Neuronal populations and single cells representing learned auditory objects

The neural representations associated with learned auditory behaviours, such as recognizing individuals based on their vocalizations, are not well described. Higher vertebrates learn to recognize complex conspecific vocalizations that comprise sequences of easily identified, naturally occurring auditory objects, which should facilitate the analysis of higher auditory pathways. Here we describe the first example of neurons selective for learned conspecific vocalizations in adult animals--in starlings that have been trained operantly to recognize conspecific songs. The neuronal population is found in a non-primary forebrain auditory region, exhibits increased responses to the set of learned songs compared with novel songs, and shows differential responses to categories of learned songs based on recognition training contingencies. Within the population, many cells respond highly selectively to a subset of specific motifs (acoustic objects) present only in the learned songs. Such neuronal selectivity may contribute to song-recognition behaviour, which in starlings is sensitive to motif identity. In this system, both top-down and bottom-up processes may modify the tuning properties of neurons during recognition learning, giving rise to plastic representations of behaviourally meaningful auditory objects.     

p53 mutant mice that display early ageing-associated phenotypes.

The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.     

Developmental plasticity and human health

Many plants and animals are capable of developing in a variety of ways, forming characteristics that are well adapted to the environments in which they are likely to live. In adverse circumstances, for example, small size and slow metabolism can facilitate survival, whereas larger size and more rapid metabolism have advantages for reproductive success when resources are more abundant. Often these characteristics are induced in early life or are even set by cues to which their parents or grandparents were exposed. Individuals developmentally adapted to one environment may, however, be at risk when exposed to another when they are older. The biological evidence may be relevant to the understanding of human development and susceptibility to disease. As the nutritional state of many human mothers has improved around the world, the characteristics of their offspring--such as body size and metabolism--have also changed. Responsiveness to their mothers' condition before birth may generally prepare individuals so that they are best suited to the environment forecast by cues available in early life. Paradoxically, however, rapid improvements in nutrition and other environmental conditions may have damaging effects on the health of those people whose parents and grandparents lived in impoverished conditions. A fuller understanding of patterns of human plasticity in response to early nutrition and other environmental factors will have implications for the administration of public health.     

Eastern Pacific cooling and Atlantic overturning circulation during the last deglaciation

Surface ocean conditions in the equatorial Pacific Ocean could hold the clue to whether millennial-scale global climate change during glacial times was initiated through tropical ocean-atmosphere feedbacks or by changes in the Atlantic thermohaline circulation. North Atlantic cold periods during Heinrich events and millennial-scale cold events (stadials) have been linked with climatic changes in the tropical Atlantic Ocean and South America, as well as the Indian and East Asian monsoon systems, but not with tropical Pacific sea surface temperatures. Here we present a high-resolution record of sea surface temperatures in the eastern tropical Pacific derived from alkenone unsaturation measurements. Our data show a temperature drop of approximately 1 degrees C, synchronous (within dating uncertainties) with the shutdown of the Atlantic meridional overturning circulation during Heinrich event 1, and a smaller temperature drop of approximately 0.5 degrees C synchronous with the smaller reduction in the overturning circulation during the Younger Dryas event. Both cold events coincide with maxima in surface ocean productivity as inferred from 230Th-normalized carbon burial fluxes, suggesting increased upwelling at the time. From the concurrence of equatorial Pacific cooling with the two North Atlantic cold periods during deglaciation, we conclude that these millennial-scale climate changes were probably driven by a reorganization of the oceans' thermohaline circulation, although possibly amplified by tropical ocean-atmosphere interaction as suggested before.     

Oxysterols direct B-cell migration through EBI2

EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection. Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism. The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors. Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7α,25-dihydroxycholesterol (OHC), with a dissociation constant of 450?pM for EBI2. In vitro, 7α,25-OHC stimulated the migration of EBI2-expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells. In vivo, EBI2-deficient B cells or normal B cells desensitized by 7α,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7α,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7α,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules.