular, correspondent patterns have been demonstrated outside of the tropics in captive model species. Congruity in daily rhythms and links to physiological and life-history state across disparate taxa and environments may promote the yet unresolved utility of corticosterone release as a global metric for population health. However, certain results of this study also deviate from laboratory and field research at higher latitudes, cautioning generalization. Environmental distinctions such as high productivity and tempered seasonality may precipitate unique life-history strategies and underlying hormonal mechanisms in tropical rainforest birds. [ABSTRACT FROM AUTHOR]

Purpose: Systemic Lupus Erythematosus (SLE) is an autoimmune disease which is characterised by elevated levels of autoantibodies and cytokines in the body. Via alteration of the regulation of inflammation, damage to different organ systems, including the central nervous system (CNS), was found in SLE patients. Patients diagnosed with SLE were reported to suffer from different kinds of psychiatric signs and symptoms. As neurogenesis has been suggested to be a potential key player of psychiatric symptoms and emotional behavior disturbances, this study aims to investigate whether neurogenesis is altered in an animal model of SLE. Also, neuroinflammation was studied. Methods: Female NZB/W F1 mice were used as an animal model of SLE. Animals were divided into two groups: 1. prediseased mice (lupus-prone NZB/W F1 female mice, age 10-15 weeks, negative for proteinuria and with basal levels of serum anti-dsDNA autoantibodies) and 2. diseased mice (NZB/W F1 female mice, > 25 weeks of age, with elevated serum levels of anti-dsDNA autoantibodies and with persistent proteinuria of > 3 mg/ml for more than 2 weeks). Comparisons of the levels of neurogenesis and neuroinflammtion between two groups of mice were studied by the immunohistochemistry. Results: After the onset of SLE symptoms, a reduction of neurogenesis in the hippocampus was found, while there was a dramatic increase of doublecortin (DCX+) neuronal precursor cells in the corpus callosum (CC) and in the subventricular zone (SVZ). Meanwhile, exacerbated inflammation was present in the corpus callosum of the diseased mice, which was suggested by the increased number of GFAP+ cells and IBA-1+ cells. Conclusion: To the best of our knowledge, this is the first study showing an increase of neuronal precursor cells in the corpus callosum of the female NZB/W F1 mice. The present study suggests a coincidence but not a causal relationship between neurogenesis and neuroinflammation. The present results have also provided new insight showing that the altered neurogenesis and neuroinflammation may be a potential neurological mechanism for the cognitive and mood disturbance found in the SLE patients [ABSTRACT FROM AUTHOR]

Daily restricted access to food leads to the development of food anticipatory activity and metabolism, which depends upon an as yet unidentified food-entrainable oscillator(s). A premeal anticipatory peak in circulating hormones, including corticosterone is also elicited by daily restricted feeding. High-fat feeding is associated with elevated levels of corticosterone with disrupted circadian rhythms and a failure to develop robust meal anticipation. It is not clear whether the disrupted corticosterone rhythm, resulting from high-fat feeding contributes to attenuated meal anticipation in high-fat fed rats. Our aim was to better characterize meal anticipation in rats fed a low- or high-fat diet, and to better understand the role of corticosterone in this process. To this end, we utilized behavioral observations, hypothalamic c-Fos expression, and indirect calorimetry to assess meal entrainment. We also used the glucocorticoid receptor antagonist, RU486, to dissect out the role of corticosterone in meal anticipation in rats given daily access to a meal with different fat content. Restricted access to a low-fat diet led to robust meal anticipation, as well as entrainment of hypothalamic c-Fos expression, metabolism, and circulating corticosterone. These measures were significantly attenuated in response to a high-fat diet, and animals on this diet exhibited a postanticipatory rise in corticosterone. Interestingly, antagonism of glucocorticoid activity using RU486 attenuated meal anticipation in low-fat fed rats, but promoted meal anticipation in high-fat-fed rats. These findings suggest an important role for corticosterone in the regulation of meal anticipation in a manner dependent upon dietary fat content. [ABSTRACT FROM AUTHOR]

Temperate ectotherms are expected to benefit from climate change (e.g., increased activity time), but the impacts of climate warming during the winter have mostly been overlooked. Milder winters are expected to decrease body condition upon emergence, and thus to affect crucial life-history traits, such as survival and reproduction. Mild winter temperature could also trigger a state of chronic physiological stress due to inadequate thermal conditions that preclude both dormancy and activity. We tested these hypotheses on a typical temperate ectothermic vertebrate, the aspic viper ( Vipera aspis ). We simulated different wintering conditions for three groups of aspic vipers (cold: ~ 6 °C, mild: ~ 14 °C and no wintering: ~ 24 °C) during a one month long period. We found that mild wintering conditions induced a marked decrease in body condition, and provoked an alteration of some hormonal mechanisms involved in emergence. Such effects are likely to bear ultimate consequences on reproduction, and thus population persistence. We emphasize that future studies should incorporate the critical, albeit neglected, winter season when assessing the potential impacts of global changes on ectotherms. [ABSTRACT FROM AUTHOR]

