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• A high-fat diet impairs learning and memory in male mice and increases anxiety-like behavior across sexes and ages. • A high-fat diet exacerbates systemic inflammation across age and sex in mice and induces microglia in aged male mice. • Hypothalamic proteome reveals metabolic stress induced by a high-fat diet in aged male mice. Aging and age-related diseases are associated with cellular stress, metabolic imbalance, oxidative stress, and neuroinflammation, accompanied by cognitive impairment. Lifestyle factors such as diet, sleep fragmentation, and stress can potentiate damaging cellular cascades and lead to an acceleration of brain aging and cognitive impairment. High-fat diet (HFD) has been associated with obesity, metabolic disorders like diabetes, and cardiovascular disease. HFD also induces neuroinflammation, impairs learning and memory, and may increase anxiety-like behavior. Effects of a HFD may also vary between sexes. The interaction between Age- and Sex- and Diet-related changes in neuroinflammation and cognitive function is an important and poorly understood area of research. This study was designed to examine the effects of HFD on neuroinflammation, behavior, and neurodegeneration in mice in the context of aging or sex differences. In a series of studies, young (2–3 months) or old (12–13 months) C57BL/6J male mice or young male and female C57Bl/6J mice were fed either a standard diet (SD) or a HFD for 5–6 months. Behavior was assessed in Activity Chamber, Y-maze, Novel Place Recognition, Novel Object Recognition, Elevated Plus Maze, Open Field, Morris Water Maze, and Fear Conditioning. Post-mortem analyses assessed a panel of inflammatory markers in the plasma and hippocampus. Additionally, proteomic analysis of the hypothalamus, neurodegeneration, neuroinflammation in the locus coeruleus, and neuroinflammation in the hippocampus were assessed in a subset of young and aged male mice. We show that HFD increased body weight and decreased locomotor activity across groups compared to control mice fed a SD. HFD altered anxiety-related exploratory behavior. HFD impaired spatial learning and recall in young male mice and impaired recall in cued fear conditioning in young and aged male mice, with no effects on spatial learning or fear conditioning in young female mice. Effects of Age and Sex were observed on neuroinflammatory cytokines, with only limited effects of HFD. HFD had a more significant impact on systemic inflammation in plasma across age and sex. Aged male mice had induction of microglial immunoreactivity in both the locus coeruleus (LC) and hippocampus an effect that HFD exacerbated in the hippocampal CA1 region. Proteomic analysis of the hypothalamus revealed changes in pathways related to metabolism and neurodegeneration with both aging and HFD in male mice. Our findings suggest that HFD induces widespread systemic inflammation and limited neuroinflammation. In addition, HFD alters exploratory behavior in male and female mice, and impairs learning and memory in male mice. These results provide valuable insight into the impact of diet on cognition and aging pathophysiology. [ABSTRACT FROM AUTHOR]

When social animals forage together, they may engage in frequency-dependent strategies either as producers, those who acquire food with their own energy, or as scroungers, those who feed on what the producers discover. An individual's choice of strategy may depend on the frequency of strategies within the group, or it may depend on the individual's own traits. Most of our understanding of producer–scrounger relationships comes from highly social species, but we may gain different insights by studying less social species. We used novel puzzle box experiments to study social foraging relationships and identify the traits associated with strategy choice in facultatively social yellow-bellied marmots, Marmota flaviventer. We found that marmots had consistent strategies as either producers or scroungers. Furthermore, several individuals specialized as scroungers, following the producers to the puzzle box before other scroungers. However, their roles were only associated with sex (males were more likely to produce), and not with age, boldness or dominance rank. Marmots' lack of trait-regulated foraging roles may be associated with their relatively abundant and not-entirely defensible food, or may emerge from their lack of obligate social structure. We discuss how multiple factors may explain variation in social foraging behaviour. • Producer–scrounger relationships are often studied in highly social species. • We used novel puzzle box experiments to study them in a facultatively social marmot. • Marmots had consistent strategies as either producers or scroungers. • Sex, but not age, boldness or dominance rank, explained production. • Producer–scrounger relationships may be meaningfully studied in less social species. [ABSTRACT FROM AUTHOR]

