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Automated, Quantitative Cognitive/Behavioral Screening of Mice: For Genetics, Pharmacology, Animal Cognition and Undergraduate Instruction

We describe a high-throughput, high-volume, fully automated, live-in 24/7 behavioral testing system for assessing the effects of genetic and ...

Fairfield University

Bactericidal/permeability-increasing protein (BPI), an antibacterial and lipopolysaccharide-neutralizing protein, also has an antiangiogenic effect. To evaluate the therapeutic role of BPI in ischemic retinopathies, the antiangiogenic activity of a human recombinant 21-kDa modified N-terminal fragment of BPI (rBPI(21)), which has the biological properties of the holoprotein, and a peptidomimetic (XMP.Z) derived from BPI were examined.

Differential effects of bactericidal/permeability-increasing protein (BPI) analogues on retinal neovascularization and retinal pericyte growth.

In the peak procedure, starts and stops in responding bracket the target time at which food is expected. The variability in start and stop times is proportional to the target time (scalar variability), as is the systematic error in the mean center (scalar error). The authors investigated the source of the error and the variability, using head poking in the mouse, with target intervals of 5 s, 15 s, and 45 s, in the standard procedure, and in a variant with 3 different target intervals at 3 different locations in a single trial. The authors conclude that the systematic error is due to the asymmetric location of start and stop decision criteria, and the scalar variability derives primarily from sources other than memory.

Sources of variability and systematic error in mouse timing behavior.

Ovariectomized (OVX) ewes were assigned to receive vehicle, progesterone (P4, 0.9-g controlled internal drug release vaginal implants), estradiol-17beta (E2, 5 microg/kg bolus + 6 microg kg(-1) day(-1)), or P4 + E2 for 10 days (n = 3/group). Uterine artery endothelial proteins were mechanically isolated on Day 10. The samples were used for protein expression profiling by the Ciphergen Proteinchip system and immunoblotting analysis of endothelial nitric oxide synthase (NOS3, also termed eNOS) and caveolin 1. Uterine artery rings were cut and analyzed by immunohistochemistry to localize NOS3 and caveolin 1 expression. With the use of the IMAC3 protein chip with loading as little as 2 microg protein/sample, many protein peaks could be detected. Compared to vehicle controls, a approximately 133.1-kDa protein was identified to be upregulated by 2- to 4-fold in OVX ewes receiving E2, P4, and their combination, whereas a approximately 22.6-kDa protein was downregulated by 2- to 4-fold in OVX ewes receiving E2 and E2/P4, but not P4 treatments. Western blot analysis revealed that E2, P4, and their combination all increased NOS3 protein, whereas E2 and its combination with P4, but not P4 alone, downregulated caveolin 1 expression. Immunohistochemical analysis revealed that NOS3 was mainly localized in the endothelium and upregulated by E2, whereas caveolin 1 was localized in both endothelium and smooth muscle and downregulated by E2. Thus, our data demonstrate that uterine artery endothelial NOS3 and caveolin 1 are regulated reciprocally by estrogen replacement therapy. In keeping with the facts that E2, but not P4, causes uterine vasodilatation and that E2 and P4 increase NOS3 expression, but only E2 decrease caveolin 1 expression, our current study suggests that both increased NOS3 expression and decreased caveolin 1 expression are needed to facilitate estrogen-induced uterine vasodilatation.

Global protein expression profiling underlines reciprocal regulation of caveolin 1 and endothelial nitric oxide synthase expression in ovariectomized sheep uterine artery by estrogen/progesterone replacement therapy.

Evidence suggests that the online combination of non-verbal magnitudes (durations, numerosities) is central to learning in both human and non-human animals [Gallistel, C.R., 1990. The Organization of Learning. MIT Press, Cambridge, MA]. The molecular basis of these computations, however, is an open question at this point. The current study provides the first direct test of temporal subtraction in a species in which the genetic code is available. In two experiments, mice were run in an adaptation of Gibbon and Church's [Gibbon, J., Church, R.M., 1981. Time left: linear versus logarithmic subjective time. J. Exp. Anal. Behav. 7, 87-107] time left paradigm in order to characterize typical responding in this task. Both experiments suggest that mice engaged in online subtraction of temporal values, although the generalization of a learned response rule to novel stimulus values resulted in slightly less systematic responding. Potential explanations for this pattern of results are discussed.

Time left in the mouse.