Fecal corticosterone concentration (FCC) was measured in 14 buck rabbits individually housed in standard-dimension cages (SC) or in bigger cages (BC; with a volume more than double that of SC and equipped with a plastic foot mat) during 4 consecutive reproductive cycles. Cage type and reproductive phase (estrous synchronization of doe rabbits, artificial insemination, partum, preweaning, and postweaning) were not statistically significant but tendentially affected FCCs (.05 < p < .10). Buck rabbits housed in SC showed higher FCCs than those housed in BC (27.42 pg g− 1dried feces and 25.57 pg g− 1, respectively;SEM = 2.952). The highest FCC values were detected at artificial insemination (BC, 27.91 pg g− 1; SC, 30.45 pg g− 1;SEM = 3.520), highlighting that the phase of semen collection could be one of the most critical moments for buck rabbits, although further investigations are needed. These preliminary results suggest that measurement of FCC could be used as an indicator of chronic stress in buck rabbits. [ABSTRACT FROM AUTHOR]

Doublecortin-like kinase 1 (Dclk1), a microtubule-associated kinase, marks the fifth lineage of intestinal epithelial cells called tuft cells that function as tumor stem cells in Apc mutant models of colon cancer. In order to determine the role of Dclk1 in dextran sulfate sodium (DSS) induced colonic inflammation both intestinal epithelial specific Dclk1 deficient (VillinCre;Dclk1f/f) and control (Dclk1f/f) mice were fed 3% DSS in drinking water for 9 days, allowed to recover for 2 days, and killed. The clinical and histological features of DSS-induced colitis were scored and immunohistochemical, gene expression, pro-inflammatory cytokines/chemokines, and immunoblotting analyses were used to examine epithelial barrier integrity, inflammation, and stem and tuft cell features. In DSS-induced colitis, VillinCre;Dclk1f/f mice demonstrated exacerbated injury including higher clinical colitis scores, increased epithelial barrier permeability, higher levels of pro-inflammatory cytokines and chemokines, decreased levels of Lgr5, and dysregulated Wnt/b-Catenin pathway genes. These results suggest that Dclk1 plays an important role in regulating colonic inflammatory response and colonic epithelial integrity. [ABSTRACT FROM AUTHOR]

Using the single prolonged stress (SPS) animal model of post-traumatic stress disorder (PTSD), previous studies suggest that enhanced glucocorticoid receptor (GR) expression leads to cued fear extinction retention deficits. However, it is unknown how the endogenous ligand of GRs, corticosterone (CORT), may contribute to extinction retention deficits in the SPS model. Given that CORT synthesis during fear learning is critical for fear memory consolidation and SPS enhances GR expression, CORT synthesis during fear memory formation could strengthen fear memory in SPS rats by enhancing GR activation during fear learning. In turn, this could lead to cued fear extinction retention deficits. We tested the hypothesis that CORT synthesis during fear learning leads to cued fear extinction retention deficits in SPS rats by administering the CORT synthesis inhibitor metyrapone to SPS and control rats prior to fear conditioning, and observed the effect this had on extinction memory. Inhibiting CORT synthesis during fear memory formation in control rats tended to decrease cued freezing, though this effect never reached statistical significance. Contrary to our hypothesis, inhibiting CORT synthesis during fear memory formation disrupted extinction retention in SPS rats. This finding suggests that even though SPS exposure leads to cued fear extinction memory deficits, CORT synthesis during fear memory formation enhances extinction retention in SPS rats. This suggests that stress-induced CORT synthesis in previously stressed rats can be beneficial. [ABSTRACT FROM AUTHOR]

