Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Transcriptional control of the multi-drug transporter ABCB1 by transcription factor Sp3 in different human tissues

The ATP-binding cassette (ABC) transporter ABCB1, encoded by the multidrug resistance gene MDR1, is expressed on brain microvascular endothelium and several types of epithelium, but not on endothelia outside the CNS. It is an essential component of the blood-brain barrier. The aim of this study was to identify cell-specific controls on the transcription of MDR1 in human brain endothelium. Reporter assays identified a region of 500bp around the transcription start site that was optimally active in brain endothelium. Chromatin immunoprecipitation identified Sp3 and TFIID associated with this region and EMSA (electrophoretic mobility shift assays) confirmed that Sp3 binds preferentially to an Sp-target site (GC-box) on the MDR1 promoter in brain endothelium. This result contrasts with findings in other cell types and with the colon carcinoma line Caco-2, in which Sp1 preferentially associates with the MDR1 promoter. Differences in MDR1 transcriptional control between brain endothelium and Caco-2 could not be explained by the relative abundance of Sp1:Sp3 nor by the ratio of Sp3 variants, because activating variants of Sp3 were present in both cell types. However differential binding of other transcription factors was also detected in two additional upstream regions of the MDR1 promoter. Identification of cell-specific controls on the transcription of MDR1 indicates that it may be possible to modulate multi-drug resistance on tumours, while leaving the blood brain barrier intact

On the Origin and Trigger of the Notothenioid Adaptive Radiation

Adaptive radiation is usually triggered by ecological opportunity, arising through (i) the colonization of a new habitat by its progenitor; (ii) the extinction of competitors; or (iii) the emergence of an evolutionary key innovation in the ancestral lineage. Support for the key innovation hypothesis is scarce, however, even in textbook examples of adaptive radiation. Antifreeze glycoproteins (AFGPs) have been proposed as putative key innovation for the adaptive radiation of notothenioid fishes in the ice-cold waters of Antarctica. A crucial prerequisite for this assumption is the concurrence of the notothenioid radiation with the onset of Antarctic sea ice conditions. Here, we use a fossil-calibrated multi-marker phylogeny of nothothenioid and related acanthomorph fishes to date AFGP emergence and the notothenioid radiation. All time-constraints are cross-validated to assess their reliability resulting in six powerful calibration points. We find that the notothenioid radiation began near the Oligocene-Miocene transition, which coincides with the increasing presence of Antarctic sea ice. Divergence dates of notothenioids are thus consistent with the key innovation hypothesis of AFGP. Early notothenioid divergences are furthermore congruent with vicariant speciation and the breakup of Gondwana

Demographic History of Indigenous Populations in Mesoamerica Based on mtDNA Sequence Data

The genetic characterization of Native American groups provides insights into their history and demographic events. We sequenced the mitochondrial D-loop region (control region) of 520 samples from eight Mexican indigenous groups. In addition to an analysis of the genetic diversity, structure and genetic relationship between 28 Native American populations, we applied Bayesian skyline methodology for a deeper insight into the history of Mesoamerica. AMOVA tests applying cultural, linguistic and geographic criteria were performed. MDS plots showed a central cluster of Oaxaca and Maya populations, whereas those from the North and West were located on the periphery. Demographic reconstruction indicates higher values of the effective number of breeding females (Nef) in Central Mesoamerica during the Preclassic period, whereas this pattern moves toward the Classic period for groups in the North and West. Conversely, Nef minimum values are distributed either in the Lithic period (i.e. founder effects) or in recent periods (i.e. population declines). The Mesomerican regions showed differences in population fluctuation as indicated by the maximum Inter-Generational Rate (IGRmax): i) Center-South from the lithic period until the Preclassic; ii) West from the beginning of the Preclassic period until early Classic; iii) North characterized by a wide range of temporal variation from the Lithic to the Preclassic. Our findings are consistent with the genetic variations observed between central, South and Southeast Mesoamerica and the North-West region that are related to differences in genetic drift, structure, and temporal survival strategies (agriculture versus hunter-gathering, respectively). Interestingly, although the European contact had a major negative demographic impact, we detect a previous decline in Mesoamerica that had begun a few hundred years before

A Test of Ideal Free Distribution Predictions Using Targeted Survey and Excavation on California’s Northern Channel Islands

Using targeted survey, excavation, and radiocarbon dating, we assess the extent to which human settlement patterns on California’s northern Channel Islands fit predictions arising from the ideal free distribution (IFD): (1) people first established and expanded permanent settlements in the regions ranked high for environmental resource suitability; (2) as population grew, they settled in progressively lower ranked habitats; and (3) changes in the archaeological record associated with high population levels such as increases in faunal diversity and evenness in high-ranked habitats are coinci- dent with the expansion to other areas. On Santa Rosa Island, the early permanent settlements were located in both high- and middle-ranked locations, with the most extensive settlement at the highest ranked locations and only isolated sites elsewhere. Settlement at a low-ranked habitat was confined to the late Holocene (after 3600 cal BP). Drought influenced the relative rank of different locations, which is an example of climate adding a temporal dimension to the model that episodically stimulated popu- lation movement and habitat abandonment. Because the IFD includes a wide range of cultural and environmental variables, it has the potential to be a central model for guiding archaeological analysis and targeted field research