Experimentally naive mice matched the proportions of their temporal investments (visit durations) in two feeding hoppers to the proportions of the food income (pellets per unit session time) derived from them in three experiments that varied the coupling between the behavioral investment and food income, from no coupling to strict coupling. Matching was observed from the outset; it did not improve with training. When the numbers of pellets received were proportional to time invested, investment was unstable, swinging abruptly from sustained, almost complete investment in one hopper, to sustained, almost complete investment in the other-in the absence of appropriate local fluctuations in returns (pellets obtained per time invested). The abruptness of the swings strongly constrains possible models. We suggest that matching reflects an innate (unconditioned) program that matches the ratio of expected visit durations to the ratio between the current estimates of expected incomes. A model that processes the income stream looking for changes in the income and generates discontinuous income estimates when a change is detected is shown to account for salient features of the data.

Is matching innate?

Drug seekers. We need more answers when it comes to treating these patients.

There is preliminary evidence that BMI is positively correlated with movement variability of standing posture. However, this negative effect of obesity on postural control may be mediated by the change in other body scale variables (e.g., mechanical and fitness) that also occur with changes in BMI. This study investigated the influence of selected body scale (height, body mass, BMI), body composition (body fat percentage), mechanical (moment of inertia - MI) and strength (S) variables as predictors of the control of postural motion in adolescents. 125 healthy adolescents (65 boys, 60 girls) with a wide range of BMI (13.8-31.0 kg/m(2)) performed a battery of tests that assessed body composition, anthropometry, muscular strength and postural control. Multiple measures of postural motion variability were derived for analysis with body scale, mechanical and lower extremity strength variables separately for boys and girls. BMI, height and body mass, considered both separately and collectively, were poor and/or inconsistent predictors of variability in all three posture tasks. However, the ratio of lower extremity strength to whole body moment of inertia showed the highest positive correlation to most postural variability measures in both boys and girls and these effects were strongest in the less stable tasks of single leg standing and recovery of stance. Our findings support the hypothesis that diminished lower extremity strength to mechanical constraint ratio compromises the robustness of the strength to body scale relation in movement and postural control.

Obesity, mechanical and strength relationships to postural control in adolescence.

The eyebrows and eyebrow fat pads, key structures in upper facial aesthetics, are particularly vulnerable to age-related changes.

A three-dimensional construct of the aging eyebrow: the illusion of volume loss.

To compare soft tissue and fat volumes in the supraorbital area of healthy patients and patients with thyroid-associated orbitopathy (TAO) using 3-dimensional reconstruction software.

Thyroid-associated periorbitopathy: eyebrow fat and soft tissue expansion in patients with thyroid-associated orbitopathy.

This experiment was setup to investigate the deterministic and stochastic properties of the recurrent dynamics of the center of pressure trajectories of each leg (COP(left) and COP(right)) and whole-body (COP(net)) as a function of different foot positions in postural stance (side-by-side, staggered, and tandem standing) and the availability of visual information. The foot position of postural stance can induce degrees of asymmetry of postural instabilities as well as load on each leg that it was hypothesized would influence the deterministic and stochastic properties of COP fluctuations of each leg and of COP(net). Young adults performed two 60 s trials of quiet standing at each posture-vision condition. The availability of visual information increased COP path length, but had no effect on the recurrent dynamics of COP trajectories. Recurrence quantification analysis showed that recurrence, determinism, and entropy were dependent on the direction (AP/ML) of COP motion and foot position during postural stances. The degree of asymmetry between the left and right leg COP dynamics differed across all postural stances and COP(net) dynamics were more similar to those of the more loaded leg. The cross-recurrence quantification analysis also revealed asymmetries in the coordination coupling of AP/ML under each leg; although, these differences were markedly reduced in tandem postures. The findings support the postulation that the asymmetry generated through mechanical constraints (foot position and load) is related to asymmetrical recurrent dynamics of the individual leg and COP(net) based on the degree of postural instability.

Asymmetry of recurrent dynamics as a function of postural stance.

Individual differences in learning a motor task are rarely assessed even though they can potentially contribute to our understanding of the problem of motor redundancy-i.e., how individuals can exploit multiple different strategies to realize the task goal. This study examined individual variations in the preferred movement strategy of a redundant motor task. Thirty-two participants performed a star tracing task on a digitizing tablet with the goal of minimizing a performance score that was given as feedback. The performance score was a weighted combination of spatial error and movement time, meaning that multiple strategies could yield the same score. A cluster analysis revealed three distinct groups of individuals based on their initial movement strategy preferences. These groups were not only different on their initial performance, but also exhibited differences in both local (trial-to-trial change) and global (average change) search strategies that were reflected through differential modification of spatial and temporal components. Overall, the results in this space-time task reveal that the intrinsic dynamics of the individual channel the initial exploratory solutions to learning a redundant motor task.

Individual differences in the exploration of a redundant space-time motor task.