Corticosterone is known to accumulate in brain after various stressors including alcohol intoxication. Just as severe alcohol intoxication is typically required to impair memory formation only high concentrations of ethanol (60 mM) acutely inhibit long-term potentiation (LTP), a cellular memory mechanism, in naïve hippocampal slices. This LTP inhibition involves synthesis of neurosteroids, including allopregnanolone, and appears to involve a form of cellular stress. In the CA1 region of rat hippocampal slices, we examined whether a lower concentration of ethanol (20 mM) inhibits LTP in the presence of corticosterone, a stress-related modulator, and whether corticosterone stimulates local neurosteroid synthesis. Although low micromolar corticosterone alone did not inhibit LTP induction, we found that 20 mM ethanol inhibited LTP in the presence of corticosterone. At 20 mM, ethanol alone did not stimulate neurosteroid synthesis or inhibit LTP. LTP inhibition by corticosterone plus ethanol was blocked by finasteride, an inhibitor of 5α-reductase, suggesting a role for neurosteroid synthesis. We also found that corticosterone alone enhanced neurosteroid immunostaining in CA1 pyramidal neurons and that this immunostaining was further augmented by 20 mM ethanol. The enhanced neurosteroid staining was blocked by finasteride and the N-methyl-D-aspartate antagonist, 2-amino-5-phosphonovalerate (APV). These results indicate that corticosterone promotes neurosteroid synthesis in hippocampal pyramidal neurons and can participate in ethanol-mediated synaptic dysfunction even at moderate ethanol levels. These effects may contribute to the influence of stress on alcohol-induced cognitive impairment. [ABSTRACT FROM AUTHOR]

Bioluminescence imaging is a sensitive approach for longitudinal neuroimaging. Transgenic mice expressing luciferase under the promoter of doublecortin (DCX-luc), a specific marker of neuronal progenitor cells (NPC), allow monitoring of neurogenesis in living mice. Since the extent and time course of neurogenesis during autoimmune brain inflammation are controversial, we investigated neurogenesis in MOG-peptide induced experimental allergic encephalomyelitis (EAE) using DCX-luc reporter mice. We observed a marked, 2- to 4-fold increase of the bioluminescence signal intensity 10 days after EAE induction and a gradual decline 1–2 weeks thereafter. In contrast, immunostaining for DCX revealed no differences between EAE and control mice 2 and 4 weeks after immunization in zones of adult murine neurogenesis such as the dentate gyrus. Ex vivo bioluminescence imaging showed similar luciferase expression in brain homogenates of EAE and control animals. Apart from complete immunization including MOG-peptide also incomplete immunization with complete Freund´s adjuvant and pertussis toxin resulted in a rapid increase of the in vivo bioluminescence signal. Blood-brain barrier (BBB) leakage was demonstrated 10 days after both complete and incomplete immunization and might explain the increased bioluminescence signal in vivo. We conclude, that acute autoimmune inflammation in EAE does not alter neurogenesis, at least at the stage of DCX-expressing NPC. Effects of immunization on the BBB integrity must be considered when luciferase is used as a reporter within the CNS during the active stage of EAE. Models with stable CNS-restricted luciferase expression could serve as technically convenient way to evaluate BBB integrity in a longitudinal manner. [ABSTRACT FROM AUTHOR]

Background: Doublecortin-like kinase 1 (DCLK1), a putative tumor stem cell marker has been shown to be highly expressed in the stromal and epithelial compartments in colon and pancreatic cancer as well as Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Aim: To prospectively investigate whether the immunohistochemical expression of DCLK1 was associated with detectable DCLK1 plasma expression in patients with existing BE and EAC. Methods: Immunohistochemistry was performed on paraffin-embedded sections using DCLK1 antibody and scored based on staining intensity and tissue involvement. Purified human plasma samples were subjected to Western blot and ELISA analysis. Results: Forty (40) patients were enrolled: 10 controls (normal endoscopy) and 30 with BE/EAC (13 nondysplastic BE [NDBE], 9 dysplastic BE [DBE] and 8 EAC). Mean epithelial DCLK1 staining was as follows: controls = 0.11, NDBE = 3.83, DBE = 6.0, EAC = 7.17. Mean stromal DCLK1 staining was as follows: NDBE = 5.83, DBE = 5.375, EAC = 10.83. DCLK1 was detected by plasma Western blot in 1 control and in all patients with BE/EAC p < 0.0005. Plasma DCLK1 was elevated by ELISA in EAC compared to other groups, p < 0.05. Conclusions: Increased expression of DCLK1 was observed in the epithelium, stroma and plasma of patients with BE/EAC. Furthermore, the presence of detectable DCLK1 in plasma of BE/EAC patients may provide a less invasive, detection tool in those patients as well as represent a novel molecular marker distinguishing between normal esophageal mucosa and BE or EAC. [ABSTRACT FROM AUTHOR]

Doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC) patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II) compared to healthy volunteers (normal controls). No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT). Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance. [ABSTRACT FROM AUTHOR]

