Integrating morphology and physiology of the key endocrine organ during tadpole development: The interrenal gland.

Indirect development is widespread in anurans and is considered an ancestral condition. The metamorphosis of larvae into juveniles involves highly coordinated morphological, physiological, biochemical, and behavioral changes, promoted by the thyroid hormone and interrenal corticosteroids. Stress response to environmental changes is also mediated by corticosteroids, affecting the timing and rate of metamorphosis and leading to great developmental plasticity in tadpoles. Given the potential effect of interrenal gland ontogeny alterations on metamorphosis and the lack of studies addressing both the morphology and endocrinology of this gland in tadpoles, we present corticosterone (CORT) production and histological changes through the ontogeny of interrenal gland in the generalized pond-type tadpole of Rhinella arenarum (Anura, Bufonidae). This species shows the highest concentration of whole-body CORT by the early climax when drastic metamorphic changes begin. This is coincident with the morphological differentiation of steroidogenic cells and the formation of interrenal cords. By this stage, steroidogenic cells have a shrunken cytoplasm, with a significantly higher nucleus-to-cell diameter ratio. The lowest CORT concentration during premetamorphosis and late climax is associated with small undifferentiated cells with lipid inclusions surrounding large blood vessels between kidneys, and with cords of differentiated steroidogenic cells with a significantly lower nucleus-to-cell diameter ratio, respectively. Our study characterizes the morphological and physiological pattern of interrenal gland development, showing an association between certain histological and morphometric characteristics and CORT levels. Variations in this morpho-physiological pattern should be considered when studying the phenotypic plasticity or variable growth rates of tadpoles.

Excitation-Inhibition Imbalance Leads to Alteration of Neuronal Coherence and Neurovascular Coupling under Acute Stress.

A single stressful event can cause morphologic and functional changes in neurons and even malfunction of vascular systems, which can lead to acute stress disorder or post-traumatic stress disorder. However, there is a lack of evidence regarding how acute stress impacts neuronal activity, the concurrent vascular response, and the relationship between these two factors, which is defined as neurovascular coupling. Here, using in vivo two-photon imaging, we found that NMDA-evoked calcium transients of excitatory neurons were impaired and that vasodilation of penetrating arterioles was concomitantly disrupted in acutely stressed male mice. Furthermore, acute stress altered the relationship between excitatory neuronal calcium coherence and vascular responses. By measuring NMDA-evoked excitatory and inhibitory neuronal calcium activity in acute brain slices, we confirmed that neuronal coherence both between excitatory neurons and between excitatory and inhibitory neurons was reduced by acute stress but restored by blockade of glucocorticoid receptor signaling. Furthermore, the ratio of sEPSCs to sIPSCs was altered by acute stress, suggesting that the excitation-inhibition balance was disrupted by acute stress. In summary, in vivo, ex vivo, and whole-cell recording studies demonstrate that acute stress modifies excitatory-inhibitory neuronal coherence, disrupts the excitation-inhibition balance, and causes consequent neurovascular coupling changes, providing critical insights into the neural mechanism of stress-induced disorders.SIGNIFICANCE STATEMENT Acute stress can cause pathologic conditions, such as acute stress disorder and post-traumatic stress disorder, by affecting the functions of neurons and blood vessels. However, investigations into the impacts of acute stress on neurovascular coupling, the tight connection between local neural activity and subsequent blood flow changes, are lacking. Through investigations at the in vivo, ex vivo, and whole-cell recording levels, we found that acute stress alters the NMDA-evoked vascular response, impairs the function and coherence of excitatory and inhibitory neurons, and disrupts the excitatory and inhibitory balance. These novel findings provide insights into the relevance of the excitatory-inhibitory balance, neuronal coherence, and neurovascular coupling to stress-induced disorders.

Constitutive differences in glucocorticoid responsiveness are related to divergent spatial information processing abilities.

