No abstract

The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Preemption, Personalization, & 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.

Population dynamics predicts that on average parents should invest equally in male and female offspring; similarly, the physiology of mammalian sex determination is supposedly stochastic, producing equal numbers of sons and daughters. However, a high quality parent can maximize fitness by biasing their birth sex ratio (SR) to the sex with the greatest potential to disproportionately outperform peers. All SR manipulation theories share a fundamental prediction: grandparents who bias birth SR should produce more grandoffspring via the favored sex. The celebrated examples of biased birth SRs in nature consistent with SR manipulation theories provide compelling circumstantial evidence. However, this prediction has never been directly tested in mammals, primarily because the complete three-generation pedigrees needed to test whether individual favored offspring produce more grandoffspring for the biasing grandparent are essentially impossible to obtain in nature. Three-generation pedigrees were constructed using 90 years of captive breeding records from 198 mammalian species. Male and female grandparents consistently biased their birth SR toward the sex that maximized second-generation success. The most strongly male-biased granddams and grandsires produced respectively 29% and 25% more grandoffspring than non-skewing conspecifics. The sons of the most male-biasing granddams were 2.7 times as fecund as those of granddams with a 50∶50 bias (similar results are seen in grandsires). Daughters of the strongest female-biasing granddams were 1.2 times as fecund as those of non-biasing females (this effect is not seen in grandsires). To our knowledge, these results are the first formal test of the hypothesis that birth SR manipulation is adaptive in mammals in terms of grandchildren produced, showing that SR manipulation can explain biased birth SR in general across mammalian species. These findings also have practical implications: parental control of birth SR has the potential to accelerate genetic loss and risk of extinction within captive populations of endangered species.

Insufficient feeder space for laying hens could increase competition at the feed trough, leading to disrupted feeding, inadequate nutrient intake, stress, and reduced productivity. The effects of feeder space allocation (FSA) on physiology and productivity were evaluated in beak-trimmed Hy-Line W-36 hens (n=480). They were obtained at 16.5 wk of age and housed on 4 tiers of shallow conventional cages. Five pullets/cage were housed at a stocking density of 434 cm2/hen and a feeder space of 12.2 cm/hen. After 1.5 wk of acclimation, baseline measurements were taken for feed utilization, bone mineralization, and heterophil:lymphocyte ratios. At 20 wk of age, pullets were given 5.8, 7.1, 8.4, 9.7, 10.9, or 12.2 cm of feeder space/bird (16 cages/treatment). Physiological and production measures were calculated monthly or twice a month for 12 mo. The heart, spleen, and right adrenal gland were collected from each hen at the end of the study. Data were analyzed using a repeated measures GLM incorporating cage, tier, FSA, and hen age. There were no effects of FSA on total egg production, bone mineral density, bone mineral content, heterophil:lymphocyte ratios, or organ weights. Hens with reduced FSA utilized more feed (P<0.001), had poorer feed conversion (P<0.001), and laid eggs with slightly thicker and heavier shells (P<0.001). There were effects of FSA on total egg weight (P<0.001) and hen-day egg production (P<0.001), but they were of low magnitude and not linear (P>0.05). Because BW was similar among FSA treatments, the results suggest that reduced feeder space did not limit feed intake. In addition, reduced FSA did not lower bone mineralization or cause physiological stress in W-36 hens housed in shallow cages, suggesting that it did not impair hen welfare. However, it did result in poorer feed efficiency, possibly related to greater feed wastage, predictive of an adverse economic effect from reducing feeder space.

Insufficient feeder space for laying hens could increase competition at the feed trough, resulting in exclusion of low-ranking hens from the feeder. To test this hypothesis, the effects of feeder space allocation (FSA) on feeding behavior, aggression, feather scores, BW, and mortality were evaluated in a common commercial strain of egg-laying chickens. Beak-trimmed Hy-Line W-36 hens (n = 480) were obtained as pullets at 16.5 wk of age and housed in conventional cages on 4 tiers. Five pullets/cage were housed at a stocking density of 434 cm(2)/pullet and an FSA of 12.2 cm/pullet. After 1.5 wk of acclimation, baseline measurements were taken for 2 wk and then pullets were given either 5.8, 7.1, 8.4, 9.7, 10.9, or 12.2 cm of feeder space/hen (16 cages/treatment). Feeding behavior was evaluated in each cage over a 24-h period each month. For each hen, percentage of time spent feeding and synchrony (mean number of additional hens feeding at the same time) were determined and scores were averaged for each cage. For each cage, feeder switching (number of observations in which hens changed from feeding to not feeding) and feeder sharing (probability that feeder access was equally distributed among all hens) were calculated. At monthly intervals, individual hens were weighed and their feathers scored using a 5-point scale on 8 body regions. Data were analyzed using a repeated measures GLM incorporating cage, tier, FSA, and age of the hen. Hens with reduced feeder space spent less time feeding (P < 0.001), synchronized their feeding bouts to a lesser extent (P < 0.001), made fewer switches at the feeder (P < 0.001), and shared the feeder less (P < 0.001). However, feather scores, BW, and BW uniformity were not affected by FSA. There was almost no aggressive behavior and little mortality. These results demonstrate that Hy-Line W-36 hens did not respond to reduced feeder space by aggressively excluding cage-mates from the feeder but instead desynchronized their feeding behavior.