Expression of doublecortin (DCX), a 43-53 kDa microtubule binding protein, is frequently used as (i) an early neuronal marker to identify the stage of neuronal maturation of in vivo grafted neuronal precursors (NSCs), and (ii) a neuronal fate marker transiently expressed by immature neurons during development. Reliable identification of the origin of DCX-immunoreactive cells (i.e., host vs. graft) requires detailed spatial and temporal mapping of endogenous DCX expression at graft-targeted brain or spinal cord regions. Accordingly, in the present study, we analyzed (i) the time course of DCX expression in pre- and postnatal rat and porcine spinal cord, and (ii) the DCX expression in spinally grafted porcine-induced pluripotent stem cells (iPS)-derived NSCs and human embryonic stem cell (ES)-derived NSCs. In addition, complementary temporospatial GFAP expression study in porcine spinal cord was also performed. In 21-day-old rat fetuses, an intense DCX immunoreactivity distributed between the dorsal horn (DH) and ventral horn was seen and was still present in the DH neurons on postnatal day 20. In animals older than 8 weeks, no DCX immunoreactivity was seen at any spinal cord laminae. In contrast to rat, in porcine spinal cord (gestational period 113-114 days), DCX was only expressed during the pre-natal period (up to 100 days) but was no longer present in newborn piglets or in adult animals. Immunohistochemical analysis was confirmed with a comparable expression profile by western blot analysis. Contrary, the expression of porcine GFAP started within 70-80 days of the pre-natal period. Spinally grafted porcine iPS-NSCs and human ES-NSCs showed clear DCX expression at 3-4 weeks postgrafting. These data indicate that in spinal grafting studies which employ postnatal or adult porcine models, the expression of DCX can be used as a reliable marker of grafted neurons. In contrast, if grafted neurons are to be analyzed during the first 4 postnatal weeks in the rat spinal cord, additional markers or grafted cell-specific labeling techniques need to be employed to reliably identify grafted early postmitotic neurons and to differentiate the DCX expression from the neurons of the host. [ABSTRACT FROM AUTHOR]

Muscle satellite cells are indispensable for muscle regeneration, but the functional diversity of their daughter cells is unknown. Here, we show that many Pax7+MyoD- cells locate both beneath and outside the basal lamina during myofiber maturation. A large majority of these Pax7+MyoD- cells are not self-renewed satellite cells, but have different potentials for both proliferation and differentiation from Pax7++MyoD+ myoblasts (classical daughter cells), and are specifically marked by expression of the double cortin (Dcx) gene. Transplantation and lineage-tracing experiments demonstrated that Dcx-expressing cells originate from quiescent satellite cells and that the microenvironment induces Dcx in myoblasts. Expression of Dcx seems to be necessary for myofiber maturation because Dcx-deficient mice exhibited impaired myofiber maturation resulting from a decrease in the number of myonuclei. Furthermore, in vitro and in vivo studies suggest that one function of Dcx in myogenic cells is acceleration of cell motility. These results indicate that Dcx is a new marker for the Pax7+MyoD- subpopulation, which contributes to myofiber maturation during muscle regeneration. [ABSTRACT FROM AUTHOR]

Doublecortin (DCX) is predominantly expressed in neuronal precursor cells and young immature neurons of the developing and adult brain, where it is involved in neuronal differentiation, migration and plasticity. Moreover, its expression pattern reflects neurogenesis, and transgenic DCX promoter-driven reporter models have been previously used to investigate adult neurogenesis. In this study, we characterize dsRed2 reporter protein-expressing cells in the adult retina of the transgenic DCX promoter-dsRed2 rat model, with the aim to identify cells with putative neurogenic activity. Additionally, we confirmed the expression of the dsRed2 protein in DCX-expressing cells in the adult hippocampal dentate gyrus. Adult DCX-dsRed2 rat retinas were analyzed by immunohistochemistry for expression of DCX, NF200, Brn3a, Sox2, NeuN, calbindin, calretinin, PKC-a, Otx2, ChAT, PSA-NCAM and the glial markers GFAP and CRALBP, followed by confocal laser-scanning microscopy. In addition, brain sections of transgenic rats were analyzed for dsRed2 expression and co-localization with DCX, NeuN, GFAP and Sox2 in the cortex and dentate gyrus. Endogenous DCX expression in the adult retina was confined to horizontal cells, and these cells co-expressed the DCX promoter-driven dsRed2 reporter protein. In addition, we encountered dsRed2 expression in various other cell types in the retina: retinal ganglion cells (RGCs), a subpopulation of amacrine cells, a minority of bipolar cells and in perivascular cells. Since also RGCs expressed dsRed2, the DCX-dsRed2 rat model might offer a useful tool to study RGCs in vivo under various conditions. Müller glial cells, which have previously been identified as cells with stem cell features and with neurogenic potential, did express neither endogenous DCX nor the dsRed2 reporter. However, and surprisingly, we identified a perivascular glial cell type expressing the dsRed2 reporter, enmeshed with the glia/stem cell marker GFAP and colocalizing with the neural stem cell marker Sox2. These findings suggest the so far undiscovered existence of perivascular associated cell with neural stem cell-like properties in the adult retina. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ectopic MCP-1, MIP-1α and GRO-α redirect Dcx+ cell migration after 4weeks of expression. [•] Ectopic MCP-1 and MIP-1α, but not GRO-α redirect Dcx+ cells after 8weeks of expression. [•] GRO-α is less effective in inducing Dcx+ cell migration when compared to MCP-1. [Copyright &y& Elsevier]

Abstract: Aside from the well-known biologically active angiotensin II, other biologically active angiotensins have been discovered, including angiotensin IV and angiotensin-(1–7). Some years ago, we and others discovered that the Mas proto-oncogene encodes a G protein-coupled receptor being essential for angiotensin-(1–7) signaling. Mas is not only expressed in the periphery but also within the brain, e.g. in the dentate gyrus (DG) and the piriform cortex (PC). Since the DG is capable of adult neurogenesis, we examined the impact of a deletion of Mas upon adult neurogenesis. Deletion of Mas did not alter cell proliferation in the adult DG (as monitored with phosphohistone H3) and did not alter cell death (as monitored with activated Caspase 3). However, Mas deficiency resulted in an increase in the number of doublecortin (DCX) positive cells, indicating that lack of Mas increases the number of this cell population. Concerning the PC, it is discussed whether adult neurogenesis occurs under physiological conditions in this area. We could demonstrate that Mas deficiency has an impact on cell division and on the population of DCX-positive cells within the PC. Since Mas is not expressed before birth within the brain, our data may suggest that adult hippocampal neurogenesis and neurogenesis occurring during prenatal development share several common mechanisms, but are, at least in part, differentially regulated. Moreover, since deficiency for Mas increases the numbers of DCX-positive young neurons, blockage of Mas might be beneficial in stimulating neurogenesis in adults. [Copyright &y& Elsevier]

Highlights: [•] We investigate group-selection silviculture on stress reactivity in Ovenbirds. [•] Group-selection increases stress-induced corticosterone by approximately 50–60%. [•] Baseline levels did not differ significantly across treatments. [•] There is a lack of repeatability across years in corticosterone levels. [ABSTRACT FROM AUTHOR]

Highlights: [•] Corticosterone assays from feces often are not related to individuals. [•] This can lead to confounding or pseudoreplication in analyses. [•] We used Bayesian hierarchical modeling to explore the consequences of this failure. [•] We discuss consequences of assumptions about bird identity for ecological inference. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV)-induced alterations in lipid metabolism and cellular protein expression contribute to viral pathogenesis. The mechanism of pleiotropic actions of cholesterol-lowering drugs, statins, against HCV and multiple cancers are not well understood. We investigated effects of fluvastatin (FLV) on microtubule-associated and cancer stem cell marker (CSC), doublecortin-like kinase 1 (DCLK1) during HCV-induced hepatocarcinogenesis. HCV replication models, cancer cell lines and normal human hepatocytes were used to investigate the antiviral and antitumor effects of statins. FLV treatment resulted in induction of microtubule bundling, cell-cycle arrest and alterations in cellular DCLK1 distribution in HCV-expressing hepatoma cells. These events adversely affected the survival of liver-derived tumor cells without affecting normal human hepatocytes. FLV downregulated HCV replication in cell culture where the ATP pool and cell viability were not compromised. Pravastatin did not exhibit these effects on HCV replication, microtubules and cancer cells. The levels of miR-122 that regulates liver homeostasis and provides HCV genomic stability remained at steady state whereas DCLK1 mRNA levels were considerably reduced during FLV treatment. We further demonstrated that HCV replication was increased with DCLK1 overexpression. In conclusion, unique effects of FLV on microtubules and their binding partner DCLK1 are likely to contribute to its anti-HCV and antitumor activities in addition to its known inhibitory effects on 3-hydroxy-3-methylglutary-CoA reductase (HMGCR). [ABSTRACT FROM AUTHOR]

Highlights: [&#x2022;] Repeated restraint stress gives rise to susceptible and resilient responses. [&#x2022;] Different stress susceptibility is associated with different anxiety behavior. [&#x2022;] Basal level of corticosterone is strongly correlated with stress susceptibility. [ABSTRACT FROM AUTHOR]

