Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: an illustration of the 4P's modeling approach

The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders.

Environment and climate of the last 51,000 years – new insights from the Potrok Aike maar lake Sediment Archive Drilling prOject (PASADO)

In this introductory paper we summarize the history and achievements of the Potrok Aike maar lake Sediment Archive Drilling prOject (PASADO), an interdisciplinary project embedded in the International Continental Scientific Drilling Program (ICDP). The stringent multiproxy approach adopted in this research combined with radiocarbon and luminescence dating provided the opportunity to synthesize a large body of hydrologically relevant data from Laguna Potrok Aike (southern Patagonia, Argentina). At this site, lake level was high from 51 ka until the early Holocene when the Southern Hemisphere Westerlies (SHW) were located further to the north. At 9.3 ka cal. BP the SHW moved southward and over the latitude of the study area (52 degrees S) causing a pronounced negative water balance with a lake level decrease of more than 50 m. Two millennia later, the SHW diminished in intensity and lake level rose to a subsequent maximum during the Little Ice Age. Since the 20th century, a strengthening of the SHW increased the evaporative stress resulting in a more negative water balance. A comparison of our data with other hydrological fluctuations at a regional scale in south-eastern Patagonia, provides new insights and also calls for better chronologies and high-resolution records of climate variability.