Student Theses and Dissertations

Date of Award

2010

Document Type

Thesis

RU Laboratory

McEwen Laboratory

Keywords

post-traumatic stress disorder (PTSD), human stress response, neuropeptide Y, anxiety, amygdala, CART neuropeptide

Abstract

Although many people are exposed to stressful experiences during their lifetime, only 5-35% will be diagnosed with Post-Traumatic Stress Disorder (PTSD). While most animal models of stress are effective at producing behavioral changes in an entire group of animals, they fail to account for individual differences in the human stress response or for the variability in baseline anxiety. Animal models of acute and chronic stress increase anxiety behavior and induce structural and neurochemical changes in brain regions necessary for learning, memory, fear responses, and executive function; the hippocampus, amygdala and medial prefrontal cortex (mPFC). In the following experiments, we measured basal anxiety levels and compared anxiety behavior before and after stress. Individuals were grouped based on basal anxiety profiles (either “Calm” or “Anxious”) or by whether they developed changes in behavior after stress (stress vulnerable, or “PTSD-like” and stress resilient, or “Resilient”). Results showed that molecular and morphological differences were already apparent prior to stress. Anxious Sprague Dawley and Lewis rats had shorter apical dendrites in pyramidal neurons of mPFC and anxiety correlated negatively with dendritic arbor size. Densitometry analysis found individual differences in mRNA expression of the neuropeptide Cocaine-Amphetamine–Regulated-Transcript (CART). CART expression was higher in the hippocampus and medial amygdala of “Calm” individuals, and expression in the hippocampus, central amygdala, mPFC, and orbitofrontal cortex correlated with anxiety behavior. CART expression also differed in individuals in the PTSD-like and Resilient profiles. CART mRNA and protein levels were higher in the hippocampus and lower in several nuclei of the amygdala in stress-resilient animals; while CART levels in the PTSD-like group was lower in the Infralimbic mPFC. These results emphasize the importance of individual differences in behavior, and show that there are significant structural and molecular differences between adult male rats. They also illustrate the need for experiments that produce both stress-vulnerable and resilient individuals, as resilience may be an active process involving changes to many brain regions. Finally, these results present a novel role for the neuropeptide CART in establishing or predicting individual differences in anxiety, and suggest that CART may be involved in both fear behavior and neuroprotection.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/355

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