ABSTRACT Neurogenesis in the subgranular layer of the dentate gyrus (DG) has been suggested to underlie some forms of associative learning. The present study was undertaken to determine whether there was also a role of neurogenesis in the ethanol (EtOH)-induced conditioned place preference (CPP). Outbreed Swiss mice were conditioned with EtOH (2.0 g/kg) in one compartment of a non-biased place preference chamber and saline in the other compartment. This procedure produced three groups of mice: some developed a conditioned preference (EtOH_Cpp), others developed a conditioned avoidance (EtOH_Cpa) and still others demonstrated indifference to the context previously paired with ethanol (EtOH_Ind). BrdU (40 mg/kg, i.p.) was administered 4 hours after each session comprising the conditioning phase. When measured 24 hours following the CPP test, there was no effect of EtOH on doublecortin (DCX) expression or Fluoro Jade B staining. However, there were decreases in the number of BrdU+ and Ki-67+ cells in the EtOH_Cpa and EtOH_Ind groups, but not in the EtOH_Cpp group. Most of BrdU+ cells were co-labeled with DCX. Similarly, in another experiment, in that the perfusion was done 28 days after CPP test, most BrdU+ cells were co-localized with NeuN. These results suggest that conditioned appetitive response is able to maintain normal levels of neurogenesis in DG and might counteract ethanol-produced decreased cell proliferation/survival rate. [ABSTRACT FROM AUTHOR]

Highlights: [•] A mouse model with globally suppressed P450 reductase gene expression (Cpr-low). [•] Markers for neurogenesis were examined in SVZ of Cpr-low mice. [•] Abundance of cells positive for Ki67 or GFAP was increased in SVZ of Cpr-low mice. [•] Astrocyte differentiation and growth from SVZ cells of Cpr-low mice were increased. [ABSTRACT FROM AUTHOR]

By integrating gene profiling and immunohistochemical data with functional experiments in cell lines in this study we show for the first time that doublecortin (DCX) domain containing 2 (DCDC2), a protein belonging to the DCX family and involved in neuronal cell migration, is aberrantly expressed in prostate tumors whereas absent in normal prostate. Furthermore, in patients treated with radical prostatectomy, high levels of DCDC2 RNA were significantly associated with increased biochemical relapse (LogRank Mantel-Cox=0.012). Mechanistically, we found that the ETS transcription factor ESE3/EHF, which is expressed in normal prostate and frequently lost in prostate tumors, maintained DCDC2 repressed by binding to a novel identified ETS binding site in the gene promoter. Consistently, in prostate tumors and in cellular models of gain and loss of ESE3/EHF, the expression of DCDC2 and ESE3/EHF were inversely correlated. In prostate cancer cells, DCDC2 colocalized with microtubules and promoted cell migration and resistance to the microtubule-targeting drug taxol. Collectively, this study establishes DCDC2 as a novel ESE3/EHF oncogenic target in prostate cancer. These findings may be relevant for the clinical management of prostate cancer as DCDC2 may signal tumors more prone to relapse and resistant to taxol treatment. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Doublecortin (DCX) and polysialilated neural cell adhesion molecule (PSA-NCAM), two proteins associated with immature neuronal phenotypes and elevated neuroplasticity in the adult brain, have recently been identified in the mammalian amygdala, and evidence from rodent studies suggests that stress may modify their expression in this brain region. The purpose of the present study was to investigate whether the expression of proteins involved in neuroplasticity is altered in the amygdala of individuals with depression. Methods: Basolateral amygdala (BLA) and central amygdala (CeA) postmortem human brain samples were collected from individuals with a history of depression (n = 22 and 25, respectively) and psychiatrically healthy controls (CTRL; n = 14). Proteins associated with neuroplasticity were quantified using Western blotting. Results: Immunoblots revealed that depressed subjects displayed increased expression of DCX (p = 0.033) and PSA-NCAM (p = 0.027) in the BLA as compared to CTRLs. Subsequent analyses revealed that this effect was due primarily to a subset of depressed subjects who had not died by suicide (DNS). DNS subjects displayed higher DCX than CTRLs (p < 0.001) and depressed suicides (p = 0.001), and higher PSA-NCAM than CTRLs (p = 0.007). Conversely, within the CeA, DNS subjects displayed a tendency toward lower DCX expression than CTRLs (p = 0.062), and higher BDNF levels than DS subjects (p = 0.045). Conclusion: These results suggest that the BLA and CeA display contrasting patterns of neuroplasticity in depression, and that greater impairment of amygdalar neuroplasticity may be associated with increased risk of suicide. [Copyright &y& Elsevier]

