Model Systems of Stress

The first step of an expression profiling strategy is the choice of the model system. Several model systems in which corticosteroid levels are pharmacologically manipulated can be used, although one must be aware that this only represents the hormonal part of the stress response and is not the same as stress. For instance, surgically removing the adrenals from rats results in complete absence of endogenous corticosteroids and lack of hippocampal MR and GR occupancy.

Adrenalectomized rats can be further manipulated by (1) replacing them with low concentration corticosteroid-secreting pellets, resulting in occupancy of hippocampal MRs, and (2) administering high- concentration corticosteroid injections in order to additionally occupy hippocampal GRs. After isolating the hippocampi from these animals, gene expression profiles can be generated.

Additionally, ex vivo hippocampal slices, which are derived from isolated hippocampi and are kept alive in carbogenated buffer, have also been used as a model to study the effects of corticosteroids on gene expression. In these slices, corticosteroid receptors can be directly activated by adding the hormone to the solution, thereby circumventing peripheral effects of injections into animals and removing the influence of projections from other brain areas to the hippocampus.

Another way of looking at the effects of stress on gene expression is to subject intact animals to a stressor, causing physiological activation of their HPA axis and a rise in plasma CORT levels. Several stress paradigms have been described in the literature, both for acute stress and for chronic stress. For example, placing a rat or mouse in a novel environment is sufficient to elicit a stress response, or placing a rat on top of the cage of a mouse will give rise to a stress response in the mouse.

Purely physical stressors, such as cold stress or shaking stress, can be distinguished from psychological stressors such as psychosocial defeat and chronic unpredictable stress, in which experimental animals are subjected to a variety of different stressors in an unpredictable manner over several weeks.

A disadvantage of the physiological approach is that it can be difficult to control for interindividual differences in HPA response. Pharmacological manipulation of CORT levels in combination with a relevant psychological stressor may therefore be a good choice, depending on the focus of the study.