The stress response facilitates survival through adaptation and is intimately related to cognitive processes. The Morris water maze task probes spatial learning and memory in rodents and glucocorticoids (i.e. corticosterone (CORT) in rats) have been suggested to elicit a facilitating action on memory formation. Moreover, the early aging period (around 16-18 months of age) is susceptible to stress- and glucocorticoid-mediated acceleration of cognitive decline. In this study, we tested three lines of rats selectively bred according to their individual differences in CORT responsiveness to repeated stress exposure during juvenility. We investigated whether endogenous differences in glucocorticoid responses influenced spatial learning, long-term memory, and reversal learning abilities in a Morris water maze task at early aging. Additionally, we assessed the quality of the different swimming strategies of the rats. Our results indicate that rats with differential CORT responsiveness exhibit similar spatial learning abilities but different long-term memory retention and reversal learning. Specifically, the high CORT responding line had a better long-term spatial memory, while the low CORT responding line was impaired for both long-term retention and reversal learning. Our modeling analysis of performance strategies revealed further important line-related differences. Therefore, our findings support the view that individuals with high CORT responsiveness would form stronger long-term memories to navigate in stressful environments. Conversely, individuals with low CORT responsiveness would be impaired at different phases of spatial learning and memory.

Developing a Stopover-CORT hypothesis: Corticosterone predicts body composition and refueling rate in Gray Catbirds during migratory stopover.

Migratory flight is energetically challenging, requiring alternating phases of fuel catabolism and fuel accumulation, accompanied by dramatic changes in body composition and behavior. Baseline corticosterone (CORT; the primary glucocorticoid in birds) is thought to underlie transitions between fuel catabolism during flight, fuel deposition during stopover, and the initiation of migratory flight. However, studies of CORT on stopover physiology and behavior remain disparate efforts, lacking the cohesion of a general hypothesis. Here we develop a Stopover-CORT hypothesis formalizing the relationships among CORT, body condition, and refueling rate in migratory birds. First we expect body mass to increase with triglycerides (TRIG) as birds refuel. Second, based on a synthesis of previous literature, we predict a U-shaped CORT curve over the course of stopover, postulating that elevated CORT at arrival is reactive, responding to poor body condition, while CORT elevation before departure is preparative, driving changes in behavior and body condition. We tested these predictions in Gray Catbirds (Dumetella carolinensis) following a trans-Gulf flight during spring migration. We found baseline CORT was negatively correlated with body condition and TRIG, corresponding with our predictions for arriving and refueling-but not departing-birds. It is possible catbirds undergo regional habitat translocations rather than complete the entire stopover phase at our study site. We propose the Stopover-CORT hypothesis as a useful predictive framework for future studies of the mechanistic basis of stopover physiology. By studying the regulation of stopover refueling and departure, we may better understand physiological limitations to overall migration rate and improve assessments of habitat quality for refueling birds.

Maternal corticosterone in the mouse alters oxidative stress markers, antioxidant function and mitochondrial content in placentas of female fetuses.

KEY POINTS: Maternal exposure to the stress hormone corticosterone is known to programme a range of sex specific disease outcomes in offspring. Sex differences in placental adaptations are thought to mediate these processes. Placental oxidative stress is implicated in a range of pregnancy disorders but the role of placental oxidative stress in sex specific disease outcomes following prenatal corticosterone exposure is unknown. This study demonstrates that maternal corticosterone reduced placental hydrogen peroxide and 8-hydroxy-2'-deoxyguanosine concentrations but increased protein carbonyl content and advanced glycation end product concentrations in placentas of female fetuses but not male fetuses. These results highlight that placentas of female fetuses respond differently to maternal corticosterone exposure, with oxidative stress a major finding in placentas of female fetuses. ABSTRACT: Maternal exposure to glucocorticoids during pregnancy increases offspring risk of developing a range of sex specific disease phenotypes. These sex specific disease outcomes are thought to be in part mediated by different placental adaptations in males and females. The placenta is a highly metabolic organ which is vulnerable to the effects of oxidative stress. In other tissues, males and females have been shown to respond differently to the pro-oxidant effects of glucocorticoids. This study therefore used a well characterized animal model of maternal corticosterone exposure to investigate sex specific alterations in reactive oxygen species production, antioxidant concentrations and mitochondrial properties that might contribute to sex differences in placental outcomes. C57BL/6 mice were implanted with osmotic minipumps containing corticosterone (33 µg kg-1  h-1 ) at embryonic day (E) 12.5 and placentas collected at E14.5 for analysis. Corticosterone exposure reduced placental hydrogen peroxide (H2 O2 ) and 8-hydroxy-2'-deoxyguanosine concentrations but increased protein carbonyl content and advanced glycation end product concentrations in placentas of female fetuses but not male fetuses. This dysregulation of different markers of oxidative stress may be due to increased placental activity of thioredoxin reductase in female but not male fetuses. Corticosterone reduced placental mitochondrial content but increased protein expression of the autophagosome cargo protein p62. This study demonstrates that placentas of female fetuses respond differently to maternal corticosterone exposure and highlights an important role of reactive oxygen species, mitochondrial adaptations and antioxidant responses in glucocorticoid induced programmed disease.

Morphine-Induced Dendritic Spine Remodeling in Rat Nucleus Accumbens Is Corticosterone Dependent.

BACKGROUND: Chronic morphine treatments produce important morphological changes in multiple brain areas including the nucleus accumbens. METHODS: In this study, we have investigated the effect of chronic morphine treatment at a relatively low dose on the morphology of medium spiny neurons in the core and shell of the nucleus accumbens in rats 1 day after the last injection of a chronic morphine treatment (5 mg/kg once per day for 14 days). Medium spiny neurons were labeled with 1,1' dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate crystal and analyzed by confocal laser-scanning microscope. RESULTS: Our results show an increase of thin spines and a decrease of stubby spines specifically in the shell of morphine-treated rats compared with control. Since morphine-treated rats also presented an elevation of corticosterone level in plasma, we explored whether spine alterations induced by morphine treatment in the nucleus accumbens could be affected by the depletion of the hormone. Thus, bilaterally adrenalectomized rats were treated with morphine in the same conditions. No more alteration in stubby spines in the shell was detected in morphine-treated rats with a depletion of corticosterone, while a significant increase was observed in mushroom spines in the shell and stubby spines in the core. Regarding the thin spines, the increase observed with morphine compared with saline was lower in adrenalectomized rats than in nonadrenalectomized animals. CONCLUSION: These results indicate that dendritic spine remodeling in nucleus accumbens following chronic morphine treatment at relatively low doses is dependent on corticosterone levels.

Comparing the preventive effect of sodium hydrosulfide, leptin, and curcumin against L-arginine induced acute pancreatitis in rats: role of corticosterone and inducible nitric oxide synthase.

OBJECTIVES: Acute pancreatitis (AP) is a life-threatening condition. Using antioxidants in AP is insufficient and conflicting. Therefore, this study compared the effect of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS), leptin or curcumin pretreatment on AP induced by L-arginine. METHODS: Forty adult male rats were used and classified into: 1) control; 2) AP group [each rat was intraperitoneally (i.p.) injected with 2 doses of L-arginine of 250 mg/100 g body weight (b.w.) with an interval of 1 h]; 3) NaHS+AP group (each rat was i.p. injected with 10 mg/kg b.w. of NaHS 1 h before induction of AP); 4) leptin+AP group (each rat was pretreated with 10 µg/kg b.w. of leptin 30 min before induction of AP; and 5) curcumin+AP group (in which rats were i.p. injected with 150 mg/kg b.w. of curcumin 30 min before induction of AP). Serum amylase, lipase, nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and corticosterone (CORT) levels were assayed. In addition, pancreatic tissues were obtained for histopathological examination and malondialde-hyde (MDA), total antioxidant capacity (TAC), and inducible nitric oxide synthase (iNOS) levels were measured. RESULTS: All AP treated groups showed significant decrease in serum levels of pancreatic enzymes, NO, and TNF-α, and pancreatic MDA and iNOS levels, while TAC levels were significantly increased. NaHS caused more limitation of inflammation than leptin and curcumin by affecting iNOS. Leptin was more potent than curcumin due to the stimulatory effect of leptin on glucocorticoid release to counteract inflammation. CONCLUSIONS: NaHS was more effective in AP amelioration than the leptin and curcumin.

Contrasting effects of acute and long-term corticosterone treatment on amyloid-ß, beta-secretase 1 expression, and nuclear factor kappa B nuclear translocation.

Regulation of neuroinflammation is critical to control the detrimental impact of chronic stress in the central nervous system. Neuroinflammation occurs in response to chronic stress, leading to enhanced neuronal damage in the brain. We investigated the regulatory effects of stress hormone corticosterone on neuroinflammation regulator, as well as amyloid-ß and Beta-secretase 1 related signaling. We demonstrate that corticosterone can both positively and negatively regulate amyloid-ß expression, which may be related to the ratio of neuroinflammation regulator and Beta-secretase 1 signaling in rat primary cortical neurons. Thirty minutes of treatment with 1 µM corticosterone significantly decreased the nuclear translocation of neuroinflammation mediator neuroinflammation regulator (Western Blot: P < 0.05, Immunofluorescence: P < 0.001) and production of Beta-secretase 1 enzyme (P < 0.01), which was accompanied by a reduction in amyloid-ß1-42 levels (P < 0.01). In contrast, 1 µM corticosterone treatment over 3 days increased nuclear neuroinflammation regulator localization (P < 0.001), followed by the upregulation of Beta-secretase 1 (P < 0.01) and amyloid-ß1-42 (P < 0.05) expression. This work is the first to demonstrate that the duration of corticosterone exposure can promote or inhibit amyloid-ß production, and to link this effect with Beta-secretase 1 / neuroinflammation regulator signaling, together with providing valuable insight into the mechanisms of neuroinflammation and neuroprotection.