If the fitness benefits gained from producing male and female offspring differ due to parental or environmental conditions, parents should adjust their level of investment accordingly. We studied sex allocation and reproductive investment in a population of common guillemots (Uria aalge) in 2 breeding seasons. The common guillemot is a single-egg species and the male is only slightly larger than the female implying small, if any differential costs of raising male and female offspring. We use 4 variables to characterize reproductive allocation: 1) sex of the chick at hatching, 2) adult male and female body condition, 3) baseline corticosterone (CORT) level of adults early and late in the chick-rearing period, and 4) body mass of the chicks just prior to fledging. Females that produced female offspring were in better body condition during early chick-rearing than those producing males and both parents raising a female offspring lost more body mass during the chick-rearing period. Female offspring were heavier than male offspring at the end of the chick-rearing period. Whereas hatching sex ratio was at unity in one of the years, it was strongly skewed toward females (72.5%) in the other year, and this pattern was consistent for a subset of pairs studied in both years. Early baseline CORT levels of adults were lower in the year when the sex ratio was skewed toward female offspring. We discuss this unexpected pattern of sex allocation in relation to variation in feeding conditions and the role of females in competing for good nesting sites. [ABSTRACT FROM PUBLISHER]

The way we study cortical development has undergone a revolution in the last few years following the ability to use shRNA in the developing brain of the rodent embryo. The first gene to be knocked-down in the developing brain was doublecortin (Dcx). Here we will review knockdown experiments in the developing brain and compare them with knockout experiments, thus highlighting the advantages and disadvantages using the different systems. Our review will focus on experiments relating to the doublecortin superfamily of proteins. [ABSTRACT FROM AUTHOR]

Phenotypic flexibility allows animals to adjust their physiology to diverse environmental conditions encountered over the year. Examining how these varying traits covary gives insights into potential constraints or freedoms that may shape evolutionary trajectories. In this study, we examined relationships among haematocrit, baseline corticosterone concentration, constitutive immune function and basal metabolic rate in red knot Calidris canutus islandica individuals subjected to experimentally manipulated temperature treatments over an entire annual cycle. If covariation among traits is constrained, we predict consistent covariation within and among individuals. We further predict consistent correlations between physiological and metabolic traits if constraints underlie species-level patterns found along the slow-fast pace-of-life continuum. We found no consistent correlations among haematocrit, baseline corticosterone concentration, immune function and basal metabolic rate either within or among individuals. This provides no evidence for constraints limiting relationships among these measures of the cardiovascular, endocrine, immune and metabolic systems in individual red knots. Rather, our data suggest that knots are free to adjust individual parts of their physiology independently. This makes good sense if one places the animal within its ecological context where different aspects of the environment might put different pressures on different aspects of physiology. [ABSTRACT FROM AUTHOR]

Abstract: Elucidation of the ‘fear circuit’ has opened exciting avenues for understanding and treating human anxiety disorders. However, the translation of rodent to human studies, and vice versa, depends on understanding the homology in relevant circuits across species. Although abundant evidence indicates that the hippocampal–amygdala circuit mediates contextual fear learning, previous studies indicate that this pathway is more restricted in primates than in rodents. Moreover, cellular components of the amygdala differ across species. The paralaminar nucleus (PL) of the amygdala, a structure that is closely associated with the basal nucleus, is one example, having no clear homologue in rodents. In both human and nonhuman primates, the PL contains a subpopulation of immature-appearing neurons, which merge into the corticoamygdaloid transition area (CTA). To understand whether immature-appearing neurons are positioned to participate in fear circuitry, we first mapped the hippocampal–amygdala projection in the monkey. We then determined whether immature-appearing neurons were targets of this path. Retrograde results show that the hippocampal inputs to the amygdala originate in uncal region (CA1′) and the rostral prosubiculum, consistent with earlier studies. The amygdalohippocampal area, ventral basal nucleus, the medial paralaminar nucleus, and its confluence with the CTA are the main targets of this projection. Immature neurons are prominent in the PL and CTA, and are overlapped by anterogradely labeled fibers from CA1′, particularly in the medial PL and CTA. Hippocampal inputs to the amygdala are more focused in higher primates compared to rodents, supporting previous anatomic studies and recent data from human functional imaging studies of contextual fear. At the cellular level, a hippocampal interaction with immature neurons in the amygdala suggests a novel substrate for cellular plasticity, with implications for mechanisms underlying contextual learning and emotional memory processes. [Copyright &y& Elsevier]

