Major Projects

Development of a Model of Anxiety in Rodents.

Mood disorders such as anxiety currently affect more than 20 million people in the United States alone, with females comprising about 2/3 of this number. An overall feature found in patients suffering from anxiety or depression is a dysregulation of the HPA axis. This has led to the use of CRF antagonists to reverse behaviors considered to be linked to these disorders. While this therapeutic approach is promising, the finding of altered HPA axis in patients with mood disorders makes it imperative to obtain a more complete understanding of the mechanisms leading to these neuroendocrine changes because this will eventually lead to the development of more effective therapies. Consequently, animal models of anxiety have been actively sought to probe the cellular and molecular mechanisms that participate in these psychiatric disorders. However, animal models that provide consistent and stable models of anxiety/depression have been very difficult to obtain. We recently developed a model of prenatal stress in rats that provides adult offspring with measurable symptoms of anxiety, as well as altered HPA axis activity. We found that when pregnant rats were exposed to restraint or a random sequence of mild varied stressors, their female offspring’ response to a stressor in adulthood caused a prolonged corticosterone response as well as increased passive anxiety-like behavior. These changes were very stable and consistent. In contrast, male offspring displayed few differences, compared to controls.

These data demonstrate that we have established a reliable model of anxiety. Of special interest, they also exemplify the differential sensitivity of the developing nervous system to stress with regard to gender. The gender difference that we observed with regard to the development of anxiety mimics that observed in humans.

References

Richardson HN, Zorrilla EP, Mandyam CD and Rivier CL. 2006 Exposure to repetitive versus varied stress during prenatal development generates two distinct anxiogenic and neuroendocrine profiles in adulthood. Endocrinology 147:2506-2517.

Mandyam CD, Crawford EF, Eisch AJ, Rivier CL and Richardson HN. 2008 Stress experienced in utero reduces sexual dichotomies in neurogenesis, microenvironment, and cell death in the adult rat hippocampus. Dev Neurobiol 68:575-589.