Acute stress enhances learning and memory by activating acid-sensing ion channels in rats.

Acute stress has been shown to enhance learning and memory ability, predominantly through the action of corticosteroid stress hormones. However, the valuable targets for promoting learning and memory induced by acute stress and the underlying molecular mechanisms remain unclear. Acid-sensing ion channels (ASICs) play an important role in central neuronal systems and involves in depression, synaptic plasticity and learning and memory. In the current study, we used a combination of electrophysiological and behavioral approaches in an effort to explore the effects of acute stress on ASICs. We found that corticosterone (CORT) induced by acute stress caused a potentiation of ASICs current via glucocorticoid receptors (GRs) not mineralocorticoid receptors (MRs). Meanwhile, CORT did not produce an increase of ASICs current by pretreated with GF109203X, an antagonist of protein kinase C (PKC), whereas CORT did result in a markedly enhancement of ASICs current by bryostatin 1, an agonist of PKC, suggesting that potentiation of ASICs function may be depended on PKC activating. More importantly, an antagonist of ASICs, amiloride (10 µM) reduced the performance of learning and memory induced by acute stress, which is further suggesting that ASICs as the key components involves in cognitive processes induced by acute stress. These results indicate that acute stress causes the enhancement of ASICs function by activating PKC signaling pathway, which leads to potentiated learning and memory.

Diverse action of repeated corticosterone treatment on synaptic transmission, neuronal plasticity, and morphology in superficial and deep layers of the rat motor cortex.

One of the adverse effects of prolonged stress in rats is impaired performance of skilled reaching and walking tasks. The mechanisms that lead to these abnormalities are incompletely understood. Therefore, we compared the effects of twice daily repeated corticosterone injections for 7 days on miniature excitatory postsynaptic currents (mEPSCs), as well as on synaptic plasticity and morphology of layers II/III and V pyramidal neurons of the primary motor cortex (M1) of male Wistar rats. Corticosterone treatment resulted in increased frequency, but not amplitude, of mEPSCs in layer II/III neurons accompanied by increased complexity of the apical part of their dendritic tree, with no changes in the density of dendritic spines. The frequency and amplitude of mEPSCs as well as the parameters characterizing the complexity of the dendritic tree were not changed in layer V cells; however, their dendritic spine density was increased. While corticosterone treatment resulted in an increase in the amplitude of field potentials evoked in intralaminar connections within layer II/III, it did not influence field responses in layer V intralaminar connections, as well as the extent of chemically induced layer V long-term potentiation (chemLTP) by the application of tetraethylammonium (TEA, 25 mM). However, chemLTP induction in layer II/III was impaired in slices prepared from corticosterone-treated animals. These data indicate that repeated 7-day administration of exogenous corticosterone induces structural and functional plasticity in the M1, which occurs mainly in layer II/III pyramidal neurons. These findings shed light on potential sites of action and mechanisms underlying stress-induced impairment of motor functions.

Corticosterone and timing of migratory departure in a songbird.

Bird migration entails replenishing fuel stores at stopover sites. There, individuals make daily decisions whether to resume migration, and must also decide their time of departure. Variation in departure timing affects the total time required to complete a migratory journey, which in turn affects fitness through arrival time at the breeding and wintering grounds. It is well established that stopover departure decisions are based on cues from innate rhythms, intrinsic factors and extrinsic factors. Yet, virtually nothing is known about the physiological mechanism(s) linking these cues to departure decisions. Here, we show for a nocturnal migratory songbird, the northern wheatear (Oenanthe oenanthe), that baseline corticosterone levels of birds at stopover increased both over the migratory season and with wind assistance towards the migratory destination. Corticosterone in turn predicted departure probability; individuals with high baseline corticosterone levels were more likely to resume migration on a given night. Corticosterone further predicted the departure time within the night, with high baseline levels being associated with early departures. These novel findings indicate that corticosterone may be mediating between departure cues and the timing of departure from a stopover site, which is a major step towards understanding the hormonal control of animal migration.

Stress hormones predict a host superspreader phenotype in the West Nile virus system.

Glucocorticoid stress hormones, such as corticosterone (CORT), have profound effects on the behaviour and physiology of organisms, and thus have the potential to alter host competence and the contributions of individuals to population- and community-level pathogen dynamics. For example, CORT could alter the rate of contacts among hosts, pathogens and vectors through its widespread effects on host metabolism and activity levels. CORT could also affect the intensity and duration of pathogen shedding and risk of host mortality during infection. We experimentally manipulated songbird CORT, asking how CORT affected behavioural and physiological responses to a standardized West Nile virus (WNV) challenge. Although all birds became infected after exposure to the virus, only birds with elevated CORT had viral loads at or above the infectious threshold. Moreover, though the rate of mortality was faster in birds with elevated CORT compared with controls, most hosts with elevated CORT survived past the day of peak infectiousness. CORT concentrations just prior to inoculation with WNV and anti-inflammatory cytokine concentrations following viral exposure were predictive of individual duration of infectiousness and the ability to maintain physical performance during infection (i.e. tolerance), revealing putative biomarkers of competence. Collectively, our results suggest that glucocorticoid stress hormones could directly and indirectly mediate the spread of pathogens.

Influence of postnatal glucocorticoids on hippocampal-dependent learning varies with elevation patterns and administration methods.

Recent interest in the lasting effects of early-life stress has expanded to include effects on cognitive performance. An increase in circulating glucocorticoids is induced by stress exposure and glucocorticoid effects on the hippocampus likely underlie many of the cognitive consequences. Here we review studies showing that corticosterone administered to young rats at the conclusion of the stress-hyporesponsiveness period affects later performance in hippocampally-mediated trace eyeblink conditioning. The nature and even direction of these effects varies with the elevation patterns (level, duration, temporal fluctuation) achieved by different administration methods. We present new time course data indicating that constant glucocorticoid elevations generally corresponded with hippocampus-mediated learning deficits, whereas acute, cyclical elevations corresponded with improved initial acquisition. Sensitivity was greater for males than for females. Further, changes in hippocampal neurogenesis paralleled some but not all effects. The findings demonstrate that specific patterns of glucocorticoid elevation produced by different drug administration procedures can have markedly different, sex-specific consequences on basic cognitive performance and underlying hippocampal physiology. Implications of these findings for glucocorticoid medications prescribed in childhood are discussed.

Correlating bacterial shedding with fecal corticosterone levels and serological responses from layer hens experimentally infected with Salmonella Typhimurium.

Salmonella Enteriditis and Salmonella Typhimurium are commonly isolated during egg-related outbreaks of salmonellosis and represent a significant international public health issue. In Australia, Salmonella Typhimurium is the most common serovar identified in egg product related foodborne outbreaks. While a number of studies have investigated Salmonella shedding and host responses to infection, they have been conducted over a short time period. The present study sought to characterise bacterial shedding and host responses to infection in hens infected with only Salmonella Typhimurium or co-infected with both Salmonella Typhimurium and Salmonella Mbandaka over a 16 week period. Salmonella shedding was quantified using the most probable number and qPCR methods and was highly variable over the course of the experiment. On day 1, fecal corticosterone metabolites in birds infected with Salmonella Typhimurium (674.2 ± 109.3 pg/mg) were significantly higher than control (238.0 ± 12.62 pg/mg) or co-infected (175.4 ± 8.58 pg/mg) birds. The onset of lay occurred between weeks 6-8 post-infection (pi) and Fecal corticosterone metabolite (FCM) concentrations increased in both control and co-infected birds. Antibody responses to infection were monitored in both serum and yolk samples. Salmonella Typhimurium specific antibody was lower in co-infected animals than monoinfected animals. Bacterial loads in internal organs were characterised to determine persistence. Spleen, liver and caecal tonsils were positive for bacteria in both groups, indicating that Salmonella was not cleared from the birds and internal organ colonization could serve as a reservoir for continued bacterial shedding.

Ultradian corticosterone pulses balance glutamatergic transmission and synaptic plasticity.