Doublecortin on X chromosome (DCX) is one of two major genetic loci underlying human lissencephaly, a neurodevelopmental disorder with defects in neuronal migration and axon outgrowth. DCX is a microtubule-binding protein, and much work has focused on its microtubule-associated functions. DCX has other reported binding partners, including the cell adhesion molecule neurofascin, but the functional significance of the DCX-neurofascin interaction is not understood. Neurofascin localizes strongly to the axon initial segment in mature neurons, where it plays a role in assembling and maintaining other axon initial segment components. During development, neurofascin likely plays additional roles in axon guidance and in GABAergic synaptogenesis. We show here that DCX can modulate the surface distribution of neurofascin in developing cultured rat neurons and thereby the relative extent of accumulation between the axon initial segment and soma and dendrites. Mechanistically, DCX acts via increasing endocytosis of neurofascin from soma and dendrites. Surprisingly, DCX increases neurofascin endocytosis apparently independently of its microtubule-binding activity. We additionally show that the patient allele DCXG253D still binds microtubules but is deficient in promoting neurofascin endocytosis. We propose that DCX acts as an endocytic adaptor for neurofascin to fine-tune its surface distribution during neuronal development. [ABSTRACT FROM AUTHOR]

Abstract: Even though the term “stress” is widely used, a precise definition is notoriously difficult. Notwithstanding this difficulty, stress continues to be an important concept in biology because it attempts to describe how animals cope with environmental change under emergency conditions. Without a precise definition, however, it becomes nearly impossible to make testable a priori predictions about how physiological and hormonal systems will respond to emergency conditions and what the ultimate impact on the animal will be. The reactive scope model is a recent attempt to formulate testable predictions. This model provides a physiological basis to explain why corticosterone negative feedback, but not baseline corticosterone concentrations, corticosterone responses to acute stress, or the interrenal capacity to secrete corticosterone, is correlated with survival during famine conditions in Galápagos marine iguanas. Reactive scope thus provides a foundation for interpreting and predicting physiological stress responses. [Copyright &y& Elsevier]

Background and Aims: Adequate thyroid hormone is critical for cerebellar development. Developmental hypothyroidism induced by iodine deficiency during the perinatal period results in permanent impairments of cerebellar development with an unclear mechanism. In the present study we investigated effects of perinatal iodine deficiency and hypothyroidism on cerebellar cell apoptosis, doublecortin (Dcx) and reelin. Apoptosis is an essential part of neural development. Dcx and reelin are two important molecules involved in neuronal migration, structure, and development in cerebellum. Methods: Two developmental rat models were created by administering dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 ppm or 15 ppm)-added drinking water from gestational day (GD) 6 until postnatal day (PND) 28. TUNEL assay and protein levels of Dcx and reelin in cerebella were assessed on PND14, 21 and 28. Results: Apoptotic cells were increased in the iodine-deficient and PTU-treated rats. Dcx protein levels in the cerebella of iodine-deficient and PTU-treated rats were significantly downregulated on PND14. Interestingly, iodine deficiency and PTU treatment upregulated the levels of Dcx protein on PND21 and 28. Reelin expressions in iodine-deficient and PTU-treated rats were significantly decreased on PND14 and 21. On PND28, reelin expressions of three treated groups were still lower than control group, although without significant difference. Conclusions: These findings may implicate alterations in cell apoptosis and levels of Dcx and reelin in the impairments of cerebellar development induced by developmental iodine deficiency and hypothyroidism. [ABSTRACT FROM AUTHOR]

Abstract: Regulation of the hypothalamic–pituitary–adrenal (HPA) axis is a key component of the vertebrate stress response. Prior studies have found that variation in HPA responses were correlated to measures of fitness and physiological condition. In addition, sexually-selected traits have also been found to correlate to measures of condition. The proximate mechanisms responsible for such covariation between sexually selected traits and measures of quality are unclear, but could involve variation in HPA regulation. We investigated whether HPA activity is related to song complexity, body size/condition and leukocyte profiles in wild male song sparrows (Melospiza melodia). We characterized three aspects of HPA activity: 1) response to restraint stress; 2) negative feedback, assessed by the ability of exogenous dexamethasone to suppress corticosterone levels; and 3) adrenal sensitivity to exogenous adrenocorticotropic hormone (ACTH). Birds with lower responses to restraint stress had more complex song and more heterophils and higher heterophil to lymphocyte (H:L) ratios. Birds with more effective negative feedback were larger and had fewer heterophils and lower H:L ratios, suggesting lower levels of physiological stress or infection. We observed no relationship between adrenal sensitivity to exogenous ACTH and any of the factors. These findings illustrate important relationships between HPA activity, song complexity, and morphological and physiological traits. Song complexity may thus provide receivers with information about the ability of the singer to cope with stressors. [Copyright &y& Elsevier]