It is thought that the elasmobranch corticosteroid hormone 1α-hydroxycorticosterone (1α-B) functions as both a glucocorticoid (GC) and mineralocorticoid (MC). Classical antinatriuretic MC activities would run counter to the osmoregulatory strategy of euryhaline elasmobranchs acclimating to fresh water (FW). Therefore we hypothesize that FW acclimation will be accompanied by a decrease in plasma corticosteroids in these animals. However, events that activate the “fight-or-flight” response could mask changes associated with acclimation to lower salinities. To better define the MC role of corticosteroids in elasmobranchs, we designed a transfer system that allows the acclimation of Atlantic stingrays ( Dasyatis sabina ) from seawater (SW) to FW over 12 h while minimizing other extraneous stressors. Blood and interrenal glands were sampled from one group of stingrays 24 h after FW transfer, while another group was sampled two weeks after FW transfer. Two other groups served as mock-transfer controls in that they were treated and sampled in the same way, but remained in SW for the entire period. Plasma corticosteroids, osmolality, chloride, and urea were significantly lower in FW-acclimated stingrays (compared to mock-transfer stingrays) 24 h after FW transfer. This pattern remained after two weeks in FW, with the exception that plasma corticosteroids returned to pre-acclimation levels. There were no significant differences between experimental groups in interrenal levels of mRNAs encoding key steroidogenic proteins (steroidogenic acute regulatory protein and cholesterol side chain cleavage enzyme). Temporally decreased corticosteroid levels during FW acclimation are consistent with the unique strategy of euryhaline elasmobranchs, whereby lower plasma osmolality is maintained in FW vs. SW environments to reduce hydromineral gradients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Metallic airway stents are often used in the management of central airway malignancies. The presence of a metallic foreign body may affect radiation dose in tissue. We studied the effect of a metallic airway stent on radiation dose delivery in a phantom and an in vivo porcine model. Methods: A metallic tracheal stent was fitted onto a support in a water phantom. Point dosimeters were positioned in the phantom around the support and the stent. Irradiation was then performed on a linear accelerator with and without the stent. Metallic tracheal stents were deployed in the trachea of three pigs. Dosimeters were implanted in the tissues near (Group 1) and away (Group 2) from the stent. The pigs were then irradiated, and the dose perturbation factor was calculated by comparing the actual dose detected by the dosimeters versus the planned dose. Results: The difference in the dose detected by the dosimeters and the planned dose ranged from 1.8% to 6.1% for the phantom with the stent and 0%–5.3% for the phantom without the stent. These values were largely within the manufacturer's specified error of 5%. No significant difference was observed in the dose perturbation factor for Group 1 and Group 2 dosimeters (0.836 ± 0.058 versus 0.877 ± 0.088, P = 0.220) in all the three pigs. Conclusions: Metallic airway stents do not significantly affect radiation dose in the airway and surrounding tissues in a phantom and porcine model. Radiation treatment planning systems can account for the presence of the stent. External beam radiation can be delivered without concern for significant dose perturbation. [Copyright &y& Elsevier]

Highlight: [•] In T. gondii infected rats, examining cyst distribution, microglia and behavior revealed altered behavior by 3weeks, only in rats with cysts in specific brain regions. [Copyright &y& Elsevier]

Abstract: The rate-limiting and regulated step in steroidogenesis, the conversion of cholesterol to pregnenolone, is facilitated by the steroidogenic acute regulatory protein (StAR) and cytochrome P450 cholesterol side-chain cleavage (P450scc). We have isolated cDNAs encoding StAR and P450scc from the Atlantic stingray, Dasyatis sabina, and characterized the steroidogenic activity of the encoded proteins using a heterologous expression system. Green monkey kidney (COS-1) cells cotransfected with D. sabina StAR and human P450scc/adrenodoxin reductase/adrenodoxin fusion (F2) constructs produced significantly more pregnenolone than cells transfected with the F2 construct alone. COS-1 cells transfected with a modified F2 construct (F2DS) in which human P450scc is replaced by D. sabina P450scc had higher rates than cells transfected with D. sabina P450scc alone. In other vertebrates, the stress peptide adrenocorticotropic hormone (ACTH) elicits its effects on corticosteroidogenesis in part through regulation of StAR and P450scc mRNAs. In vitro incubation of D. sabina interrenal tissue with porcine ACTH significantly increased intracellular cAMP and corticosteroid production. As demonstrated by quantitative PCR, ACTH also induced significant increases in mRNA abundance of both StAR and P450scc. Our results suggest that, as in higher vertebrates, chronic ACTH-induced glucocorticoid synthesis in elasmobranchs is mediated by regulation of primary steroidogenic mRNAs. This study is the first to demonstrate steroidogenic activity of an elasmobranch P450scc protein and express a composite elasmobranch steroidogenic pathway in a heterologous cell line. Also, the regulation of StAR and P450scc mRNAs has not previously been demonstrated in elasmobranch fishes. [Copyright &y& Elsevier]

