Nature and nurture: Comparing mouse behavior in classic versus revised anxiety-like and social behavioral assays in genetically or environmentally defined groups.

Widely used rodent anxiety assays like the elevated plus maze (EPM) and the open field test (OFT) are conflated with rodents' natural preference for dark over light environments or protected over open spaces. The EPM and OFT have been used for decades but are often criticized by behavioral scientists. Years ago, two revised anxiety assays were designed to improve upon the "classic" tests by excluding the possibility to avoid or escape aversion. The 3-D radial arm maze (3DR) and the 3-D open field test (3Doft) utilize continual motivational conflict to better model anxiety; each consist of an open space connected to ambiguous paths toward uncertain escape. Despite their utility, the revised assays have not caught on. This could be because no study yet has directly compared classic and revised assays in the same animals. To remedy this, we contrasted behavior from a battery of assays (EPM, OFT, 3DR, 3Doft and a sociability test) in mice defined genetically by isogenic strain, or environmentally by postnatal experience. One major motivation for this work is to inform future studies by offering a transparent look at individual outcomes on these assays, as there is no one-size-fits-all test to assess rodent anxiety-like behavior. Findings suggest that classic assays may sufficiently characterize differences across genetically defined groups, but the revised 3DR may be advantageous for investigating more nuanced behavioral differences such as those stemming from environmental factors. Finally, exposure to multiple assays significantly affected sociability, highlighting concerns for designing and interpreting batteries of rodent behavioral tests.

Nature and nurture: comparing mouse behavior in classic versus revised anxiety-like and social behavioral assays in genetically or environmentally defined groups.

Widely used rodent anxiety assays like the elevated plus maze (EPM) and the open field test (OFT) are often conflated with rodents' natural preference for dark over light environments or protected over open spaces. The EPM and OFT have been used for many decades, yet have also been criticized by generations of behavioral scientists. Several years ago, two revised anxiety assays were designed to improve upon the "classic" tests by excluding the possibility to avoid or escape aversive areas of each maze. The 3-D radial arm maze (3DR) and the 3-D open field test (3Doft) each consist of an open space connected to ambiguous paths toward uncertain escape. This introduces continual motivational conflict, thereby increasing external validity as an anxiety model. But despite this improvement, the revised assays have not caught on. One issue may be that studies to date have not directly compared classic and revised assays in the same animals. To remedy this, we contrasted behavior in a battery of assays (EPM, OFT, 3DR, 3Doft, and a sociability test) in mice defined either genetically by isogenic strain, or environmentally by postnatal experience. Findings indicate that the optimal assay to assess anxiety-like behavior may depend upon grouping variable (e.g. genetic versus environment). We argue that the 3DR may be the most ecologically valid of the anxiety assays tested, while the OFT and 3Doft provided the least useful information. Finally, exposure to multiple assays significantly affected sociability measures, raising concerns for designing and interpreting batteries of behavioral tests in mice.

TNFR2-deficient memory CD8 T cells provide superior protection against tumor cell growth.

TNF receptor-2 (TNFR2) plays a critical role in promoting the activation and survival of naive T cells during the primary response. Interestingly, anti-CD3 plus IL-2 activated TNFR2(-/-) CD8 T cells are highly resistant to activation-induced cell death (AICD), which correlates with high expression levels of prosurvival molecules such as Bcl-2, survivin, and CD127 (IL-7Ralpha). We determined whether the resistance of activated TNFR2(-/-) CD8 T cells to AICD contributes to more effective protection against tumor cell growth. We found that during a primary tumor challenge, despite initial inferiority in controlling tumor cell growth, TNFR2(-/-) mice were able to more effectively control tumor burden over time compared with wild-type (WT) mice. Furthermore, vaccination of TNFR2(-/-) mice with recombinant Listeria monocytogenes that express OVA confers better protection against the growth of OVA-expressing E.G7 tumor cells relative to similarly vaccinated WT mice. The enhanced protection against tumor cell growth was not due to more effective activation of OVA-specific memory CD8 T cells in vaccinated TNFR2(-/-) mice. In vitro studies indicate that optimally activated OVA-specific TNFR2(-/-) CD8 T cells proliferated to the same extent and possess similar cytotoxicity against E.G7 tumor cells as WT CD8 T cells. However, relative to WT cells, activated OVA-specific TNFR2(-/-) CD8 T cells were highly resistant to AICD. Thus, the enhanced protection against E.G7 in TNFR2(-/-) mice is likely due to the recruitment and activation of OVA-specific memory TNFR2(-/-) CD8 T cells and their prolonged survival at the tumor site.