Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT(1A) or 5-HT(1B) receptor knockout mice

Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT(1A) or 5-HT(1B) knockout and wild-type mice of the 129/Sv strain. In 5-HT(1A) knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT(1A) knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT(1B) knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT(1B) knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts.     

Partially unfolded species populated during equilibrium denaturation of the beta-sheet protein Y74W apo-pseudoazurin

Apo-pseudoazurin is a single domain cupredoxin. We have engineered a mutant in which a unique tryptophan replaces the tyrosine residue found in the tyrosine corner of this Greek key protein, a region that has been proposed to have an important role in folding. Equilibrium denaturation of Y74W apo-pseudoazurin demonstrated multistate unfolding in urea (pH 7.0, 0.5 M Na(2)SO(4) at 15 degrees C), in which one or more partially folded species are populated in 4. 3 M urea. Using a variety of biophysical techniques, we show that these species, on average, have lost a substantial portion of the native secondary structure, lack fixed tertiary packing involving tryptophan and tyrosine residues, are less compact than the native state as determined by fluorescence lifetimes and time-resolved anisotropy, but retain significant residual structure involving the trytophan residue. Peptides ranging in length from 11 to 30 residues encompassing this region, however, did not contain detectable nonrandom structure, suggesting that long-range interactions are important for stabilizing the equilibrium partially unfolded species in the intact protein. On the basis of these results, we suggest that the equilibrium denaturation of Y74W apo-pseudoazurin generates one or more partially unfolded species that are globally collapsed and retain elements of the native structure involving the newly introduced tryptophan residue. We speculate on the role of such intermediates in the generation of the complex Greek key fold.     

Infectious disease,behavioural flexibility and the evolution of culture in primates

Culturally transmitted traits are observed in a wide array of animal species, yet we understand little about the costs of the behavioural patterns that underlie culture, such as innovation and social learning. We propose that infectious diseases are a significant cost associated with cultural transmission. We investigated two hypotheses that may explain such a connection: that social learning and exploratory behaviours (specifically, innovation and extractive foraging) either compensate for existing infection or increase exposure to infectious agents. We used Bayesian comparative methods, controlling for sampling effort, body mass, group size, geographical range size, terrestriality, latitude and phylogenetic uncertainty. Across 127 primate species, we found a positive association between pathogen richness and rates of innovation, extractive foraging and social learning. This relationship was driven by two independent phenomena: socially contagious diseases were positively associated with rates of social learning, and environmentally transmitted diseases were positively associated with rates of exploration. Because higher pathogen burdens can contribute to morbidity and mortality, we propose that parasitism is a significant cost associated with the behavioural patterns that underpin culture, and that increased pathogen exposure is likely to have played an important role in the evolution of culture in both non-human primates and humans.     

Transplantation of young ovaries restored cardioprotective influence in postreproductive-aged mice

The female cardioprotective advantage, present in mammals of a reproductively competent age, is lost during the transition to a postreproductive state. The role of reproductive hormones in this transition is most evident in women with premature ovarian failure, where reduced estrogen production has been associated with an increased incidence of early death from cardiovascular disease. Previously, we reported that postreproductive-aged mice that received young ovaries displayed an increased life span. Subsequent histopathological analysis suggested the presence of a cardioprotective effect associated with the restoration of ovarian influence. This restoration in postreproductive-aged mice produced a sharp decrease in evidence of significant cardiomyopathy at death, compared with sham-transplanted mice (36.0% vs. 73.3%, respectively). Within the intact transplant group, evidence of cardiomyopathy at death was decreased in mice that were reproductively cycling at the time of transplant, compared with acyclic mice (26.7% vs. 50.0%, respectively). This observation reflects the importance of timing in restoration of ovarian influence in this study. Transplantation of young ovaries to intact, postreproductive-aged female mice provided significant, long-term restoration of a cardioprotective benefit, similar to that previously present during a reproductively competent age. In these mice, restoration of ovarian influence through ovarian transplantation may, in effect, have postponed the advance of age-associated cardiomyopathy to a point where the disease did not reach a clinically relevant threshold during the lifetime of the recipients. These results offer support for previous clinical observations suggesting that hormone replacement therapy can produce divergent results if initiated during the perimenopausal period, compared with the postmenopausal ages.     

Individual consistency and flexibility in human social information use

Copying others appears to be a cost-effective way of obtaining adaptive information, particularly when flexibly employed. However, adult humans differ considerably in their propensity to use information from others, even when this ‘social information’ is beneficial, raising the possibility that stable individual differences constrain flexibility in social information use. We used two dissimilar decision-making computer games to investigate whether individuals flexibly adjusted their use of social information to current conditions or whether they valued social information similarly in both games. Participants also completed established personality questionnaires. We found that participants demonstrated considerable flexibility, adjusting social information use to current conditions. In particular, individuals employed a ‘copy-when-uncertain’ social learning strategy, supporting a core, but untested, assumption of influential theoretical models of cultural transmission. Moreover, participants adjusted the amount invested in their decision based on the perceived reliability of personally gathered information combined with the available social information. However, despite this strategic flexibility, participants also exhibited consistent individual differences in their propensities to use and value social information. Moreover, individuals who favoured social information self-reported as more collectivist than others. We discuss the implications of our results for social information use and cultural transmission.     