Abstract: The steroidogenic acute regulatory protein (StAR), a member of the StAR-related lipid transfer domain (START) family, is critical to regulated steroidogenesis in vertebrates. We have isolated a cDNA encoding StAR from a well-studied model of teleost physiology, the Atlantic croaker Micropogonias undulatus. This cDNA (1204 nucleotides total length) contains an open reading frame of 858 nucleotides encoding a protein of 286 amino acids. Molecular phylogenetic analysis indicates the putative Atlantic croaker StAR protein is more closely related to StAR proteins (62–85% identity) than to the related START protein MLN-64 (28–31% identity). Green monkey kidney cells (COS-1) cotransfected with Atlantic croaker StAR and human cholesterol side chain cleavage (SCC) expression constructs are able to produce significantly more pregnenolone than cells transfected with SCC alone. StAR mRNA is detected in the Atlantic croaker head kidney by reverse transcriptase-polymerase chain reaction (RT-PCR) and in the kidney and hypothalamus in some individuals. Gonadal StAR gene expression is below the level of detection by RT-PCR in most individuals, but can be detected using fluorescent probes in quantitative RT-PCR. StAR mRNA is not detected in the Atlantic croaker brain. Six hour in vitro treatment of Atlantic croaker ovarian follicles with human chorionic gonadotropin (hCG) is insufficient to significantly alter StAR mRNA levels; however, 24h hCG treatment induces StAR mRNA levels 17-fold over untreated controls. Neither 6 nor 24h treatment with hCG significantly alters StAR mRNA levels in Atlantic croaker testicular minces. Likewise, 6h in vitro treatment with estradiol, testosterone or the maturation-inducing steroid 17,20β,21-trihydroxy-4-pregnen-3-one is without effect on gonadal StAR mRNA levels. [Copyright &y& Elsevier]

Abstract: Peripheral immune activation results in physiological and behavioral responses including changes in the level of behavioral arousal. One mechanism through which immune activation can influence these responses is via actions on brainstem neuromodulatory systems, including serotonergic systems. To investigate the effects of peripheral immune activation on serotonergic systems and behavior, and the potential role of prostanoids in mediating these effects, we compared the effects of intraperitoneal injections of lipopolysaccharide (LPS), in the presence or absence of the cyclooxygenase inhibitor indomethacin, on total plasma l-tryptophan concentrations, Fos expression in subdivisions of the brainstem raphe complex, and home cage behaviors. Peripheral LPS administration had no effect on total plasma l-tryptophan concentrations but increased Fos expression in serotonergic neurons selectively within the interfascicular (DRI) and ventrolateral (DRVL) subdivisions of the dorsal raphe nucleus 4h following treatment; pretreatment with indomethacin blocked the LPS-induced increases in Fos expression within the DRI and DRVL. Peripheral LPS administration decreased measures of behavioral arousal including locomotion, rearing, climbing, and self-grooming; LPS administration had no effect on these behaviors in mice pretreated with indomethacin. The indomethacin-sensitive effects of LPS on Fos expression in the DRI may be due to selective activation of Type II serotonergic neurons which are largely restricted to the DRI region and have unique afferent regulatory mechanisms and behavioral correlates. Further studies of the effects of peripheral immune activation on DRI serotonergic systems may lead to a better understanding of the relationships among immune function, serotonergic systems, and behavior. [Copyright &y& Elsevier]

Abstract: Neuroendocrine factors that produce species differences in aggregation behavior (“sociality”) are largely unknown, although relevant studies should yield important insights into mechanisms of affiliation and social evolution. We here focused on five species in the avian family Estrildidae that differ selectively in their species-typical group sizes (all species are monogamous and occupy similar habitats). These include two highly gregarious species that independently evolved coloniality; two territorial species that independently evolved territoriality; and an intermediate, modestly gregarious species that is a sympatric congener of one of the territorial species. Using males and females of each species, we examined binding sites for 125I-vasoactive intestinal polypeptide (VIP), 125I-sauvagine (SG; a ligand for corticotropin releasing factor, CRF, receptors) and a linear 125I-V1a vasopressin antagonist (to localize receptors for vasotocin, VT). VIP, CRF and VT are neuropeptides that influence stress, anxiety and/or various social behaviors. For numerous areas (particularly within the septal complex), binding densities in the territorial species differed significantly from binding in the more gregarious species, and in most of these cases, binding densities for the moderately gregarious species were either comparable to the two colonial species or were intermediate to the territorial and colonial species. Such patterns were observed for 125I-VIP binding in the medial bed nucleus of the stria terminalis, medial septum, septohippocampal septum, and subpallial zones of the lateral septum; for 125I-SG binding in the infundibular hypothalamus, and lateral and medial divisions of the ventromedial hypothalamus; and for the linear 125I-V1a antagonist in the medial septum, and the pallial and subpallial zones of the caudal lateral septum. With the exception of 125I-SG binding in the infundibular hypothalamus, binding densitites are positively related to sociality. [Copyright &y& Elsevier]