The authors investigated the influence of task difficulty on warm-up decrement and learning across practice sessions. Three groups of participants practiced a star-tracing task over 3 consecutive days with different levels (e.g., easy, medium, hard) of task difficulty. The performance data were modeled with a 2 time scale function that represented the transient, fast time scale process of warm-up decrement superimposed with the persistent, slow time scale process of learning. Movement time decreased as a function of practice with the most difficult condition exhibiting the greatest reduction though still the longest movement time. The 2 time scale model provided a better fit to the data than an exponential or power law function and showed that the 3 difficulty conditions exhibited similar rates of change for the respective slow (i.e., learning) and fast (i.e., warm-up decrement) time scale processes that varied by an order of magnitude. Task difficulty was inversely related to the initial level of warm-up decrement but not the rate of performance recovery early in a practice session. The findings support the postulation that there is a persistent learned component to the initial conditions in subsequent practice sessions but that there is a common time scale of accommodating the transient process of warm-up decrement.

Task difficulty and the time scales of warm-up and motor learning.

This experiment was set up to investigate the influence of constant and variable practice on performance accuracy and the time- and frequency-dependent structure of the force output dynamics in the learning of an irregular isometric force pattern. Traditional approaches to the variability of practice hypothesis have demonstrated benefits of task-induced variability at the outcome level of behavior, but there have been limited investigations of the effect of practice conditions on movement execution and particularly the multiple time scale processes of force output. During the practice phase, variability was induced along the force-time dimension of the target pattern for the variable practice condition (different wave forms), but the wave forms exhibited the same distributional properties of the frequency content (1/f noise: β = -1.5) as the constant practice condition. The results showed that both practice conditions exhibited similar reductions in task error as a function of practice. However, constant practice produced greater changes in the time- and frequency-dependent properties of force output than variable practice, including a higher relative change in the contribution from faster (4-12 Hz) time scale mechanisms. Generalization tests to novel target patterns revealed that the task dynamics had a greater influence than the effect of practice conditions. Collectively, the findings support the adaptive nature of force output structure and the perspective that practice conditions can produce differential effects on the outcome and execution levels of motor behavior.

The learning of isometric force time scales is differentially influenced by constant and variable practice.

Clinical, radiographic, and molecular studies have shown that patients with thyroid-associated orbitopathy exhibit volumetric expansion of eyebrow tissues. This clinicopathologic entity has been termed thyroid-associated periorbitopathy. The goal of this study was to determine whether high-resolution ultrasonography could be used to reliably quantify thyroid-associated periorbitopathy.

Article	Year
Differential effects of bactericidal/permeability-increasing protein (BPI) analogues on retinal neovascularization and retinal pericyte growth. Investigative ophthalmology & visual science\| PubMed ID: 11818397	2002
Sources of variability and systematic error in mouse timing behavior. Journal of experimental psychology. Animal behavior processes\| PubMed ID: 14709111	2004
Global protein expression profiling underlines reciprocal regulation of caveolin 1 and endothelial nitric oxide synthase expression in ovariectomized sheep uterine artery by estrogen/progest... Biology of reproduction\| PubMed ID: 16436525	2006
Time left in the mouse. Behavioural processes\| PubMed ID: 17101237	2007
Is matching innate? Journal of the experimental analysis of behavior\| PubMed ID: 17465311	2007
Drug seekers. We need more answers when it comes to treating these patients. EMS world\| PubMed ID: 21361227	2011
Obesity, mechanical and strength relationships to postural control in adolescence. Gait & posture\| PubMed ID: 22018701	2012
A three-dimensional construct of the aging eyebrow: the illusion of volume loss. Aesthetic surgery journal / the American Society for Aesthetic Plastic surgery\| PubMed ID: 22231412	2012
Thyroid-associated periorbitopathy: eyebrow fat and soft tissue expansion in patients with thyroid-associated orbitopathy. Archives of ophthalmology\| PubMed ID: 22411661	2012
Asymmetry of recurrent dynamics as a function of postural stance. Experimental brain research\| PubMed ID: 22692646	2012
Individual differences in the exploration of a redundant space-time motor task. Neuroscience letters\| PubMed ID: 22914583	2012
Task difficulty and the time scales of warm-up and motor learning. Journal of motor behavior\| PubMed ID: 23611248	2013
The learning of isometric force time scales is differentially influenced by constant and variable practice. Experimental brain research\| PubMed ID: 23625075	2013
High-resolution ultrasound as an effective and practical tool to analyze eyebrow profile expansion in thyroid-associated periorbitopathy. Ophthalmic plastic and reconstructive surgery\| PubMed ID: 23924986	2013

Adam King

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