A self-adjusting, progressive shock strength procedure to investigate resistance to punishment: Characterization in male and female rats.

Indifference to harmful consequences is one of the main characteristics of compulsive behaviors and addiction. Animal models that provide a rapid and effective measure of resistance to punishment could be critical for the investigation of mechanisms underlying these maladaptive behaviors. Here, analogous to the progressive ratio (PR) procedure widely used to evaluate appetitive motivation as the response requirement is increased, we developed a self-adjusting, progressive shock strength (PSS) procedure. The PSS provides, within a single session, a break point that quantifies the propensity to work for a reward in spite of receiving electric footshock that progressively increases in duration. In both male and female rats, the PSS break point was sensitive to 1) hunger; and 2) changes in the qualitative, but not quantitative, incentive value of the reward. In systematic comparisons between PSS and PR procedures in the same rats, we found that both measures are sensitive to manipulations of motivational states, but they are not intercorrelated, suggesting that they measure overlapping but partially distinct processes. Importantly, the PSS procedure represents a refinement in the 3Rs principles of animal research because animals can control the strength of shock that they are willing to tolerate. This self-adjusting PSS procedure may represent a useful tool to investigate mechanisms underlying maladaptive behavior that persists in certain individuals despite harmful consequences.

The First 3D Model of the Full-Length KIT Cytoplasmic Domain Reveals a New Look for an Old Receptor.

Receptor tyrosine kinases (RTKs) are key regulators of normal cellular processes and have a critical role in the development and progression of many diseases. RTK ligand-induced stimulation leads to activation of the cytoplasmic kinase domain that controls the intracellular signalling. Although the kinase domain of RTKs has been extensively studied using X-ray analysis, the kinase insert domain (KID) and the C-terminal are partially or fully missing in all reported structures. We communicate the first structural model of the full-length RTK KIT cytoplasmic domain, a crucial target for cancer therapy. This model was achieved by integration of ab initio KID and C-terminal probe models into an X-ray structure, and by their further exploration through molecular dynamics (MD) simulation. An extended (2-µs) MD simulation of the proper model provided insight into the structure and conformational dynamics of the full-length cytoplasmic domain of KIT, which can be exploited in the description of the KIT transduction processes.