Abstract: Sequence analysis of the murine gamma-herpesvirus 68 (γHV68) genome previously identified several open reading frames (ORFs) located at the left end of the viral genome that do not share homology with other known herpesvirus or cellular genes. Here, we show that one of these ORFs, M4, encodes a secreted glycoprotein that influences the establishment of splenic latency at early times post-infection. We generated a mutant virus containing a premature translation termination codon in the M4 ORF (M4.STOP), and demonstrated that this mutant virus replicates in vitro equivalent to wild type and marker rescue (M4.MR) viruses. M4.STOP was also capable of high-titer lytic replication in vivo, but at 16 days post-infection the establishment of latency in the spleen was significantly impaired. The defect in the establishment of splenic latency was apparent following either intranasal or intraperitoneal inoculation. In contrast, the M4.STOP mutant did not exhibit a defect in the establishment of latency in peritoneal cells. These results suggest that M4 mediates an extracellular host-pathogen interaction that impacts the establishment of latent infection in the spleen, but not the peritoneum. [Copyright &y& Elsevier]

The present experiments were conducted to determine (1) which basal forebrain regions and/or their peptidergic components are responsive to social challenge and nonsocial stress, and (2) the influence of an arginine vasopressin V1 antagonist (AVPa) on these responses. Experiments were conducted in wild-caught male song sparrows (Melospiza melodia) that were housed on seminatural territories (field-based flight cages). Subjects were each fitted with a chronic guide cannula directed at the lateral ventricle and exposed to one of five conditions before sacrifice and histochemistry: saline + simulated territorial intrusion (STI; consisting of song playback and presentation of a caged conspecific male), AVPa + STI, saline + empty cage, AVPa + empty cage, unhandled. Two tissue series were prepared and immunofluorescently double-labeled for ZENK (egr-1) protein and either arginine vasotocin (AVT; avian homologue of AVP) or corticotropin releasing factor (CRF). The results indicate that the neuronal populations that are sensitive to nonsocial stress (capture, handling and infusion) and STI are at least partially segregated. Increases in ZENK-immunoreactive (-ir) nuclei following handling and infusion were observed in a large number of areas, whereas neural responses that were specific to STI were more limited. However, multiple areas showed responses to both handling and STI. AVPa infusions significantly reduced or eliminated most experimental increases in ZENK-ir, suggesting a broad role for endogenous AVT in the modulation of baseline activity and/or stress responsivity, and a much more limited role in the specific response to social challenge. Particular attention is given to the numerous zones of the lateral septum (LS), which are differentially responsive to handling, STI, and V1-like receptor blockade. These data suggest that septal AVT modulates neural responses to general stressors, not social stimuli specifically. Thus, species differences in septal AVT function (as previously described in songbirds) likely reflect differences in the relationship of stress or anxiety to species-specific behaviors, or to behavior in species-typical contexts. [Copyright &y& Elsevier]

Adrenergic systems regulate both cognitive function and immune function. The primary source of adrenergic signaling in the brain is norepinephrine (NE) neurons of the locus coeruleus (LC), which are vulnerable to age-related degeneration and are one of the earliest sites of pathology and degeneration in neurodegenerative disorders such as Alzheimer's Disease (AD). Loss of adrenergic tone may potentiate neuroinflammation both in aging and neurodegenerative conditions. Importantly, beta-blockers (beta-adrenergic antagonists) are a common treatment for hypertension, co-morbid with aging, and may further exacerbate neuroinflammation associated with loss of adrenergic tone in the central nervous system (CNS). The present studies were designed to both examine proinflammatory consequences of beta-blocker administration in an acute lipopolysaccharide (LPS) model as well as to examine chronic effects of beta-blocker administration on neuroinflammation and behavior in an amyloid-beta protein precursor (APP) mouse model of AD. We provide evidence for robust potentiation of peripheral inflammation with 4 different beta-blockers in an acute model of LPS. However, beta-blockers did not potentiate CNS inflammation in this model. Notably, in this same model, the genetic knockdown of either beta1- or beta2-adrenergic receptors in microglia did potentiate CNS inflammation. Furthermore, in an APP mouse model of amyloid pathology, chronic beta-blocker administration did potentiate CNS inflammation. The beta-blocker, metoprolol, also induced markers of phagocytosis and impaired cognitive behavior in both wild-type and APP mice. Given the induction of markers of phagocytosis in vivo , we examined phagocytosis of synaptosomes in an in vitro primary microglia culture and showed that beta-blockers enhanced whereas beta-adrenergic agonists inhibited phagocytosis of synaptosomes. In conclusion, beta-blockers potentiated inflammation peripherally in a systemic model of inflammation and centrally in an amyloidosis model of neuroinflammation. Additionally, beta-blockers impaired learning and memory and modulated synaptic phagocytosis with implications for synaptic degeneration. These findings warrant further consideration of the proinflammatory consequences of chronic beta-blocker administration, which are not restricted to the periphery in patients with neurodegenerative disorders. • Beta-blockers potentiate peripheral inflammation following systemic LPS. • Beta-blockers potentiate neuroinflammation in a mouse model of amyloidosis. • Beta-blockers potentiate microglial phagocytosis of synaptosomes in vitro. [ABSTRACT FROM AUTHOR]

Abstract: The ability to sense and respond appropriately to increases in ambient and body temperatures is critical for the survival of all animals. Although evidence suggests that brain serotonergic systems play a role in thermoregulation, including thermoregulatory cooling, evidence for activation of brainstem serotonergic neurons in vivo, in unanesthetized animals, during heat exposure is lacking. In this experiment we tested the hypothesis that populations of serotonergic neurons in the midbrain and medullary raphe complex are activated following exposure to warm ambient temperature. Rats were exposed to an incubation chamber at either warm ambient temperature (37°C) or room temperature (RT; 23°C) for 105min. Brains then were removed and processed for immunohistochemical detection of the protein product of the immediate-early gene c-fos (as a marker of neuronal activation) and tryptophan hydroxylase (as a marker of serotonergic neurons). Exposure to warm ambient temperature increased body temperature and c-Fos expression in topographically organized populations of serotonergic neurons in the dorsal raphe nucleus. Activation of the dorsal raphe nucleus serotonergic system was positively correlated with body temperature following exposure to the incubation chamber. In the medulla, exposure to warm ambient temperature, compared with exposure to RT, decreased c-Fos expression in serotonergic neurons in the raphe pallidus nucleus and in non-serotonergic cells in the rostral ventrolateral medulla. Together, these results provide evidence for multiple but anatomically discrete thermosensitive serotonergic systems that may have implications for the regulation of body temperature, as well as, via projections to forebrain targets, cognitive and affective functions. [ABSTRACT FROM AUTHOR]

Sharks and rays are popular species used in wildlife ecotourism and aquariums to educate the public on the behavior, ecology and conservation challenges of elasmobranchs. To understand long-term physiological health and welfare under varying social and husbandry conditions, we developed and validated an enzyme immunoassay (EIA) to measure stress/ionoregulatory hormones in managed and semi-free range southern rays ( Hypanus americanus ). Banked serum and interrenal samples from 27 female rays managed at Disney’s The Seas with Nemo and Friends® and Castaway Cay were used to evaluate measurement of 1α-hydroxycorticosterone (1αOHB) relative to corticosterone (B). Although commercial EIAs are available for B, those tested exhibit only low relative cross-reactivity to 1αOHB (3–5%). To improve measurement of 1αOHB, we developed a monoclonal antibody using a synthesized 1αOHB-derivative for evaluation using high-performance liquid chromatography (HPLC) and EIA. Relative displacements of cross-reactant compounds showed that the antibody had good sensitivity for the target antigen 1αOHB, and low sensitivity to related steroids (desoxycorticosterone and B), but greater sensitivity to 11-dehydrocorticosterone. Tests of competitive vs. noncompetitive EIA formats, reagent titration, and incubation times of the antibody and conjugate were used to optimize sensitivity, repeatability and precision of measured 1αOHB in standards and samples (4 ng/ml, 90% binding). Tests of sample pre-treatment (pH adjustment) and extraction with varying solvent polarity were used to optimize measurement of 1αOHB in <1 ml (serum) or 1 g (interrenal) samples. HPLC analysis revealed the 1αOHB EIA to be superior for measurement of 1αOHB compared to use of a B EIA with or without HPLC fractioning. Results may prove useful for extrapolation to guide best practices for 1αOHB measurement in other elasmobranch species. Improved measurement of stress/ionoregulatory hormones in sharks and rays will be important for many aspects of collection, transport, medical treatment in aquaria and conservation management of these charismatic and ecologically important species. [ABSTRACT FROM AUTHOR]