Phasic dopamine (DA) release is believed to guide associative learning. Most studies have focused on projections from the ventral tegmental area (VTA) to the striatum, and the action of DA in other VTA target regions remains unclear. Using optogenetic activation of VTA projections, we examined DA function in the medial prefrontal cortex (mPFC). We found that mice perceived optogenetically induced DA release in mPFC as neither rewarding nor aversive, and did not change their previously learned behavior in response to DA transients. However, repetitive temporal pairing of an auditory conditioned stimulus (CS) with mPFC DA release resulted in faster learning of a subsequent task involving discrimination of the same CS against unpaired stimuli. Similar results were obtained using both appetitive and aversive unconditioned stimuli, supporting the notion that DA transients in mPFC do not represent valence. Using extracellular recordings, we found that CS-DA pairings increased firing of mPFC neurons in response to CSs, and administration of D 1 or D 2 DAreceptor antagonists in mPFC during learning impaired stimulus discrimination. We conclude that DA transients tune mPFC neurons for the recognition of behaviorally relevant events during learning.learning | attention | dopamine T he firing activity of dopamine (DA) neurons in the ventral tegmental area (VTA) is consistent with a role of reward prediction error signal, which is believed to guide behavioral adaptation through DA release in target brain regions (1-7). Experiments using optogenetic manipulations have established a causal link between the activity of DA neurons in VTA and the reinforcing signal that mediates learning and conditioning (8-10). Stimulation of VTA, however, results in transient DA release in many target areas, and it is unclear how each of these regions contributes to learning. For example, compared with the striatum, the medial prefrontal cortex (mPFC) receives fewer DA projections (11), expresses fewer DA reuptake transporters (12), and exhibits an overall lower level of DA (13,14). Nevertheless, pharmacological studies have implicated DA as a powerful neuromodulator of mPFC, able to influence many cognitive functions that support learning (15-21). Furthermore, DA neurons in VTA projecting to either the striatum or mPFC have distinct intrinsic neuronal properties and receive distinct inputs (22-24); thus, they are likely to serve different roles. It remains unclear what function phasic DA release might have in mPFC, whether it carries any valence, or how it affects stimulus-specific learning.In this study, we addressed specifically the role of phasic DA release in stimulus-response association. Using optogenetically timed release of DA from VTA neuronal projections in mPFC, we found that DA transients enhance the firing of mPFC neurons in response to the paired conditioned stimuli (CSs), whereas blocking DA receptors in mPFC during learning impairs stimulus discrimination. Furthermore, pairing a CS with optogenetic stimulation of DA fibers in ...

Phthalates are known endocrine disruptors and found in almost all people with several associated adverse health outcomes reported in humans and animal models. Limited data are available on the relationship between exposure to endocrine disrupting chemicals and the human metabolome. We examined the relationship of metabolomic profiles in plasma and urine of 115 pregnant women with eleven urine phthalate metabolites measured at 26 weeks of gestation to identify potential biomarkers and relevant pathways. Targeted metabolomics was performed by selected reaction monitoring liquid chromatography and triple quadrupole mass spectrometry to measure 415 metabolites in plasma and 151 metabolites in urine samples. We have chosen metabolites with the best defined peaks for more detailed analysis (138 in plasma and 40 in urine). Relationship between urine phthalate metabolites and concurrent metabolomic markers in plasma and urine suggested potential involvement of diverse pathways including lipid, steroid, and nucleic acid metabolism and enhanced inflammatory response. Most of the correlations were positive for both urine and plasma, and further confirmed by regression and PCA analysis. However, after the FDR adjustment for multiple comparisons, only 9 urine associations remained statistically significant (q-values 0.0001–0.0451), including Nicotinamide mononucleotide, Cysteine T2, Cystine, and L-Aspartic acid. Additionally, we found negative associations of maternal pre-pregnancy body mass index (BMI) with more than 20 metabolomic markers related to lipid and amino-acid metabolism and inflammation pathways in plasma (p = 0.01–0.0004), while Mevalonic acid was positively associated (p = 0.009). Nicotinic acid, the only significant metabolite in urine, had a positive association with maternal BMI (p = 0.002). In summary, when evaluated in the context of metabolic pathways, the findings suggest enhanced lipid biogenesis, inflammation and altered nucleic acid metabolism in association with higher phthalate levels. These results provide new insights into the relationship between phthalates, common in most human populations, and metabolomics, a novel approach to exposure and health biomonitoring.

Aim: Topographically complex areas are hypothesized to be mesic refugia in arid environments during periods of climatic change. We tested the hypothesis that an elevated and topographically complex range has been a historical refugium in an arid environment during Pleistocene climatic oscillations for a widespread eucalypt.Location: Pilbara region, north-west Australia.Methods: We evaluated genetic diversity and differentiation in chloroplast and nuclear genomes using microsatellite loci in 20 populations of Eucalyptus leucophloia from across the distribution in the Pilbara bioregion, including two ranges with differing topographical complexity and elevation. We evaluated phylogeographical structure using Permut and Network analysis, and assessed genetic structure using principle coordinate (PCoA) and Bayesian analyses. Results:We found moderate levels of genetic diversity and low genetic differentiation among populations, typical of widespread eucalypts. There was no evidence of genetic structure across the sampled range. Populations in both the Hamersley and Chichester ranges showed higher levels of chloroplast haplotype and nuclear diversity than those in surrounding areas. Diversity was negatively correlated with evapotranspiration, and positively correlated with precipitation.Main conclusions: Genetic signals of high diversity and low differentiation indicated population persistence throughout historical climate change in ranges, with a signal of expansion in surrounding areas. Our analysis was consistent with the hypothesis of the elevated, topographically complex Hamersley Range acting as a refugium, but revealed an unexpected result of the lower elevation, less rugged Chichester Range also being a refugium. Our results suggest refinement to expectations of environmental characteristics that facilitate persistence, where thresholds of mesic environments for refugia may be lower than expected and moisture availability may be an important contributory aspect of elevation and topographical complexity. In contrast to patterns in reptile species, lack of genetic structure associated with geological substrate and geomorphological features indicates dispersal is not impeded by these landscape features for this widespread eucalypt.

The dentition is an extremely important organ in mammals with variation in timing and sequence of eruption, crown morphology, and tooth size enabling a range of behavioral, dietary, and functional adaptations across the class. Within this suite of variable mammalian dental phenotypes, relative sizes of teeth reflect variation in the underlying genetic and developmental mechanisms. Two ratios of postcanine tooth lengths capture the relative size of premolars to molars (premolar–molar module, PMM), and among the three molars (molar module component, MMC), and are known to be heritable, independent of body size, and to vary significantly across primates. Here, we explore how these dental traits vary across mammals more broadly, focusing on terrestrial taxa in the clade of Boreoeutheria (Euarchontoglires and Laurasiatheria). We measured the postcanine teeth of N = 1,523 boreoeutherian mammals spanning six orders, 14 families, 36 genera, and 49 species to test hypotheses about associations between dental proportions and phylogenetic relatedness, diet, and life history in mammals. Boreoeutherian postcanine dental proportions sampled in this study carry conserved phylogenetic signal and are not associated with variation in diet. The incorporation of paleontological data provides further evidence that dental proportions may be slower to change than is dietary specialization. These results have implications for our understanding of dental variation and dietary adaptation in mammals.

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