The rodent adrenal hormone corticosterone (CORT) reaches the brain in hourly ultradian pulses, with a steep rise in amplitude before awakening. The impact of a single CORT pulse on glutamatergic transmission is well documented, but it remains poorly understood how consecutive pulses impact on glutamate receptor trafficking and synaptic plasticity. By using high-resolution imaging and electrophysiological approaches, we report that a single pulse of CORT to hippocampal networks causes synaptic enrichment of glutamate receptors and increased responses to spontaneously released glutamatergic vesicles, collectively abrogating the ability to subsequently induce synaptic long-term potentiation. Strikingly, a second pulse of CORT one hour after the first--mimicking ultradian pulses--completely normalizes all aspects of glutamate transmission investigated, restoring the plastic range of the synapse. The effect of the second pulse is precisely timed and depends on a nongenomic glucocorticoid receptor-dependent pathway. This normalizing effect through a sequence of CORT pulses--as seen around awakening--may ensure that hippocampal glutamatergic synapses remain fully responsive and able to encode new stress-related information when daily activities start.

Does corticosterone regulate the onset of breeding in free-living birds?: The CORT-Flexibility Hypothesis and six potential mechanisms for priming corticosteroid function.

For many avian species, the decision to initiate breeding is based on information from a variety of environmental cues, including photoperiod, temperature, food availability, and social interactions. There is evidence that the hormone corticosterone may be involved in delaying the onset of breeding in cases where supplemental cues, such as low food availability and inclement weather, indicate that the environment is not suitable. However, not all studies have found the expected relationships between breeding delays and corticosterone titers. In this review, we present the hypothesis that corticosterone physiology mediates flexibility in breeding initiation (the "CORT-Flexibility Hypothesis"), and propose six possible corticosterone-driven mechanisms in pre-breeding birds that may delay breeding initiation: altering hormone titers, negative feedback regulation, plasma binding globulin concentrations, intracellular receptor concentrations, enzyme activity and interacting hormone systems. Based on the length of the breeding season and species-specific natural history, we also predict variation in corticosterone-regulated pre-breeding flexibility. Although few studies thus far have examined mechanisms beyond plasma hormone titers, the CORT-Flexibility Hypothesis is grounded on a solid foundation of research showing seasonal variation in the physiological stress response and knowledge of physiological mechanisms modulating corticosteroid effects. We propose six possible mechanisms as testable and falsifiable predictions to help clarify the extent of HPA axis regulation of the initiation of breeding.

The stress response is attenuated during inclement weather in parental, but not in pre-parental, Lapland longspurs (Calcarius lapponicus) breeding in the Low Arctic.

Birds breeding at high latitudes can be faced with extreme weather events throughout the breeding season. In response to environmental perturbations, vertebrates activate the hypothalamic-pituitary-adrenal (HPA) axis and synthesize corticosterone, which promotes changes in behavior and physiology to help the animal survive. The parental care hypothesis suggests that the HPA axis activity should be downregulated during the parental stage of breeding to prevent nest abandonment. However, it is unknown what happens to HPA axis activity in response to severe weather at the transition from the pre-parental to parental stages of breeding. We sampled baseline corticosterone levels and the time course of corticosterone elevation over 60min of restraint stress and assessed body condition and fat stores in Lapland longspurs (Calcarius lapponicus) breeding in the Low Arctic in the presence and absence of snowstorms. The results showed that during the pre-parental stage, HPA axis activity was up-regulated in response to snowstorms, with corticosterone levels continuing to increase through 60min of restraint. However, once birds were parental, HPA axis activity was unaffected by snowstorms and levels peaked at 10min. Fat levels and body condition did not change in response to snowstorms but fat levels declined in males during the pre-parental stage. These data suggest that the parental care hypothesis can be applied to severe storm events; parental birds restrained the activity of the HPA axis, likely to focus on the reproductive effort that is already underway, while pre-parental birds greatly upregulated HPA axis activity in response to snowstorms to maximize self-preservation.

Endocrine and neuroendocrine regulation of fathering behavior in birds.