Meningoencephalitis Due to Listeria monocytogenes in a Pregnant Rhesus Macaque (Macaca mulatta)

We here report a spontaneous case of meningoencephalitis due to Listeria monocytogenes in an adult primiparous rhesus macaque (Macaca mulatta) during an outbreak of listeriosis in an outdoor enclosure. Clinical signs included tremors, abnormal posture, and altered mental status. Hematology and analyses of cerebrospinal fluid were consistent with bacterial infection. Pure cultures of L. monocytogenes were recovered from the placenta–abortus, cerebrospinal fluid, and brain tissue. The macaque did not respond to treatment and was euthanized. Histopathologic examination of the brain revealed acute meningoencephalitis. This case represents an unusual clinical and pathologic presentation of listeriosis in a nonhuman primate in which the dam and fetus both were affected.Listeria monocytogenes is a ubiquitous, facultative anaerobic, intracellular gram-positive coccobacillus. This bacterium is found in diverse environments including (but not limited to) soil, water, plant matter, food items, and the intestinal tract of mammalian hosts.^15,18 The organism is environmentally resistant, being able to survive in dried media for several months and in moist soil for up to a year.¹⁵ L. monocytogenes is the causative agent of listeriosis, a bacterial infection that has a worldwide distribution and affects a wide range of mammals and birds, including human beings.In people, L. monocytogenes is a relatively uncommon foodborne pathogen; its abilities to survive food processing and grow in cold conditions allow it to persist in appropriately stored or refrigerated foods.² In people, listeriosis occurs both sporadically and as large outbreaks,¹⁸ generally comprising 3 separate syndromes with clinical manifestations ranging from mild to life-threatening.³⁵ The most common form is seen in immunocompetent, nonpregnant adults as a febrile gastroenteritis.^2,18,21 The other 2 forms, which occur in fetuses and immunocompromised patients, are more severe.^19,21 In pregnant women, maternal listeriosis is asymptomatic or causes mild, flu-like symptoms, but the bacterium''s ability to cross the placenta and the blood–brain barrier of the fetus results in neonatal septicemia, meningitis, abortion, and stillbirth.¹⁶ In elderly and immunocompromised patients, septicemia and meningoencephalitis are life-threatening manifestations of literiosis.²⁶ The worldwide case fatality rate varies widely among countries, sometimes exceeding 50% despite what is considered to be appropriate antibiotic therapy.¹⁸ In 2009, the Centers for Disease Control reported 524 cases of listeriosis in the United States, which were associated with a 19% resulting in death.⁴In ruminants, listeriosis is also known as ‘circling disease’ and ‘silage disease.’^8,18,21 Foodborne infection with L. monocytogenes is well described, and many studies have shown that spoiled silage may be a source of listeria outbreaks.^8,18 Rhombencephalitis and diffuse meningoencephalitis are the most recognized forms of the infection in ruminants; sporadic abortion is reported also.²² Clinical signs of listeria encephalitis in cattle, sheep, and goats are characterized by unilateral or bilateral brainstem dysfunction and cranial nerve deficits. In sheep and goats, the course of the disease is acute, but the disease in cattle has a more chronic progression, with neurologic manifestations that can last 4 to 14 d.^1,22In rabbits, infection with L. monocytogenes is characterized by abortion in pregnant does or sudden death; neurologic signs are rare.¹ In poultry, an acute form with septicemia and sudden death occurs in adults, in contrast to a subacute–chronic form, with encephalitis, in the young.⁶The literature on L. monocytogenes in nonhuman primates is sparse^5,11,17,33 and more recently limited to experimental infection of pregnant animals. In pregnant rhesus macaques (Macaca mulatta), experimental infection during the last trimester of gestation can cause stillbirth with no other clinical signs.^23,24 In our colony, however, infection with L. monocytogenes is endemic. Every year, several spontaneous abortions or stillbirths in our outdoor colony are caused by infection of the dam with this organism. Culture of L. monocytogenes from both the abortus–fetus and placenta are well documented. As described in the literature,^23,24 the dams in our colony do not demonstrate any clinical signs prior to the abortion or stillbirth.During the winter to spring of 2011, one of our outdoor housing enclosures experienced an outbreak of listeriosis. This outside corral housed 100 rhesus macaques in a social group that included 42 reproductive females. Of these reproductive females, 37 (88%) were confirmed pregnant by abdominal palpation or ultrasonography or both. From January 2011 to May 2011, 19 (51%) stillbirths and neonatal deaths (in infants younger than 3 d) were reported in this enclosure; 13 (68%) of these tissues (placenta, 3; fetal lungs, 8; fetal peritoneum, 2) were culture-positive for L. monocytogenes. In all cases except the one presented here, the dam did not manifest any clinical signs prior to or after the delivery of a stillborn or premature birth with neonatal death.Here we describe an unusual case of listeriosis in a primiparous pregnant female rhesus macaque that manifested severe neurologic impairment and intrautero death of the fetus.     

Polysialic acid, a glycan with highly restricted expression, is found on human and murine leukocytes and modulates immune responses

Polysialic acid (polySia) is a large glycan with restricted expression, typically found attached to the protein scaffold neural cell adhesion molecule (NCAM). PolySia is best known for its proposed role in modulating neuronal development. Its presence and potential functions outside the nervous systems are essentially unexplored. Herein we show the expression of polySia on hematopoietic progenitor cells, and demonstrate a role for this glycan in immune response using both acute inflammatory and tumor models. Specifically, we found that human NK cells modulate expression of NCAM and the degree of polymerization of its polySia glycans according to activation state. This contrasts with the mouse, where polySia and NCAM expression are restricted to multipotent hematopoietic progenitors and cells developing along a myeloid lineage. Sialyltransferase 8Sia IV(-/-) mice, which lacked polySia expression in the immune compartment, demonstrated an increased contact hypersensitivity response and decreased control of tumor growth as compared with wild-type animals. This is the first demonstration of polySia expression and regulation on myeloid cells, and the results in animal models suggest a role for polySia in immune regulation.