The visible burrow system: A view from across the hall.

The visible burrow system (VBS) is an ethologically relevant social stress model that creates a distinct dominance hierarchy in rats. Randall Sakai's laboratory performed an impressive series of studies documenting the very different impact of VBS exposure on the brain and behavior of dominants (DOM) and subordinates (SUBs). Hierarchy formation causes pronounced changes in metabolism in SUBs relative to both DOMs and unstressed controls, resulting in marked weight loss and metabolic imbalance. Stress testing revealed multiple phenotypes in the VBS, including DOMs, stress-responsive SUBs and stress-non-responsive SUBs. Stress-responsive SUBs have adrenal hypertrophy and elevated baseline corticosterone, consistent with prolonged HPA axis activation; however, peak acute stress responses are not sensitized. In contrast, stress non-responsive individuals do not mount a response to an acute stress, suggesting HPA axis hypofunction. In brain, SUBs exhibit a pattern of gene regulation consistent with impaired stress inhibition (e.g., hippocampal adrenocorticosteroid receptor down-regulation and dendritic retraction) and drive of stress pathways (e.g., increased locus coeruleus tyrosine hydroxylase expression). The non-responsive phenotype is distinguished by down-regulation of paraventricular nucleus corticotropin releasing hormone expression and enhanced neuropeptide Y expression in amygdala. The brain 'signature' created by VBS hierarchy formation differed substantially from that of another well-studied chronic stress model (chronic variable stress). Thus, the impact of VBS is mediated by neurocircuit mechanisms at least in part distinct that of other chronic stress modalities, and suggests that the nature of the stressor may be an essential consideration in development of treatment strategies for stress-related diseases.