This article is part of a Special Issue "Parental Care". Although paternal care is generally rare among vertebrates, care of eggs and young by male birds is extremely common and may take on a variety of forms across species. Thus, birds provide ample opportunities for investigating both the evolution of and the proximate mechanisms underpinning diverse aspects of fathering behavior. However, significant gaps remain in our understanding of the endocrine and neuroendocrine influences on paternal care in this vertebrate group. In this review, I focus on proximate mechanisms of paternal care in birds. I place an emphasis on specific hormones that vary predictably and/or unpredictably during the parental phase in both captive and wild birds: prolactin and progesterone are generally assumed to enhance paternal care, whereas testosterone and corticosterone are commonly-though not always correctly-assumed to inhibit paternal care. In addition, because endocrine secretions are not the sole mechanistic influence on paternal behavior, I also explore potential roles for certain neuropeptide systems (specifically the oxytocin-vasopressin nonapeptides and gonadotropin inhibitory hormone) and social and experiential factors in influencing paternal behavior in birds. Ultimately, mechanistic control of fathering behavior in birds is complex, and I suggest specific avenues for future research with the goal of narrowing gaps in our understanding of this complexity. Such avenues include (1) experimental studies that carefully consider not only endocrine and neuroendocrine mechanisms of paternal behavior, but also the ecology, phylogenetic history, and social context of focal species; (2) investigations that focus on individual variation in both hormonal and behavioral responses during the parental phase; (3) studies that investigate mechanisms of maternal and paternal care independently, rather than assuming that the mechanistic foundations of care are similar between the sexes; (4) expansion of work on interactions of the neuroendocrine system and fathering behavior to a wider array of paternal behaviors and taxa (e.g., currently, studies of the interactions of testosterone and paternal care largely focus on songbirds, whereas studies of the interactions of corticosterone, prolactin, and paternal care in times of stress focus primarily on seabirds); and (5) more deliberate study of exceptions to commonly held assumptions about hormone-paternal behavior interactions (such as the prevailing assumptions that elevations in androgens and glucocorticoids are universally disruptive to paternal care). Ultimately, investigations that take an intentionally integrative approach to understanding the social, evolutionary, and physiological influences on fathering behavior will make great strides toward refining our understanding of the complex nature by which paternal behavior in birds is regulated.

Seeding Stress Resilience through Inoculation.

Stress is a generalized set of physiological and psychological responses observed when an organism is placed under challenging circumstances. The stress response allows organisms to reattain the equilibrium in face of perturbations. Unfortunately, chronic and/or traumatic exposure to stress frequently overwhelms coping ability of an individual. This is manifested as symptoms affecting emotions and cognition in stress-related mental disorders. Thus environmental interventions that promote resilience in face of stress have much clinical relevance. Focus of the bulk of relevant neurobiological research at present remains on negative aspects of health and psychological outcomes of stress exposure. Yet exposure to the stress itself can promote resilience to subsequent stressful episodes later in the life. This is especially true if the prior stress occurs early in life, is mild in its magnitude, and is controllable by the individual. This articulation has been referred to as "stress inoculation," reminiscent of resilience to the pathology generated through vaccination by attenuated pathogen itself. Using experimental evidence from animal models, this review explores relationship between nature of the "inoculum" stress and subsequent psychological resilience.

Glucocorticoid receptor is required for foetal heart maturation.

Glucocorticoids are vital for the structural and functional maturation of foetal organs, yet excessive foetal exposure is detrimental to adult cardiovascular health. To elucidate the role of glucocorticoid signalling in late-gestation cardiovascular maturation, we have generated mice with conditional disruption of glucocorticoid receptor (GR) in cardiomyocytes and vascular smooth muscle cells using smooth muscle protein 22-driven Cre recombinase (SMGRKO mice) and compared them with mice with global deficiency in GR (GR(-/-)). Echocardiography shows impaired heart function in both SMGRKO and GR(-/-) mice at embryonic day (E)17.5, associated with generalized oedema. Cardiac ultrastructure is markedly disrupted in both SMGRKO and GR(-/-) mice at E17.5, with short, disorganized myofibrils and cardiomyocytes that fail to align in the compact myocardium. Failure to induce critical genes involved in contractile function, calcium handling and energy metabolism underpins this common phenotype. However, although hearts of GR(-/-) mice are smaller, with 22% reduced ventricular volume at E17.5, SMGRKO hearts are normally sized. Moreover, while levels of mRNA encoding atrial natriuretic peptide are reduced in E17.5 GR(-/-) hearts, they are normal in foetal SMGRKO hearts. These data demonstrate that structural, functional and biochemical maturation of the foetal heart is dependent on glucocorticoid signalling within cardiomyocytes and vascular smooth muscle, though some aspects of heart maturation (size, ANP expression) are independent of GR at these key sites.